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US20150320755A1 - Combination therapies - Google Patents

Combination therapies Download PDF

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Publication number
US20150320755A1
US20150320755A1 US14/687,768 US201514687768A US2015320755A1 US 20150320755 A1 US20150320755 A1 US 20150320755A1 US 201514687768 A US201514687768 A US 201514687768A US 2015320755 A1 US2015320755 A1 US 2015320755A1
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inhibitor
cancer
bcl
pi3k
pi3k inhibitor
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US14/687,768
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Jeffery L. Kutok
Howard M. STERN
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Infinity Pharmaceuticals Inc
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Infinity Pharmaceuticals Inc
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Priority to US14/687,768 priority Critical patent/US20150320755A1/en
Assigned to INFINITY PHARMACEUTICALS, INC. reassignment INFINITY PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KUTOK, JEFFERY L., STERN, HOWARD M.
Publication of US20150320755A1 publication Critical patent/US20150320755A1/en
Priority to US15/587,208 priority patent/US11110096B2/en
Priority to US17/391,869 priority patent/US11944631B2/en
Priority to US18/588,591 priority patent/US20250025469A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • PI3Ks The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers.
  • PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3′-OH group on phosphatidylinositols or phosphoinositides.
  • the PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation.
  • the class I PI3Ks are typically activated by tyrosine kinases or G-protein coupled receptors to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which engages downstream effectors such as those in the AKT/PDK1 pathway, mTOR, the Tec family kinases, and the Rho family GTPases.
  • PIP3 phosphatidylinositol 3-bisphosphate
  • PI(3,4)P2 phosphatidylinositol 3-bisphosphate
  • the PI3Ks are protein kinases that control cell growth (mTORC1) or monitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).
  • PI3K- ⁇ is the isoform most often found mutated in cancers and has a role in insulin signaling and glucose homeostasis (Knight et al. Cell (2006) 125(4):733-47; Vanhaesebroeck et al.
  • PI3K- ⁇ is activated in cancers where phosphatase and tensin homolog (PTEN) is deleted. Both isoforms are targets of small molecule therapeutics in development for cancer.
  • PI3K- ⁇ and - ⁇ are preferentially expressed in leukocytes and are important in leukocyte function. These isoforms also contribute to the development and maintenance of hematologic malignancies (Vanhaesebroeck et al. Current Topic Microbiol. Immunol. (2010) 347:1-19; Clayton et al. J Exp Med. (2002) 196(6):753-63; Fung-Leung Cell Signal. (2011) 23(4):603-8; Okkenhaug et al. Science (2002) 297(5583):1031-34).
  • PI3K- ⁇ is activated by cellular receptors (e.g., receptor tyrosine kinases) through interaction with the Sarc homology 2 (SH2) domains of the PI3K regulatory subunit (p85), or through direct interaction with RAS.
  • cellular receptors e.g., receptor tyrosine kinases
  • SH2 Sarc homology 2 domains of the PI3K regulatory subunit
  • the present invention provides, at least in part, compositions and methods comprising a PI3K inhibitor in combination with a Bcl-2 inhibitor.
  • a combination of a PI3K inhibitor (e.g., Compound 1) and a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) has a synergistic effect in treating a cancer (e.g., in reducing cancer cell growth or viability, or both).
  • the combination of a PI3K inhibitor and a Bcl-2 inhibitor can allow the PI3K inhibitor, the Bcl-2 inhibitor, or both, to be administered at a lower dosage, e.g., a lower dosage than would be required to achieve the same therapeutic effect if the PI3K inhibitor or Bcl-2 inhibitor were administered as a monotherapy.
  • the combination can allow the PI3K inhibitor, the Bcl-2 inhibitor, or both, to be administered at a lower frequency than if the PI3K inhibitor or Bcl-2 inhibitor were administered as a monotherapy.
  • Such combinations provide advantageous effects, e.g., in reducing (e.g., inhibiting, preventing, delaying, and/or decreasing the likelihood of occurrence of) one or more of: a side effect, toxicity, or resistance (e.g., acquired resistance) that would otherwise be associated with administration of a higher dose of the agent(s), e.g., when the agent is administered as a monotherapy.
  • compositions e.g., pharmaceutical compositions comprising a PI3K inhibitor (e.g., one or more PI3K inhibitors), or a pharmaceutically acceptable form thereof, in combination with a Bcl-2 inhibitor (e.g., one or more Bcl-2 inhibitors), or a pharmaceutically acceptable form thereof.
  • a PI3K inhibitor e.g., one or more PI3K inhibitors
  • Bcl-2 inhibitor e.g., one or more Bcl-2 inhibitors
  • the PI3K inhibitor and the Bcl-2 inhibitor are present in a single composition.
  • the PI3K inhibitor and the Bcl-2 inhibitor are present in two or more different compositions (e.g., as separate dosage forms). In some embodiments, the PI3K inhibitor and the Bcl-2 inhibitor are formulated for administration via the same administration route. In some embodiments, the PI3K inhibitor and the Bcl-2 inhibitor are formulated for administration via different administration routes.
  • the composition (e.g., one or more compositions or dosage forms) comprising the combination of PI3K inhibitor and the Bcl-2 inhibitor) is synergistic, e.g., the combination has a synergistic effect, e.g., a synergistic effect in treating a cancer (e.g., in reducing cancer cell growth or viability, or both).
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, present in the composition(s) does not exceed the level at which each agent is used individually, e.g., as a monotherapy.
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, present in the composition(s) is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, present in the composition(s) that results in a desired effect is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the frequency of administration of the PI3K inhibitor that achieves a therapeutic effect is lower (e.g., at least 20%, 30%, 40%, or 50% lower), when the PI3K inhibitor is administered in combination with the Bcl-2 inhibitor than when the PI3K inhibitor is administered alone. In some embodiments, the frequency of administration of the Bcl-2 inhibitor that achieves a therapeutic effect is lower (e.g., at least 20%, 30%, 40%, or 50% lower), when the Bcl-2 inhibitor is administered in combination with PI3K inhibitor than when the Bcl-2 inhibitor is administered alone.
  • featured herein is a method of treating (e.g., inhibiting, reducing, ameliorating, managing, or preventing) a cancer in a subject.
  • the method includes administering to the subject a PI3K inhibitor (e.g., one or more PI3K inhibitors), or a pharmaceutically acceptable form thereof, in combination with a Bcl-2 inhibitor (e.g., one or more Bcl-2 inhibitors), or pharmaceutically acceptable form thereof.
  • a PI3K inhibitor e.g., one or more PI3K inhibitors
  • Bcl-2 inhibitor e.g., one or more Bcl-2 inhibitors
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor can be administered together in a single composition or administered separately in two or more different compositions, e.g., pharmaceutical compositions or dosage forms as described herein.
  • the administration of the PI3K inhibitor and the Bcl-2 inhibitor can be in any order.
  • the PI3K inhibitor can be administered concurrently with, prior to, or subsequent to, the Bcl-2 inhibitor.
  • the Bcl-2 inhibitor is administered to a subject at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, or 24 hours before the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, is administered.
  • the Bcl-2 inhibitor is administered concurrently with the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, e.g., in a single dosage form or separate dosage forms.
  • the Bcl-2 inhibitor is administered to the subject at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, or 24 hours after the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, is administered.
  • the PI3K inhibitor and the Bcl-2 inhibitor are administered with a timing that results in both inhibitors being present at therapeutic levels at the same time in the patient.
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor is additive, e.g., the effect of the combination is similar to their individual effects added together.
  • the combination of PI3K inhibitor and the Bcl-2 inhibitor is synergistic, e.g., has a synergistic effect, e.g., a synergistic effect in treating a cancer (e.g., in reducing cancer cell growth or viability, or both).
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, used in combination does not exceed the level at which each agent is used individually, e.g., as a monotherapy. In certain embodiments, the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, used in combination is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, used in combination that results in treatment of cancer is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the frequency of administration of the PI3K inhibitor, the Bcl-2 inhibitor, or both, used in combination that results in treatment of cancer is lower (e.g., at least 20%, 30%, 40%, or 50% lower), than the frequency of administration of each agent used individually, e.g., as a monotherapy.
  • the combination of PI3K inhibitor and the Bcl-2 inhibitor can be administered during periods of active disorder, or during a period of remission or less active disease.
  • the combination can be administered before a third treatment or procedure (e.g., radiation or surgery), concurrently with the third treatment, post-treatment, or during remission of the disorder.
  • featured herein is a method of inhibiting the growth or the viability, or both, of a cancer cell.
  • the method includes contacting the cancer cell with a PI3K inhibitor (e.g., one or more PI3K inhibitors), or a pharmaceutically acceptable form thereof, in combination with a Bcl-2 inhibitor (e.g., one or more Bcl-2 inhibitors), or pharmaceutically acceptable form thereof.
  • a PI3K inhibitor e.g., one or more PI3K inhibitors
  • Bcl-2 inhibitor e.g., one or more Bcl-2 inhibitors
  • the method is for use in vitro.
  • the method is for use or in vivo, e.g., in an animal subject or as part of a therapeutic protocol.
  • the contacting of the cell with the PI3K inhibitor and the Bcl-2 inhibitor can be in any order.
  • the cell is contacted with the PI3K inhibitor concurrently, prior to, or subsequent to, the Bcl-2 inhibitor.
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor is synergistic, e.g., has a synergistic effect in reducing cancer cell growth or viability, or both.
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, used in combination does not exceed the level at which each agent is used individually, e.g., as a monotherapy.
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, used in combination is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, used in combination that results in a reducing cancer cell growth or viability, or both is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the present disclosure provides a synergistic combination of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, for use in treating cancer.
  • the present disclosure provides a synergistic combination of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, for use in a medicament.
  • the present disclosure provides a use of a synergistic combination of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, for treating cancer.
  • the present disclosure provides a use of a synergistic combination of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof for the manufacture of a medicament for treating cancer.
  • compositions and/or methods described herein include one or more of the following:
  • compositions described herein can be used, e.g., for treatment of a cancer described herein and/or for inhibiting the growth or viability of a cancer cell in vitro or in vivo.
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor used in the compositions and methods described herein is synergistic, e.g., as indicated by a combination index value that is less than 1 for the combination of the PI3K inhibitor and the Bcl-2 inhibitor. In certain embodiments, the combination is synergistic as indicated by a combination index value that is less than 0.7 for the combination of the PI3K inhibitor and the Bcl-2 inhibitor. In some embodiments, the combination is synergistic as indicated by a combination index value that is less than 0.5 for the combination of the PI3K inhibitor and the Bcl-2 inhibitor.
  • the combination is synergistic as indicated by a combination index value that is less than 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 for the combination of the PI3K inhibitor and the Bcl-2 inhibitor.
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor used in the compositions and methods described herein is additive, e.g., as indicated by a combination index value that is equal to about 1 for the combination of the PI3K inhibitor and the Bcl-2 inhibitor.
  • the combination index value is assessed at 50% or more inhibition or growth inhibition. In certain embodiments, the combination index value is assessed at 50% inhibition, e.g., as described herein in the Examples.
  • the combination index value is assessed at 50% inhibition or growth inhibition, e.g., as described herein in the Examples. In some embodiments, the combination index value is assessed at 85% inhibition or growth inhibition, e.g., as described herein in the Examples. In some embodiments, the combination index value is assessed at 110% growth inhibition, e.g., as described herein in the Examples. In some embodiments, the combination index value is assessed at 140% growth inhibition, e.g., as described herein in the Examples. In some embodiments, the combination index value is assessed at 10%, 20%, 30%, 40%, 50%, 60%, 60%, 70%, 80%, 90%, 100% inhibition.
  • the combination index value is assessed at 10%, 20%, 30%, 40%, 50%, 60%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% or more growth inhibition. In some embodiments, the combination index value is calculated as described herein.
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor used in the compositions and methods described herein is synergistic, e.g., as indicated by a synergy score value of greater than 1, 2, or 3. In certain embodiments, the combination is synergistic as indicated by a synergy score value that is 1 or more. In certain embodiments, the combination is synergistic as indicated by a synergy score value that is 3 or more. In certain embodiments, the combination is synergistic as indicated by a synergy score value that is 10 or more. In certain embodiments, the combination of the PI3K inhibitor and the second agent used in the compositions and methods described herein is additive, e.g., as indicated by a synergy score value of zero.
  • the combination is synergistic as indicated by a synergy score value that is two standard deviations or three standard deviations of the value of the self-crosses, which indicates synergy at a confidence level of 95% or 99%, respectively.
  • the synergy score is calculated as described herein.
  • the anti-cancer effect provided by the combination of the PI3K inhibitor and the Bcl-2 inhibitor used in the compositions and methods described herein is greater than the anti-cancer effect provided by an agent (e.g., the PI3K inhibitor or the Bcl-2 inhibitor) used individually, e.g., as a monotherapy.
  • the anti-cancer effect provided by the combination of the PI3K inhibitor and the Bcl-2 inhibitor is greater than the anti-cancer effect provided monotherapy with the same dose of the PI3K inhibitor.
  • the anti-cancer effect provided by the combination of the PI3K inhibitor and the Bcl-2 inhibitor is at least 2 fold greater, at least 3 fold greater, at least 5 fold greater, or at least 10 fold greater than the anti-cancer effect provided by an agent used individually, e.g., as a monotherapy (e.g., by a monotherapy with the same dose of the PI3K inhibitor, or by a monotherapy with the same dose of the Bcl-2 inhibitor).
  • a “monotherapy” refers to the use of an agent individually (also referred to herein as alone), e.g., without a second active ingredient to treat the same indication, e.g., cancer.
  • the term monotherapy includes the use of either the PI3K inhibitor or the Bcl-2 inhibitor individually or alone to treat the cancer.
  • the anti-cancer effect provided by the combination of the PI3K inhibitor and the Bcl-2 inhibitor used in the compositions and methods described herein is greater than the anti-cancer effect provided by a monotherapy with the same dose of the PI3K inhibitor.
  • the anti-cancer effect provided by the combination is at least 2 fold greater, at least 3 fold greater, at least 5 fold greater, or at least 10 fold greater than the anti-cancer effect provided by the monotherapy with the same dose of the PI3K inhibitor.
  • the anti-cancer effect of the combination of the PI3K inhibitor and the Bcl-2 inhibitor used in the compositions and methods described herein is greater than the anti-cancer effect provided by a monotherapy with the same dose of the Bcl-2 inhibitor.
  • the anti-cancer effect of the combination of the PI3K inhibitor and the Bcl-2 inhibitor is at least 2 fold greater, at least 3 fold greater, at least 5 fold greater, or at least 10 fold greater than the anti-cancer effect provided by the monotherapy with the same dose of the Bcl-2 inhibitor.
  • one or more side effects of the PI3K inhibitor, the Bcl-2 inhibitor, or both is reduced compared with the side effects of an agent (e.g., the side effects of either the PI3K inhibitor or the Bcl-2 inhibitor) when used individually, e.g., as a monotherapy (e.g., a monotherapy with the PI3K inhibitor, or by a monotherapy with the Bcl-2 inhibitor), e.g., when the monotherapy is administered at a dose that achieves the same therapeutic effect as the combination.
  • an agent e.g., the side effects of either the PI3K inhibitor or the Bcl-2 inhibitor
  • one or more side effects of the PI3K inhibitor, the Bcl-2 inhibitor, or both is reduced compared with the side effects of each agent when used individually, e.g., as a monotherapy (e.g., a monotherapy with the PI3K inhibitor, or by a monotherapy with the Bcl-2 inhibitor), e.g., when the monotherapy is administered at a dose that achieves the same therapeutic effect as the combination.
  • a monotherapy e.g., a monotherapy with the PI3K inhibitor, or by a monotherapy with the Bcl-2 inhibitor
  • one or more side effects of the compositions or methods described herein is reduced compared with the side effects of a monotherapy comprising either the Bcl-2 inhibitor (or pharmaceutically acceptable form thereof) or the PI3K inhibitor (or pharmaceutically acceptable form thereof), e.g., a monotherapy at a dose that achieves the same therapeutic effect as does the combination.
  • said one or more side effects includes a liver enzyme level, e.g., a liver enzyme level indicative of toxicity.
  • said one or more side effects include thrombocytopenia.
  • said one or more side effects include tumor lysis syndrome.
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor used in the compositions and methods described herein results in a reduction in resistance (e.g., a decrease in a measure of resistance or a decreased likelihood of developing resistance), or a delay in the development of resistance, to at least one of the agents, e.g., resistance (e.g., acquired resistance) to the PI3K inhibitor.
  • resistance is assessed at least in part by evaluating minimal residual disease (MRD).
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor used in the compositions and methods described herein results in a reduction in the level of minimal residual disease (MRD) that can be detected.
  • MRD minimal residual disease
  • the combination of a PI3K inhibitor (e.g. a PI3K inhibitor described herein) and a Bcl-2 inhibitor (e.g., a Bcl-2 inhibitor described herein) is effective to reduce the level of MRD in the subject, e.g., below a level previously measured in the subject (e.g., the level measured before the combination was administered).
  • the combination of a PI3K inhibitor and a Bcl-2 inhibitor is effective to reduce the level of MRD in the subject below the level observed during or after treatment with a monotherapy, e.g., a monotherapy comprising either the PI3K inhibitor or the Bcl-2 inhibitor.
  • a monotherapy e.g., a monotherapy comprising either the PI3K inhibitor or the Bcl-2 inhibitor.
  • the level of MRD is decreased below the level observed during treatment with a monotherapy comprising the PI3K inhibitor.
  • the level of MRD is decreased below the level observed during treatment with a monotherapy comprising the Bcl-2 inhibitor.
  • the combination is effective to reduce the level of MRD below a preselected cutoff value (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, 1 malignant cell in 10,000 normal cells, or 1 malignant cell in 100,000 normal cells).
  • a preselected cutoff value is 1 malignant cell in 1,000 or 10,000 normal cells.
  • a subject exhibits MRD negativity (or is MRD-negative) if the MRD is below a preselected cutoff value (e.g., a preselected cutoff value as described herein).
  • the level of MRD is not detectable by standard laboratory methodologies.
  • the invention features a method of treating a cancer in a subject, or a method of decreasing the level of MRD in a subject having a cancer.
  • the method comprises:
  • a PI3K inhibitor e.g., Compound 1
  • a Bcl-2 inhibitor e.g., at least one Bcl-2 inhibitor
  • the method further includes monitoring the subject after altering the combination treatment (e.g., after reducing the dose or ceasing the first treatment), e.g., for a period of at least 6 months, 9 months or 12 months. If the MRD levels increase, e.g., increase above a preselected cutoff value (e.g., a preselected cutoff value as described herein), administer a second treatment.
  • the second treatment is a PI3K inhibitor monotherapy.
  • the second treatment is a PI3K inhibitor in combination with a Bcl-2 inhibitor (e.g., at least one Bcl-2 inhibitor).
  • the second treatment is a PI3K inhibitor in combination with a third agent.
  • the second treatment is a PI3K inhibitor in combination a Bcl-2 inhibitor and a third agent.
  • the invention features a method of treating a cancer in a subject, or a method of decreasing the level of MRD detected in a subject having a cancer.
  • the method comprises:
  • a PI3K inhibitor e.g., Compound 1
  • a Bcl-2 inhibitor e.g., at least one Bcl-2 inhibitor
  • c) stop administering the first treatment (e.g., the combination) if the level of MRD in the subject is decreases below a preselected cutoff value (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells).
  • a preselected cutoff value e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells.
  • the method further comprises (d) monitoring the level of MRD in the subject, e.g., by one or more of the methods described herein or known in the art (e.g., flow cytometry, sequencing, or PCR) and (e) administering a second treatment (e.g., a monotherapy comprising a PI3K inhibitor, or administering a further combination comprising the PI3K inhibitor, or a pharmaceutically acceptable form thereof), if the level of MRD increases, e.g., increase above a preselected cutoff value (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells).
  • a preselected cutoff value e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells.
  • the method comprises repeating steps (b), (c), (d) and (e).
  • the second treatment is a PI3K inhibitor monotherapy.
  • the second treatment is a PI3K inhibitor in combination with a Bcl-2 inhibitor (e.g., at least one Bcl-2 inhibitor).
  • the second treatment is a PI3K inhibitor in combination with a third agent.
  • the second treatment is a PI3K inhibitor in combination a Bcl-2 inhibitor and a third agent.
  • compositions and methods can be used in combination with a monotherapy (e.g., a monotherapeutic administration or dose of the PI3K inhibitor, the Bcl-2 inhibitor or a third agent).
  • a monotherapy e.g., a monotherapeutic administration or dose of the PI3K inhibitor, the Bcl-2 inhibitor or a third agent.
  • the subject is administered a monotherapy with a PI3K inhibitor, which can be followed with a combination composition or method described herein.
  • a first monotherapy e.g., with a PI3K inhibitor, Bcl-2 inhibitor, or third agent
  • any of the combination compositions or methods described herein can be administered.
  • the combination compositions or methods described herein improve responsiveness (e.g., as indicated by a decrease in MRD, e.g., a decrease below the level of MRD observed during treatment with the first monotherapy).
  • administration of any of the combination compositions or methods described herein can be followed by administration of a monotherapy, e.g., with a PI3K inhibitor, Bcl-2 inhibitor, or third agent.
  • composition and methods described herein can include further agents or therapies, including but not limited to, chemotherapeutics, radiation or surgery.
  • the PI3K inhibitor is a PI3K delta inhibitor. In one embodiment, the PI3K inhibitor is a PI3K delta/gamma dual inhibitor.
  • the PI3K inhibitor is chosen from one or more of: Compound 1, AMG-319, GSK 2126458, GSK 1059615, GDC-0032, GDC-0980, GDC-0941, XL147, XL499, XL765, BKM 120, GS1101, CAL 263, SF1126, PX-866, BEZ235, CAL-120, BYL719, RP6503, RP6530, TGR1202, INK1117, PX-886, BAY 80-6946, IC87114, Palomid 529, ZSTK474, PWT33597, TG100-115, GNE-477, CUDC-907, AEZS-136, BGT-226, PF-05212384, LY3023414, PI-103, LY294002, INCB-040093, CAL-130 or wortmannin.
  • the PI3K inhibitor is Compound 1, or a pharmaceutically acceptable form thereof.
  • Compound 1 has the following structure:
  • the PI3K inhibitor is GS1101 (CAL-101), or a pharmaceutically acceptable form thereof.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor is therapeutically effective (e.g., synergistically effective), in treating a cancer in the subject, e.g., for treatment of a cancer described herein.
  • the cancer to be treating using the methods or compositions described herein is of hematopoietic origin.
  • the cancer is lymphoma or leukemia.
  • the cancer is B-cell lymphoma, mantle cell lymphoma, non-Hodgkin's lymphoma (e.g., non-Hodgkin's B-cell lymphoma), T-cell lymphoma (e.g., peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL)), cutaneous lymphoma, anaplastic large cell lymphoma, multiple myeloma, myeloma, or plasmacytoma.
  • the cancer is a multiple myeloma.
  • the cancer is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • the cancer has a high level of Bcl-2 expression.
  • the cancer is a diffuse large B-cell lymphoma with a high level of Bcl-2 expression.
  • the cancer is diffuse large B-cell lymphoma, follicular lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, non-Hodgkin B-cell lymphoma, non-Hodgkin T-cell lymphoma, indolent non-Hodgkin lymphoma, cutaneous lymphoma, anaplastic large cell lymphoma, multiple myeloma, myeloma, or plasmacytoma.
  • the cancer is a non-Hodgkin's lymphoma.
  • the cancer is a B cell non-Hodgkin's lymphoma.
  • the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma.
  • the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma activated B-cell like or a diffuse large B-cell lymphoma germinal center B-cell-like.
  • the cancer is an indolent non-Hodgkin's lymphoma, e.g., a follicular lymphoma.
  • the cancer is a mantle cell lymphoma.
  • the cancer is a T-cell non-Hodgkin's lymphoma.
  • the subject is a mammal, e.g., a human. In one embodiment, the subject is at risk or suffers from a cancer, e.g., a cancer described herein.
  • the method delays resistance of the cancer, e.g., to a therapeutic agent, e.g., to the PI3K inhibitor such as Compound 1, or to the Bcl-2 inhibitor.
  • the method reduces the risk that the cancer becomes resistant, e.g., to a therapeutic agent, e.g., to the PI3K inhibitor such as Compound 1, or to the Bcl-2 inhibitor.
  • the cancer does not become resistant (e.g., to the PI3K inhibitor) for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, or 36 months.
  • the method prolongs remission (e.g., complete remission or partial remission) in the subject.
  • the subject experiences remission (e.g., complete remission or partial remission) for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, or 36 months.
  • the method increases the likelihood that the subject experiences complete remission.
  • the method results in a reduction in the level of minimal residual disease (MRD).
  • the subject has substantially no detectable MRD.
  • the subject displays one or more of these characteristics (e.g., remission) after treatment with the PI3K inhibitor and the Bcl-2 inhibitor for a therapeutically effective period of time, e.g., at least 1, 2, 3, or 4 weeks, or 1, 2, 4, 6, 9, or 12 months.
  • the subject is resistant or refractive to a treatment, e.g., a treatment with a PI3K inhibitor (e.g., Compound 1 or GS1101).
  • a treatment with a PI3K inhibitor e.g., Compound 1 or GS1101
  • the subject is identified as having a decreased susceptibility (e.g., resistance or acquired resistance) to a monotherapy treatment with a PI3K inhibitor (e.g., Compound 1 or GS1101), or a pharmaceutically acceptable form thereof.
  • the PI3K inhibitor and the Bcl-2 inhibitor are the only therapeutically active ingredients for treating a cancer. Additional combinations of three or more agents are encompassed by the methods and compositions described herein.
  • the PI3K inhibitor and the Bcl-2 inhibitor are in a single dosage form. In other embodiments, the PI3K inhibitor and the Bcl-2 inhibitor are in separate dosage forms.
  • the combination of the PI3K inhibitor and the Bcl-2 inhibitor is synergistic, e.g., in inhibiting tumor cell growth, viability or both, or in treating a cancer.
  • the Bcl-2 inhibitor is ABT-199, ABT-263, ABT-737, G3139 (genasense or oblimersen), GX15-070 (obatoclax mesylate), HA14-1, TW-37, sabutoclax, Gossypol (AT-101), antimycin A, apogossypol, S44563, or a combination or mixture thereof.
  • the Bcl-2 inhibitor is ABT-199.
  • the Bcl-2 inhibitor is ABT-263.
  • a composition comprising a PI3K inhibitor (e.g., Compound 1 or GS1101), or a pharmaceutically acceptable form thereof, in combination with ABT-199, or a pharmaceutically acceptable form thereof.
  • a PI3K inhibitor e.g., Compound 1 or GS1101
  • the PI3K inhibitor and ABT-199 can be present in a single composition or as two or more different compositions.
  • the composition e.g., one or more compositions comprising the combination of PI3K inhibitor and ABT-199 is synergistic, e.g., has a synergistic effect in treating a cancer (e.g., in reducing cancer cell growth or viability, or both, e.g., as described herein).
  • the amount or dosage of the PI3K inhibitor, ABT-199, or both, present in the composition(s) is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • a method of treating e.g., inhibiting, managing, or preventing a cancer in a subject comprising administering to the subject a PI3K inhibitor, e.g., one or more PI3K inhibitors (e.g., Compound 1 or GS1101, or both) or a pharmaceutically acceptable form thereof, in combination with ABT-199, or a pharmaceutically acceptable form thereof.
  • a PI3K inhibitor e.g., one or more PI3K inhibitors (e.g., Compound 1 or GS1101, or both) or a pharmaceutically acceptable form thereof, in combination with ABT-199, or a pharmaceutically acceptable form thereof.
  • the combination of the PI3K inhibitor and ABT-199 is synergistic, e.g., has a synergistic effect in treating the cancer (e.g., in reducing cancer cell growth or viability, or both).
  • the amount or dosage of the PI3K inhibitor, ABT-199, or both, used in combination does not exceed the level at which each agent is used individually, e.g., as a monotherapy. In certain embodiments, the amount or dosage of the PI3K inhibitor, ABT-199, or both, used in combination is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the amount or dosage of the PI3K inhibitor, ABT-199, or both, used in combination that results in treatment of cancer is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • a composition comprising a PI3K inhibitor (e.g., Compound 1 or GS1101), or a pharmaceutically acceptable form thereof, in combination with ABT-263, or a pharmaceutically acceptable form thereof.
  • a PI3K inhibitor e.g., Compound 1 or GS1101
  • ABT-263 e.g., Compound 1 or GS1101
  • the PI3K inhibitor and ABT-263 can be present in a single composition or as two or more different compositions.
  • the composition e.g., one or more compositions comprising the combination of PI3K inhibitor and ABT-263
  • is synergistic e.g., has a synergistic effect in treating a cancer (e.g., in reducing cancer cell growth or viability, or both, e.g., as described herein).
  • the amount or dosage of the PI3K inhibitor, ABT-263, or both, present in the composition(s) is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • a method of treating e.g., inhibiting, managing, or preventing a cancer in a subject comprising administering to the subject a PI3K inhibitor, e.g., one or more PI3K inhibitors or a pharmaceutically acceptable form thereof, in combination with ABT-263, or a pharmaceutically acceptable form thereof.
  • a PI3K inhibitor e.g., one or more PI3K inhibitors or a pharmaceutically acceptable form thereof
  • ABT-263 e.g., a pharmaceutically acceptable form thereof.
  • the combination of the PI3K inhibitor and ABT-263 is synergistic, e.g., has a synergistic effect in treating the cancer (e.g., in reducing cancer cell growth or viability, or both).
  • the amount or dosage of the PI3K inhibitor, ABT-263, or both, used in combination does not exceed the level at which each agent is used individually, e.g., as a monotherapy. In certain embodiments, the amount or dosage of the PI3K inhibitor, ABT-263, or both, used in combination is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the amount or dosage of the PI3K inhibitor, ABT-263, or both, used in combination that results in treatment of cancer is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the PI3K inhibitor is chosen from one or more of: Compound 1, AMG-319, GSK 2126458, GSK 1059615, GDC-0032, GDC-0980, GDC-0941, XL147, XL499, XL765, BKM 120 GS1101, CAL 263, SF1126, PX-866, BEZ235, CAL-120, BYL719, RP6503, RP6530, TGR1202, INK1117, PX-886, BAY 80-6946, IC87114, Palomid 529, ZSTK474, PWT33597, TG100-115, GNE-477, CUDC-907, AEZS-136, BGT-226, PF-05212384, LY3023414, PI-103, LY294002, INCB-040093, CAL-130 or wortmannin.
  • the PI3K inhibitor e.g., Compound 1
  • the Bcl-2 inhibitor is administered at a dosage of from about 0.01 to about 1100 mg daily.
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, that is used in the method or composition is lower (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the amount or dosage of the PI3K inhibitor, the Bcl-2 inhibitor, or both, present in the composition(s) that results in a desired effect is lower (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the composition comprises the PI3K inhibitor, or a pharmaceutically acceptable form thereof, at an amount of in the range of from about 0.01 mg to about 75 mg.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof is in the range of from about 50:1 to about 1:50. In one embodiment, the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, is in the range of from about 10:1 to about 1:10 or from about 1:3 to about 1:7.
  • the composition comprises Compound 1, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.01 mg to about 75 mg and the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, at an amount of in the range of from about 0.01 mg to about 1100 mg.
  • the composition comprises ABT-199 at an amount of about 400 mg, about 325 mg, about 150 mg, or about 75 mg.
  • the PI3K inhibitor is Compound 1 at a dosage of 25 mg (e.g., 25 mg BID). In certain embodiments, Compound 1 is effective as a monotherapy at a dosage of 25 mg (e.g., 25 mg BID). In certain embodiments, the combination of Compound 1 and the Bcl-2 inhibitor is effective, e.g., in treating a cancer and/or in reducing cancer cell growth or viability, with Compound 1 at a dosage lower than 25 mg (e.g., 25 mg BID).
  • the dosage of Compound 1 is 22.5 mg (e.g., 22.5 mg BID), 20 mg (e.g., 20 mg BID), 17.5 mg (e.g., 17.5 mg BID), 15 mg (e.g., 15 mg BID), 12.5 mg (e.g., 12.5 mg BID), 10 mg (e.g., 10 mg BID), 7.5 mg (e.g., 7.5 mg BID), or 5 mg (e.g., 5 mg BID).
  • the PI3K inhibitor e.g., Compound 1
  • BID twice per day
  • the combination of the PI3K inhibitor (e.g., Compound 1) and the Bcl-2 inhibitor is effective, e.g., in treating a cancer and/or in reducing cancer cell growth or viability, with the PI3K inhibitor (e.g., Compound 1) administered at a dose frequency of twice per day (BID), once per day, once per two days, once per three days, once per four days, once per five days, once per six days, or once per week.
  • the PI3K inhibitor is GS1101 at a dosage of 150 mg (e.g., 150 mg BID). In certain embodiments, GS1101 is effective as a monotherapy at a dosage of 150 mg (e.g., 150 mg BID). In certain embodiments, the combination of GS1101 and the Bcl-2 inhibitor is effective, e.g., in treating a cancer and/or in reducing cancer cell growth or viability, with GS1101 at a dosage lower than 150 mg (e.g., 150 mg BID).
  • the dosage of GS1101 is 135 mg (e.g., 135 mg BID), 120 mg (e.g., 120 mg BID), 105 mg (e.g., 105 mg BID), 90 mg (e.g., 90 mg BID), 75 mg (e.g., 75 mg BID), 60 mg (e.g., 60 mg BID), 45 mg (e.g., 45 mg BID), or 30 mg (e.g., 30 mg BID).
  • 135 mg e.g., 135 mg BID
  • 120 mg e.g., 120 mg BID
  • 105 mg e.g., 105 mg BID
  • 90 mg e.g., 90 mg BID
  • 75 mg e.g., 75 mg BID
  • 60 mg e.g., 60 mg BID
  • 45 mg e.g., 45 mg BID
  • 30 mg e.g., 30 mg BID
  • the PI3K inhibitor is GS1101 and is administered at a dose frequency of twice per day, once per day, once per two days, once per three days, once per four days, once per five days, once per six days, or once per week.
  • the combination of GS1101 and the Bcl-2 inhibitor is effective, e.g., in treating a cancer and/or in reducing cancer cell growth or viability, with GS1101 administered at a dose frequency of twice per day (BID), once per day, once per two days, once per three days, once per four days, once per five days, once per six days, or once per week.
  • BID twice per day
  • the Bcl-2 inhibitor is ABT-199 at a dosage of 400 mg (e.g., 400 mg QID).
  • ABT-199 is effective as a monotherapy at a dosage of 400 mg (e.g., 400 mg QID).
  • the combination of the PI3K inhibitor and ABT-199 is effective, e.g., in treating a cancer and/or in reducing cancer cell growth or viability, with ABT-199 at a dosage lower than 400 mg (e.g., 400 mg QID).
  • the dosage of ABT-199 is 50 to 350 mg (e.g., 50 to 350 mg BID), e.g., 50 to 100 mg (e.g., 50 to 100 mg BID), 100 to 200 mg (e.g., 100 to 200 mg BID), 200 to 300 mg (e.g., 200 to 300 mg BID) or 250 to 350 mg (e.g., 250 to 350 mg BID).
  • 50 to 350 mg e.g., 50 to 350 mg BID
  • 50 to 100 mg e.g., 50 to 100 mg BID
  • 100 to 200 mg e.g., 100 to 200 mg BID
  • 200 to 300 mg e.g., 200 to 300 mg BID
  • 250 to 350 mg e.g., 250 to 350 mg BID
  • the dosage of ABT-199 is about 350 mg (e.g., 350 mg QID), 300 mg (e.g., 300 mg QID), 250 mg (e.g., 250 mg QID), 200 mg (e.g., 200 mg QID), 150 mg (e.g., 150 mg QID), 100 mg (e.g., 100 mg QID), or 50 mg (e.g., 50 mg QID).
  • the Bcl-2 inhibitor is a Bcl-2 inhibitor (e.g., ABT-199) administered at a dose frequency of four times per day (QID), three times per day, twice per day (BID), once per day, once per two days, once per three days, once per four days, once per five days, once per six days, or once per week.
  • QID four times per day
  • BID twice per day
  • the combination of the PI3K inhibitor and Bcl-2 inhibitor is effective, e.g., in treating a cancer and/or in reducing cancer cell growth or viability, when the Bcl-2 inhibitor (e.g., ABT-199) administered at a dose frequency of four times per day (QID), three times per day, twice per day (BID), once per day, once per two days, once per three days, once per four days, once per five days, once per six days, or once per week.
  • QID four times per day
  • BID twice per day
  • the Bcl-2 inhibitor is ABT-263 at a dosage of 325 mg.
  • ABT-263 is effective as a monotherapy at a dosage of 325 mg.
  • the combination of the PI3K inhibitor and ABT-263 is effective, e.g., in treating a cancer and/or in reducing cancer cell growth or viability, with ABT-263 at a dosage lower than 325 mg.
  • the dosage of ABT-263 is 50 to 300 mg (e.g., 50 to 100 mg, 100 to 200 mg, or 200 to 300 mg).
  • the dosage of ABT-263 is about 300 mg, 275 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 75 mg, or 50 mg. In certain embodiments, the dosage is for daily administration.
  • the Bcl-2 inhibitor is ABT-263 and is administered at a dose frequency of four times per day (QID), three times per day, twice per day (BID), once per day, once per two days, once per three days, once per four days, once per five days, once per six days, or once per week.
  • the combination of the PI3K inhibitor and ABT-263 is effective, e.g., in treating a cancer and/or in reducing cancer cell growth or viability, when ABT-263 administered at a dose frequency of four times per day (QID), three times per day, twice per day (BID), once per day, once per two days, once per three days, once per four days, once per five days, once per six days, or once per week.
  • the Bcl-2 inhibitor is administered to a subject at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, is administered.
  • the Bcl-2 inhibitor is administered concurrently with the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, e.g., in a single dosage form or separate dosage forms.
  • the Bcl-2 inhibitor is administered to the subject at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, is administered.
  • the PI3K inhibitor e.g., Compound 1
  • Compound 1, or a pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, are the only therapeutically active ingredients.
  • Compound 1, or a pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof are in a single dosage form. In one embodiment, Compound 1, or a pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, are in separate dosage forms. In one embodiment, the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, is in the range of from about 50:1 to about 1:50.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof is in the range of from about 10:1 to about 1:10 or from about 1:3 to about 1:7.
  • Compound 1 is administered at an amount to reach maximum plasma concentration at steady state (Cmaxss) at about 1000 ng/mL to about 5000 ng/mL; and the Bcl-2 inhibitor is administered at an amount to reach Cmaxss at about 0.1 ⁇ g/mL to about 1000 ⁇ g/mL.
  • Cmaxss maximum plasma concentration at steady state
  • Compound 1 is administered at an amount to reach an area under the plasma concentration-time curve at steady-state (AUCss) at about 5000 ng/mL*hr to about 10000 ng/mL*hr; and the Bcl-2 inhibitor is administered at an amount to reach an AUCss at about 0.1 ng/mL*hr to about 10000 ng/mL*hr.
  • AUCss area under the plasma concentration-time curve at steady-state
  • the PI3K inhibitor is Compound 1 and is effective (e.g., therapeutically effective) in the combination at an amount that is decreased by about 1.5 fold to about 50 fold of the amount that is required to achieve the same effect, e.g., the same therapeutic effect, when Compound 1 is administered as a monotherapy.
  • the Bcl-2 inhibitor is effective (e.g., therapeutically effective) in the combination at an amount that is decreased by about 1.5 fold to about 50 fold of the amount that is required to achieve the same effect, e.g., the same therapeutic effect, when Compound 1 is administered as a monotherapy.
  • the PI3K inhibitor is Compound 1
  • the Bcl-2 inhibitor is ABT-199 or ABT-263
  • the cancer is a diffuse large B-cell lymphoma.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof is in the range of from about 50:1 to about 1:50.
  • the PI3K inhibitor is Compound 1
  • the Bcl-2 inhibitor is ABT-199 or ABT-263
  • the cancer is a follicular lymphoma.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof is in the range of from about 50:1 to about 1:50.
  • the PI3K inhibitor is Compound 1
  • the Bcl-2 inhibitor is ABT-199 or ABT-263
  • the cancer is a T-cell lymphoma.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof is in the range of from about 50:1 to about 1:50.
  • the PI3K inhibitor is Compound 1
  • the Bcl-2 inhibitor is ABT-199 or ABT-263
  • the cancer is mantle cell lymphoma.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof is in the range of from about 50:1 to about 1:50.
  • a method of reducing or delaying resistance to a treatment with PI3K inhibitor e.g., a treatment with one or more PI3K inhibitors described herein
  • a method of reducing the likelihood for a subject to develop resistance to a treatment with a PI3K inhibitor e.g., a treatment with one or more PI3K inhibitors described herein
  • the method comprising:
  • a method of reducing or delaying resistance to a treatment with PI3K inhibitor e.g., a treatment with one or more PI3K inhibitors described herein
  • a method of reducing the likelihood for a subject to develop resistance to a treatment with a PI3K inhibitor e.g., a treatment with one or more PI3K inhibitors described herein
  • the method comprising:
  • the subject is identified as developing resistance (e.g., acquired resistance) to the monotherapy. In certain embodiments, the subject is identified as developing resistance based on an assessment of MRD. In certain embodiments, the subject is identified as developing resistance if the MRD is above a preselected cutoff value (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells). In certain embodiments, the preselected cutoff value is 1 malignant cell in 1000 or 10,000 normal cells. In certain embodiments, the method further comprises assessing MRD, e.g., in step (a) and/or (b).
  • a preselected cutoff value e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells. In certain embodiments, the preselected cutoff value is 1 malignant cell in 1000 or 10,000 normal cells. In certain embodiments, the method further comprises assessing MRD, e.g., in step (a) and/or
  • this disclosure provides a method of delaying resistance of a subject having a cancer, comprising administering to the subject a synergistic amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, thereby delaying resistance (e.g., resistance to the PI3K inhibitor).
  • the method may comprise administering the PI3K inhibitor before the Bcl-2 inhibitor.
  • the disclosure also provides, in certain aspects, a method of reducing the risk that a cancer becomes resistant to the PI3K inhibitor, comprising administering to a subject having a cancer a synergistic amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, thereby reducing the risk that the cancer becomes resistant to the PI3K inhibitor.
  • the disclosure also provides, in certain aspects, a method of prolonging remission (e.g., complete remission or partial remission) in a subject having a cancer, comprising administering to the subject a synergistic amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, thereby prolonging remission in the subject.
  • a method of prolonging remission e.g., complete remission or partial remission
  • the disclosure also provides, in certain aspects, a method of increasing the likelihood that a subject having a cancer experiences complete remission, comprising administering to the subject a synergistic amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, thereby increasing the likelihood that the subject experiences complete remission.
  • the disclosure also provides, in certain aspects, a method of reducing the level of minimal residual disease (MRD) compared to a reference value (e.g., compared to a pre-treatment value or a value obtained during treatment) in a subject having a cancer, comprising administering to the subject a synergistic amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, thereby reducing the level of MRD in the subject.
  • a reference value e.g., compared to a pre-treatment value or a value obtained during treatment
  • This disclosure further provides methods of assessing a subject's cells, and treating the patient with a combination of a PI3K inhibitor and a Bcl-2 inhibitor.
  • the invention features a method of evaluating the responsiveness of a cancer or tumor, or a subject having a cancer or tumor, to a treatment with a BCR pathway inhibitor (e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination).
  • a BCR pathway inhibitor e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination.
  • responsiveness to a PI3K inhibitor is evaluated.
  • the method includes: acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of an alteration or biomarker chosen from one, two, three, four or all of: an STK11 copy number, TSC1 copy number, TSC2 copy number, a p53 pathway mutation (e.g., a mutation disclosed in Table 20), or MAPK pathway mutation (e.g., a mutation disclosed in Table 18), or any combination thereof (e.g., a dual MAPK/p53 pathway mutation, e.g., a mutation disclosed in Table 18 and a mutation disclosed in Table 20).
  • the method further comprises administering a PI3K inhibitor and a Bcl-2 inhibitor to the subject.
  • the subject has, or is identified as having, a tumor that is responsive to the PI3K inhibitor. In some embodiments, the subject has, or is identified as having, a tumor that is not responsive to the PI3K inhibitor. In some embodiments, PI3K inhibitor and a Bcl-2 inhibitor are administered to a subject that has, or is identified as having, a tumor that is less responsive, e.g., not responsive to the PI3K inhibitor. In some embodiments, PI3K inhibitor and a Bcl-2 inhibitor are administered to a subject that has, or is identified as having, a tumor that is responsive to the PI3K inhibitor.
  • PI3K inhibitor and a Bcl-2 inhibitor are administered to a subject that has, or is identified as having, a tumor that is less responsive, e.g., not responsive to the PI3K inhibitor.
  • co-administration of the Bcl-2 inhibitor improves sensitivity of the tumor to the PI3K inhibitor.
  • the invention features a method of monitoring a treatment of a subject with a BCR pathway inhibitor (e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination).
  • a BCR pathway inhibitor e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination.
  • treatment with a PI3K inhibitor is monitored.
  • the method includes: acquiring, at two or more time intervals, a value (e.g., determining one or more of: the presence, absence, amount or level) of an alteration or biomarker chosen from one, two, three, four or all of: an STK11 copy number, TSC1 copy number, TSC2 copy number, a p53 pathway mutation (e.g., a mutation disclosed in Table 20), or MAPK pathway mutation (e.g., a mutation disclosed in Table 18), or any combination thereof (e.g., a dual MAPK/p53 mutation, e.g., a mutation disclosed in Table 18 and a mutation disclosed in Table 20).
  • the method further comprises administering a PI3K inhibitor and a Bcl-2 inhibitor to the subject.
  • the invention features a method of treating (e.g., inhibiting, reducing, ameliorating, managing, or preventing) a cancer or tumor in a subject.
  • the method includes: acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of an alteration or biomarker chosen from one, two, three, four or all of: an STK11 copy number, TSC1 copy number, TSC2 copy number, a p53 pathway mutation (e.g., a mutation disclosed in Table 20), or MAPK pathway mutation (e.g., a mutation disclosed in Table 18), or any combination thereof (e.g., a dual MAPK/p53 mutation, e.g., a mutation disclosed in Table 18 and a mutation disclosed in Table 20), and responsive to said value, administering to the subject a BCR pathway inhibitor, e.g., a PI3K inhibitor (e.g., one or more PI3K inhibitors) and a Bcl-2 inhibitor.
  • the invention features a method of treating a subject, comprising (i) administering a first treatment comprising a first PI3K inhibitor to the subject (ii) acquiring information regarding the presence or absence of an alteration in a biomarker in one or more samples from the subject, wherein the biomarker is selected from STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, MAP2K4, or EGFR; and (iii) continuing administration of the first treatment if the alteration is absent, or administering a second treatment if the alteration is present, wherein the second treatment includes administration of a Bcl-2 inhibitor.
  • the alteration is an STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, or MAP2K4 copy number loss (e.g., single copy loss).
  • the STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, or MAP2K4 copy number in a sample taken from the subject after the first treatment is lower than a corresponding STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, MAP2K4 copy number in a sample taken from the subject before the first treatment (e.g., there is an STK11 single copy loss).
  • the present disclosure provides a method of evaluating the responsiveness of a cancer or tumor, or a subject having a cancer or tumor, to a treatment with a BCR pathway inhibitor (e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination).
  • a BCR pathway inhibitor e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination.
  • responsiveness to a PI3K inhibitor is evaluated.
  • the method includes: acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of an anti-apoptotic factor such as Bcl-2.
  • the invention features a method of monitoring a treatment of a subject with a BCR pathway inhibitor (e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination).
  • a BCR pathway inhibitor e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination.
  • treatment with a PI3K inhibitor is monitored.
  • the method includes: acquiring, at two or more time intervals, a value (e.g., determining one or more of: the presence, absence, amount or level) of an anti-apoptotic factor such as Bcl-2.
  • the invention features a method of treating (e.g., inhibiting, reducing, ameliorating, managing, or preventing) a cancer or tumor in a subject.
  • the method includes: acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of an anti-apoptotic factor such as Bcl-2.
  • the methods that include acquiring a value of Bcl-2 also include acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of a pro-apoptotic factor or anti-apoptotic factor.
  • the pro-apoptotic factor can be, e.g., one or more of (e.g., 2, 3, 4, or all of) BMF, BIK, BIM, NOXA, PUMA, and HRK.
  • an elevated level of Bch 2 indicates that the cancer is resistant to a PI3K inhibitor.
  • a normal or reduced level of Bcl-2 indicates that the cancer is responsive to a PI3K inhibitor.
  • an elevated level of one or more pro-apoptotic factors indicates that the cancer is more responsive to a PI3K inhibitor (optionally in combination with a Bcl-2 inhibitor) than a cancer with normal or lowered levels of the pro-apoptotic factor.
  • the methods involve administering a Bcl-2 inhibitor (e.g., in combination with a PI3K inhibitor) to a subject having elevated Bcl-2 levels.
  • the methods involve administering a PI3K inhibitor as a monotherapy to a subject having normal or low Bcl-2 levels.
  • the elevated, normal, or reduced levels of a biomarker are determined with reference to a non-cancerous control value.
  • FIG. 1 shows an isobologram depicting the synergistic effect of the combination of Compound 1 and ABT-199 in SU-DHL-4 cell line.
  • FIG. 2 shows an isobologram depicting the synergistic effect of the combination of Compound 1 and ABT-199 in Mino cell line.
  • FIG. 3 shows an isobologram depicting the synergistic effect of the combination of Compound 1 and ABT-199 in WSU-NHL cell line.
  • FIG. 4 shows an isobologram depicting the synergistic effect of the combination of Compound 1 and ABT-199 in DoHH-2 cell line.
  • FIGS. 5A , 5 B, and 5 C show the change in RNA levels of selected differentially regulated genes in patients treated with Compound 1.
  • FIG. 6A is a graphical representation of the change in RNA levels of selected genes in patients treated with Compound 1 after 8 days.
  • FIG. 6B is a graphical representation of the change in RNA levels of selected genes in patients treated with Compound 1 after 28 days.
  • FIG. 7 is a graph showing the fold change in Harakiri expression level in partial remission and stable disease patients after 7 days of Compound 1 treatment.
  • FIG. 8 is a graphical representation of the relationship between mutations and responses to Compound 1.
  • Each column represents a patient.
  • Each row represents a mutation.
  • the diagnosis is coded as 1: CLL/SLL (R/R), or 2: CLL/SLL (treatment-na ⁇ ve).
  • R/R refers to a patient that has relapsed or is refractory to treatment.
  • Tx na ⁇ ve refers to a patient that is treatment na ⁇ ve, e.g., has not been previously administered Compound 1.
  • the response is coded as 3: CR/PR, 4: PRwL, 5: SD/PD, or 6: SD/PD (nodal response).
  • the ALC is coded as 7: high, 8: normal, or 9: low.
  • PR refers to partial remission
  • SD refers to stable disease
  • PD refers to progressive disease
  • CR refers to complete remission
  • FIG. 9 is a graphical representation of the relationship between mutations and responses to Compound 1. Each column represents a patient. Each row represents a mutation. The diagnosis is coded as 1: CLL/SLL (R/R), or 2: CLL/SLL (treatment-na ⁇ ve). The response is coded as IWCLL complete remission or partial remission (CR/PR) or IWCLL stable disease or progressive disease (SD/PD). Nodal responses are indicated with an asterisk (*).
  • FIG. 10 is a graphical representation of the relationship between mutations and responses to Compound 1. The diagnosis and response is coded as in FIG. 9 .
  • FIG. 11 is a graphical representation of the relationship between mutations and responses to Compound 1.
  • the diagnosis and response is coded as in FIG. 9 .
  • Nodal responses are indicated with an asterisk (*).
  • a non-assessable nodal response is indicated by a (#).
  • FIG. 12 is a graphical representation of the relationship between CLL common copy number variations (CNVs) and responses to Compound 1. The diagnosis and response is coded as in FIG. 10 .
  • CNVs CLL common copy number variations
  • FIG. 13A is a graph depicting relative expression of TP53 (RNA levels) in patients with no loss or with a loss in TP53 copy number.
  • FIG. 13B is a graph depicting relative expression of YWHAE (RNA levels) in patients with no loss or with a loss in YWHAE copy number.
  • FIG. 13C is a graph depicting relative expression of STK11 (RNA levels) in patients with no loss or with a loss in STK11 copy number.
  • FIG. 14 is a graphical representation of the relationship between and responses to Compound 1 and alterations in various pathways. “Dual” in this figure refers to dual p53 and MAPK pathways. The diagnosis and response is coded as in FIG. 9 .
  • FIG. 15 is a graph showing the IC50 for Compound 1 inhibition of several cell clones.
  • FIG. 16 is a graph showing the PTEN RNA expression level in DMSO control treated cells or cells resistant to Compound 1.
  • FPKM refers to fragments per kilobase of exon per million fragments mapped.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • agonist refers to a compound or agent having the ability to initiate or enhance a biological function of a target protein or polypeptide, such as increasing the activity or expression of the target protein or polypeptide. Accordingly, the term “agonist” is defined in the context of the biological role of the target protein or polypeptide. While some agonists herein specifically interact with (e.g., bind to) the target, compounds and/or agents that initiate or enhance a biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
  • antagonists are used interchangeably, and they refer to a compound or agent having the ability to reduce or inhibit a biological function of a target protein or polypeptide, such as by reducing or inhibiting the activity or expression of the target protein or polypeptide. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein or polypeptide. An inhibitor need not completely abrogate the biological function of a target protein or polypeptide, and in some embodiments reduces the activity by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99%.
  • While some antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway of which the target protein or polypeptide are also specifically included within this definition.
  • Non-limiting examples of biological activity inhibited by an antagonist include those associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.
  • the term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below.
  • the therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • the specific dose will vary depending on, for example, the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • a daily dosage can be achieved by a single administration of the targeted dosage amount or multiple administrations of smaller dosage amount(s).
  • a 150 mg daily dosage can be achieved by a single administration of 150 mg of the therapeutic agent per day, two administrations of 75 mg of the therapeutic agent per day, or three administrations of 50 mg of the therapeutic agent per day, or the like.
  • treatment As used herein, the terms “treatment”, “treating”, “palliating” and “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder.
  • the terms “prevention” and “preventing” are used herein to refer to an approach for obtaining beneficial or desired results including, but not limited, to prophylactic benefit.
  • the pharmaceutical compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a method of treating when applied to, for example, cancer refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in an animal, or to alleviate the symptoms of a cancer.
  • a method of treating does not necessarily mean that the cancer cells or other disorder will, in fact, be eliminated, that the number of cells or disorder will, in fact, be reduced, or that the symptoms of a cancer or other disorder will, in fact, be alleviated.
  • a method of treating cancer will be performed even with a low likelihood of success, but which, given the medical history and estimated survival expectancy of an animal, is nevertheless deemed an overall beneficial course of action.
  • terapéuticaally effective agent means a composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the “aggressiveness” of a tumor or cancer refers to the rate at which the tumor is growing. Thus, a tumor is more aggressive than another tumor or cancer if it is proliferating at a higher rate.
  • Other determinants can be used to measure the level of aggressiveness of a tumor or cancer, for example, based on the appearance of tumor or cancer cells under a microscope to determine the extent to which tumors are differentiated. A well-differentiated tumor tends to be more aggressive than a poorly-differentiated tumor or cancer.
  • selective inhibition or “selectively inhibit” as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.
  • a compound that selectively inhibits one isoform of PI3K over another isoform of PI3K has an activity of at least greater than about 1 ⁇ against a first isoform relative to the compound's activity against the second isoform (e.g., at least about 2 ⁇ , 3 ⁇ , 5 ⁇ , 10 ⁇ , 20 ⁇ , 50 ⁇ , 100 ⁇ , 200 ⁇ , 500 ⁇ , or 1000 ⁇ ).
  • these terms refer to (1) a compound described herein that selectively inhibits the gamma isoform over the alpha, beta, or delta isoform; or (2) a compound described herein that selectively inhibits the delta isoform over the alpha or beta isoform.
  • the ratio of selectivity can be greater than a factor of about 1, greater than a factor of about 2, greater than a factor of about 3, greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 50, greater than a factor of about 100, greater than a factor of about 200, greater than a factor of about 400, greater than a factor of about 600, greater than a factor of about 800, greater than a factor of about 1000, greater than a factor of about 1500, greater than a factor of about 2000, greater than a factor of about 5000, greater than a factor of about 10,000, or greater than a factor of about 20,000, where selectivity can be measured by IC 50 .
  • the IC 50 can be measured by in vitro or in vivo assays.
  • the PI3K gamma isoform IC 50 activity of a compound provided herein can be less than about 1000 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM.
  • the PI3K delta isoform IC 50 activity of a compound provided herein can be less than about 1000 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM.
  • Subject or “patient” to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys.
  • humans e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)
  • primates e.g.,
  • in vivo refers to an event that takes place in a subject's body.
  • in vitro refers to an event that takes places outside of a subject's body.
  • an in vitro assay encompasses any assay conducted outside of a subject.
  • In vitro assays encompass cell-based assays in which cells, alive or dead, are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • Combination therapy refers to the use of more than one compound or agent to treat a particular disorder or condition.
  • a PI3K inhibitor e.g., Compound 1
  • at least one additional therapeutic agent e.g. a Bcl-2 inhibitor.
  • additional therapeutic agent e.g., the BLC-2 inhibitor
  • the PI3K inhibitor e.g., Compound 1
  • each therapeutic agent will be administered at a dose and/or on a time schedule determined for that particular agent.
  • the other therapeutic agent e.g., the Bcl-2 inhibitor
  • the PI3K inhibitor e.g., Compound 1
  • Higher combinations, e.g., triple therapy, are also contemplated herein.
  • co-administration of and “co-administering” and their grammatical equivalents, as used herein, encompass administration of two or more agents to subject so that both agents and/or their metabolites are present in the subject at the same or substantially the same time.
  • co-administration of a PI3K inhibitor with an additional anti-cancer agent both components referred to hereinafter as the “two active agents” refer to any administration of the two active agents, either separately or together, where the two active agents are administered as part of an appropriate dose regimen designed to obtain the benefit of the combination therapy.
  • the two active agents can be administered either as part of the same pharmaceutical composition or in separate pharmaceutical compositions.
  • the additional agent can be administered prior to, at the same time as, or subsequent to administration of the PI3K inhibitor, or in some combination thereof.
  • the additional agent can be administered prior to, at the same time as, or subsequent to, each administration of the PI3K inhibitor, or some combination thereof, or at different intervals in relation to the PI3K inhibitor treatment, or in a single dose prior to, at any time during, or subsequent to the course of treatment with the PI3K inhibitor.
  • a first agent can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), essentially concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent.
  • a “monotherapy” refers to the use of an agent individually (e.g., as a single compound or agent), e.g., without a second active agent to treat the same indication, e.g., cancer.
  • the term monotherapy includes the use of either the PI3K inhibitor or the second agent individually to treat the cancer.
  • synergy or “synergistic” encompasses a more than additive effect of a combination of two or more agents compared to their individual effects.
  • synergy or synergistic effect refers to an advantageous effect of using two or more agents in combination, e.g., in a pharmaceutical composition, or in a method of treatment.
  • one or more advantageous effects is achieved by using a PI3K inhibitor in combination with a second therapeutic agent (e.g., one or Bcl-2 inhibitors) as described herein.
  • the synergistic effect is that a lower dosage of one or both of the agents is needed to achieve an effect.
  • the combination can provide a selected effect, e.g., a therapeutic effect, when at least one of the agents is administered at a lower dosage than the dose of that agent that would be required to achieve the same therapeutic effect when the agent is administered as a monotherapy.
  • a PI3K inhibitor e.g., Compound 1
  • a second agent as described herein e.g., a Bcl-2 inhibitor as described herein
  • the combination of a PI3K inhibitor (e.g., Compound 1) and the Bcl-2 inhibitor allows the Bcl-2 inhibitor to be administered at a lower dosage than would be required to achieve the same therapeutic effect if the Bcl-2 inhibitor were administered as a monotherapy.
  • the synergistic effect is a reduction, prevention, delay, or decrease in the occurrence or the likelihood of occurrence of one or more side effects, toxicity, resistance, that would otherwise be associated with administration of at least one of the agents.
  • the synergistic effect is a reduction in resistance (e.g., a decrease in a measure of resistance or a decreased likelihood of developing resistance), or a delay in the development of resistance, to at least one of the agents.
  • the synergistic effect is a reduction in MRD.
  • the combination of a PI3K inhibitor (e.g. a PI3K inhibitor described herein) and a second agent (e.g., a Bcl-2 inhibitor) is effective to reduce the MRD in the subject, e.g., below a level previously measured in the subject (e.g., the level measured before the combination was administered).
  • the combination of a PI3K inhibitor and a second agent is effective to reduce the MRD in the subject below the level observed during or after treatment with a monotherapy, e.g., a monotherapy comprising either the PI3K inhibitor or the second agent (e.g., the Bcl-2 inhibitor).
  • a monotherapy e.g., a monotherapy comprising either the PI3K inhibitor or the second agent (e.g., the Bcl-2 inhibitor).
  • the MRD is decreased below the level observed during treatment with a monotherapy comprising the PI3K inhibitor.
  • the MRD is decreased below the level observed during treatment with a monotherapy comprising the second agent (e.g., the Bcl-2 inhibitor).
  • the combination is effective to reduce the MRD below a preselected cutoff value (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells).
  • a preselected cutoff value e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells.
  • the preselected cutoff value is 1 malignant cell in 1000 or 10,000 normal cells.
  • a synergistic effect refers to the combination of a PI3K inhibitor (e.g., Compound 1, or a pharmaceutically acceptable form thereof), and a second therapeutic agent (e.g., one or more the Bcl-2 inhibitor(s), or a pharmaceutically acceptable forms thereof, as described herein), results in a therapeutic effect greater than the additive effect of the PI3K inhibitor and the second agent.
  • a PI3K inhibitor e.g., Compound 1, or a pharmaceutically acceptable form thereof
  • a second therapeutic agent e.g., one or more the Bcl-2 inhibitor(s), or a pharmaceutically acceptable forms thereof, as described herein
  • a synergistic effect means that combination index value is less than a selected value, e.g., for a given effect, e.g., at a selected percentage (e.g., 50%) inhibition or growth inhibition, e.g., as described herein in the Examples.
  • the selected value is 1.
  • the selected value is 0.7.
  • the selected value is 0.5.
  • a synergistic effect means that the synergy score is 1 or more. In certain embodiments, the synergy score is greater than 1. In certain embodiments, the synergy score is 3 or more. In certain embodiments, the synergy score is 10 or more.
  • Combination index is a score of the potency shifting. Chou et al., Adv Enzyme Regul 1984; 22: 27-55 and in U.S. Patent Publication No. 2013/0295102, the contents of which are incorporated herein by reference.
  • a CI value of greater than 1 indicates antagonistic effect; a CI value of 1.0 is indicative of an additive effect; and a CI value of less than 1 is indicative of a synergistic effect resulting from the combination.
  • the CI value can be determined at various percentages of inhibition or growth inhibition.
  • the CI can be thought of as an estimate of the fraction of the original (monotherapy) doses of each of two drugs would be needed in combination relative to the single agent doses required to achieve a chosen effect level.
  • the combination index has a value of 0.1
  • only about one tenth of the total fractional amounts of the individual agents are needed for the combination to reach the same chosen effect level.
  • the doses of the single agents need not be reduced by the same fractional value so long as the sum of their fractional values adds up to the combination index; thus, in this example, a dose of approximately 8 mg/kg of drug A and 4 mg/kg of drug B would also achieve the chosen effect (this is 0.08 times the original dose of drug A and 0.02 times the original dose of drug B; the sum of the fractional amounts (0.08+0.02) is equal to the combination index of 0.1.)
  • synergy score is a measure of the combination effects in excess of Loewe additivity.
  • synergy score is a scalar measure to characterize the strength of synergistic interaction.
  • the Synergy score can be calculated as:
  • the fractional inhibition for each component agent and combination point in the matrix is calculated relative to the median of all vehicle-treated control wells.
  • the example Synergy Score equation integrates the experimentally-observed activity volume at each point in the matrix in excess of a model surface numerically derived from the activity of the component agents using the Loewe model for additivity. Additional terms in the Synergy Score equation (above) are used to normalize for various dilution factors used for individual agents and to allow for comparison of synergy scores across an entire experiment.
  • the inclusion of positive inhibition gating or an I data multiplier removes noise near the zero effect level, and biases results for synergistic interactions at that occur at high activity levels.
  • a synergy score can be calculated based on a curve fitting approach where the curvature of the synergy score is extrapolated by introducing a median value and origin value (e.g., a dose zero value).
  • the synergy score measure can be used for the self-cross analysis. Synergy scores of self-crosses are expected to be additive by definition and, therefore, maintain a synergy score of zero. However, while some self-cross synergy scores are near zero, many are greater suggesting that experimental noise or non-optimal curve fitting of the single agent dose responses are contributing to the slight perturbations in the score. This strategy is cell line-centric, focusing on self-cross behavior in each cell line versus a global review of cell line panel activity. Combinations where the synergy score is greater than the mean self-cross plus two standard deviations or three standard deviations can be considered candidate synergies at 95% and 99% confidence levels, respectively. Additivity should maintain a synergy score of zero, and synergy score of two or three standard deviations indicate synergism at statistically significant levels of 95% and 99%.
  • Loewe Volume (Loewe Vol) is used to assess the overall magnitude of the combination interaction in excess of the Loewe additivity model. Loewe Volume is particularly useful when distinguishing synergistic increases in a phenotypic activity (positive Loewe Volume) versus synergistic antagonisms (negative Loewe Volume). When antagonisms are observed, the Loewe Volume should be assessed to examine if there is any correlation between antagonism and a particular drug target-activity or cellular genotype. This model defines additivity as a non-synergistic combination interaction where the combination dose matrix surface should be indistinguishable from either drug crossed with itself. The calculation for Loewe additivity is:
  • X I and Y I are the single agent effective concentrations for the observed combination effect I.
  • X I and Y I are the single agent effective concentrations for the observed combination effect I.
  • a combination of 0.5 ⁇ M of A and 0.5 ⁇ M of B should also inhibit by 50%.
  • a daily dosage can be achieved by a single administration of the targeted dosage amount or multiple administrations of smaller dosage amount(s).
  • a 150 mg daily dosage can be achieved by a single administration of 150 mg of the therapeutic agent per day, two administrations of 75 mg of the therapeutic agent per day, or three administrations of 50 mg of the therapeutic agent per day, or the like.
  • anti-cancer effect refers to the effect a therapeutic agent has on cancer, e.g., a decrease in growth, viability, or both of a cancer cell.
  • the IC 50 of cancer cells can be used as a measure the anti-cancer effect.
  • IC 50 refers to a measure of the effectiveness of a therapeutic agent in inhibiting cancer cells by 50%.
  • tumor refers to any neoplastic cell growth and proliferation, whether malignant or benign, and any pre-cancerous and cancerous cells and tissues.
  • neoplastic refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth.
  • neoplastic cells include malignant and benign cells having dysregulated or unregulated cell growth.
  • cancer includes, but is not limited to, solid tumors and blood born tumors.
  • cancer refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus.
  • Hematopoietic origin refers to involving cells generated during hematopoiesis, a process by which cellular elements of blood, such as lymphocytes, leukocytes, platelets, erythrocytes and natural killer cells are generated. Cancers of hematopoietic origin includes lymphoma and leukemia.
  • Resistant or refractive refers to when a cancer that has a reduced responsiveness to a treatment, e.g., up to the point where the cancer does not respond to treatment.
  • the cancer can be resistant at the beginning of treatment, or it may become resistant during treatment.
  • the cancer subject may have one or more mutations that cause it to become resistant to the treatment, or the subject may have developed such mutations during treatment.
  • the term “refractory” can refer to a cancer for which treatment (e.g. chemotherapy drugs, biological agents, and/or radiation therapy) has proven to be ineffective.
  • a refractory cancer tumor may shrink, but not to the point where the treatment is determined to be effective. Typically however, the tumor stays the same size as it was before treatment (stable disease), or it grows (progressive disease).
  • “Directly acquiring” means performing a process (e.g., performing a test) to obtain the value or information of the alteration or biomarker.
  • “Indirectly acquiring” refers to receiving the value or information of the alteration or biomarker from another party or source (e.g., a diagnostic provider, a third party clinician or health professional).
  • “Alteration” of a gene or gene product refers to the presence of a mutation (e.g., one or more mutations) within a gene or gene product, which affects the structure, amount or activity of the gene or gene product, as compared to a reference gene or gene product, e.g., a normal or wild-type gene or gene product, or a responder gene or gene product (e.g., a gene or gene product in a responder subject (e.g., a subject in complete or partial cancer remission)).
  • a mutation e.g., one or more mutations
  • a responder gene or gene product e.g., a gene or gene product in a responder subject (e.g., a subject in complete or partial cancer remission)
  • the alteration can be in amount, structure, and/or activity in a cancer tissue or cancer cell, as compared to its amount, structure, and/or activity, in a reference tissue or cell (e.g., a normal or healthy tissue or cell, or a responder tissue or cell (e.g., a tissue or cell from a subject in complete or partial cancer remission)).
  • a reference tissue or cell e.g., a normal or healthy tissue or cell, or a responder tissue or cell (e.g., a tissue or cell from a subject in complete or partial cancer remission)
  • the alteration can be associated with, or be indicative of, a disease state, such as cancer (e.g., a hematologic malignancy as described herein, e.g., CLL).
  • an alteration which is associated with cancer, or is predictive of responsiveness or non-responsiveness to an anti-cancer therapeutic can have an altered nucleotide sequence (e.g., a mutation), amino acid sequence, chromosomal translocation, intra-chromosomal inversion, copy number, expression level, protein level, protein activity, or methylation status, in a cancer tissue or cancer cell, as compared to a reference tissue or cell.
  • Exemplary mutations include, but are not limited to, point mutations (e.g., silent, missense, or nonsense), deletions, insertions, inversions, linking mutations, duplications, copy number changes, translocations, inter- and intra-chromosomal rearrangements. Mutations can be present in the coding or non-coding region of the gene (e.g., one or more exons, the 5′- and/or 3′-UTR).
  • the alteration(s) are associated (or not associated) with a phenotype, e.g., a cancerous phenotype (e.g., one or more of cancer risk; cancer progression; responsiveness to a cancer treatment (e.g., complete or partial remission); or decreased responsiveness or non-responsiveness to a cancer treatment (e.g., progressive or stable disease, or resistance, e.g., acquired resistance) to a cancer treatment).
  • the alteration is associated with, or is, a prognosis-positive predictor or a prognosis-negative predictor (also referred to herein as a “prognosis-positive alteration” or a “prognosis-negative alteration”).
  • the alteration is associated with, or is, a progression-positive predictor or a progression-negative predictor (also referred to herein as a “progression-positive alteration” or a “progression-negative alteration”).
  • prognosis-positive predictor refers to any alteration that indicates increased responsiveness (e.g., increased sensitivity) to a PI3K inhibitor.
  • the prognosis-positive predictor can be evaluated relative to a reference value, e.g., a normal or wild-type gene or gene product, or a responder gene or gene product (e.g., a gene or gene product in a responder subject (e.g., a subject in complete or partial cancer remission)).
  • Subjects in complete or partial cancer remission e.g., CR or PR subjects as described herein
  • prognosis-negative predictor refers to any alteration that indicates decreased responsiveness (e.g., sensitivity) to a PI3K inhibitor.
  • the prognosis-negative predictor can be evaluated relative to a reference value, e.g., a reference value disclosed herein.
  • Subjects with progressive disease or stable disease e.g., PD or SD subjects as described herein
  • progression-positive predictor refers to any alteration that indicates increased progression or increased likelihood of cancer progression.
  • the progression-positive predictor can be evaluated relative to a reference value, e.g., a reference value disclosed herein.
  • Subjects with progressive disease or stable disease e.g., PD or SD subjects as described herein
  • This term can include a subject who has resistance (e.g., has developed or acquired resistance) to a PI3K inhibitor.
  • progression-negative predictor refers to any alteration that indicates decreased progression or decreased likelihood of cancer progression.
  • the progression-negative predictor can be evaluated relative to a reference value, e.g., a reference value disclosed herein.
  • Subjects in complete or partial cancer remission e.g., CR or PR subjects as described herein can have one or more progression-negative alterations.
  • a “biomarker” or “marker” is a substance, e.g., a gene or gene product (e.g., mRNA or protein) which can be altered (e.g., having an alteration described herein), wherein said alteration is associated with, or is indicative of, a disease state, e.g., a cancer (e.g., a hematological malignancy described herein, e.g., CLL).
  • a disease state e.g., a cancer (e.g., a hematological malignancy described herein, e.g., CLL).
  • the alteration can be in amount, structure, and/or activity of the substance (e.g., gene or gene product) in a cancer tissue or cancer cell, as compared to its amount, structure, and/or activity, in a reference sample, e.g., a normal or wild-type gene or gene product, or a responder gene or gene product (e.g., a gene or gene product in a responder subject (e.g., a subject in complete or partial cancer remission).
  • a reference sample e.g., a normal or wild-type gene or gene product, or a responder gene or gene product (e.g., a gene or gene product in a responder subject (e.g., a subject in complete or partial cancer remission).
  • a biomarker described herein which is associated with cancer or predictive of responsiveness to anti-cancer therapeutics can have an altered nucleotide sequence, amino acid sequence, chromosomal translocation, intra-chromosomal inversion, copy number, expression level, protein level, protein activity, or methylation status, in a cancer tissue or cancer cell as compared to a normal, healthy tissue or cell.
  • a “biomarker” includes a molecule whose structure is altered, e.g., mutated (contains an mutation), e.g., differs from the wild type sequence at the nucleotide or amino acid level, e.g., by substitution, deletion, or insertion, when present in a tissue or cell associated with a disease state, such as cancer.
  • a biomarker can be evaluated individually, or in combinations with one or more other biomarkers.
  • prognosis-positive biomarker refers to any biomarker that indicates increased responsiveness (e.g., increased sensitivity) to a PI3K inhibitor.
  • the prognosis-positive biomarker can be evaluated relative to a reference value, e.g., a normal or wild-type gene or gene product, or a responder gene or gene product (e.g., a gene or gene product in a responder subject (e.g., a subject in complete or partial cancer remission)).
  • Subjects in complete or partial cancer remission e.g., CR or PR subjects as described herein
  • prognosis-negative biomarker refers to any biomarker that indicates decreased responsiveness (e.g., sensitivity) to a PI3K inhibitor.
  • the prognosis-negative biomarker can be evaluated relative to a reference value, e.g., a reference value disclosed herein.
  • Subjects with progressive disease or stable disease e.g., PD or SD subjects as described herein
  • progression-positive biomarker refers to any biomarker that indicates increased progression or increased likelihood of cancer progression.
  • the progression-positive biomarker can be evaluated relative to a reference value, e.g., a reference value disclosed herein.
  • Subjects with progressive disease or stable disease e.g., PD or SD subjects as described herein
  • This term can include a subject who has resistance (e.g., has developed or acquired resistance) to a PI3K inhibitor.
  • progression-negative biomarker refers to any biomarker that indicates decreased progression or decreased likelihood of cancer progression.
  • the progression-negative biomarker can be evaluated relative to a reference value, e.g., a reference value disclosed herein.
  • Subjects in complete or partial cancer remission e.g., CR or PR subjects as described herein can have one or more progression-negative biomarkers.
  • prognostic biomarker may be used as a diagnostic biomarker or a predictive biomarker, and terms such as ‘prognosis-positive’, ‘prognosis-negative’, ‘progression-positive’ and progression-negative′ and the like may refer to biomarkers used in methods involving prediction or diagnosis.
  • Codon number loss refers to the loss of one or more copies of a DNA sequence from a genome.
  • the DNA sequence comprises a gene.
  • the DNA sequence comprises a portion of a gene, e.g., such that loss of the portion reduces or abrogates the gene function.
  • copy number loss is a result of a deletion, chromosome loss, or chromosome breakage event.
  • Responsiveness to “respond” to treatment, and other forms of this term, as used herein, refer to the reaction of a subject to treatment with a therapeutic, e.g., a PI3K inhibitor, alone or in combination, e.g., monotherapy or combination therapy.
  • a response to a PI3K inhibitor is determined.
  • Responsiveness to a therapy e.g., treatment with a PI3K inhibitor alone or in combination, can be evaluated by using any of the alterations/biomarkers disclosed herein and/or comparing a subject's response to the therapy using one or more clinical criteria, such as IWCLL 2008 (for CLL) described in, e.g., Hallek, M. et al.
  • a subject having CLL can be determined to be in complete remission (CR) or partial remission (PR).
  • CR complete remission
  • PR partial remission
  • a subject is considered to be in CR if at least all of the following criteria as assessed after completion of therapy are met: (i) Peripheral blood lymphocytes (evaluated by blood and different count) below 4 ⁇ 10 9 /L (4000 ⁇ L); (ii) no hepatomegaly or splenomegaly by physical examination; (iii) absence of constitutional symptoms; and (iv) blood counts (e.g., neutrophils, platelets, hemoglobin) above the values set forth in Hallek, M. et al. supra at page 5451).
  • Partial remission (PR) for CLL is defined according to IWCLL 2008 as including one of: (i) a decrease in number of blood lymphocytes by 50% or more from the value before therapy; (ii) a reduction in lymphadenopathy, as detected by CT scan or palpation; or (iii) a reduction in pretreatment enlargement of spleen or liver by 50% or more, as detected by CT scan or palpation; and blood counts (e.g., neutrophils, platelets, hemoglobin) according to the values set forth in Hallek, M. et al. supra at page 5451).
  • blood counts e.g., neutrophils, platelets, hemoglobin
  • a subject having CLL is determined to have progressive disease (PD) or stable disease (SD).
  • PD progressive disease
  • SD stable disease
  • a subject is considered to be in PD during therapy or after therapy if at least one of the following criteria is met: (i) progression on lymphadenopathy; (ii) an increase in pretreatment enlargement of spleen or liver by 50% or more, or de novo appearance of hepatomegaly or splenomegaly; (iii) an increase in the number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per microliter; (iv) transformation to a more aggressive histology (e.g., Richter syndrome); or (v) occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL, as described in Hallek, M.
  • cytopenia neutropenia, anemia or thrombocytopenia
  • Stable disease (SD) for CLL is defined according to IWCLL 2008 as a patient who has not achieved CR or a PR, and who has not exhibited progressive disease, see Hallek, M. et al. supra at page 5452.
  • a subject with CLL responds to treatment with a PI3K inhibitor if at least one of the criteria for disease progression according to IWCLL is retarded or reduced, e.g., by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.
  • a subject responds to treatment with a PI3K inhibitor, if the subject experiences a life expectancy extension, e.g., extended by about 5%, 10%, 20%, 30%, 40%, 50% or more beyond the life expectancy predicted if no treatment is administered.
  • a subject responds to treatment with a PI3K inhibitor, if the subject has one or more of: an increased progression-free survival, overall survival or increased time to progression (TTP), e.g., as described in Hallek, M. et al. supra at page 5452.
  • a PI3K inhibitor e.g., as described in Hallek, M. et al. supra at page 5452.
  • a subject responds to treatment with a PI3K inhibitor if growth of a tumor in the subject is retarded about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.
  • a subject responds to treatment with a PI3K inhibitor, if a tumor in the subject shrinks by about 5%, 10%, 20%, 30%, 40%, 50% or more as determined by any appropriate measure, e.g., by mass or volume.
  • a subject responds to treatment with a PI3K inhibitor, if the subject experiences a life expectancy extended by about 5%, 10%, 20%, 30%, 40%, 50% or more beyond the life expectancy predicted if no treatment is administered.
  • a subject responds to treatment with a PI3K inhibitor, if the subject has an increased disease-free survival, overall survival or increased time to progression.
  • a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds.
  • a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds.
  • the pharmaceutically acceptable form is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
  • Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the pharmaceutically acceptable form is a solvate (e.g., a hydrate).
  • solvate refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • the solvate may be of a disclosed compound or a pharmaceutically acceptable salt thereof.
  • the solvent is water
  • the solvate is a “hydrate”.
  • Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term “compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.
  • the pharmaceutically acceptable form is a prodrug.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood).
  • a prodrug has improved physical and/or delivery properties over the parent compound.
  • Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent compound.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • a discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series , Vol. 14, Chp 1, pp 1-12 and in Bioreversible Carriers in Drug Design , ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
  • Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from the digestive tract, or it can enhance drug stability for long-term storage.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs examples include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • Other examples of prodrugs include compounds that comprise —NO, —NO 2 , —ONO, or —ONO 2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elsevier, New York, 1985).
  • a prodrug can comprise a pharmaceutically acceptable ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1 -C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl
  • a prodrug may be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl (C 1 -C 6 )alkoxycarbonyloxymethyl, N—(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from naturally occurring L-amino acids, P(
  • a prodrug may be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, benzyl, a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl-natural ⁇ -aminoacyl, —C(OH)C(O)OY 1 wherein Y 1 is H, (C 1 -C 6 )alkyl or benzyl, —C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkyl, amino(C 1 -C 4 )al
  • the pharmaceutically acceptable form is an isomer.
  • “Isomers” are different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • the term “isomer” includes any and all geometric isomers and stereoisomers.
  • “isomers” include geometric double bond cis- and trans-isomers, also termed E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(. ⁇ .)” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown may be designated (+) or ( ⁇ ) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • Enantiomeric purity refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which can potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)- and 20% (R)-, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%.
  • the enantiomeric purity of a compound may be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or the Pirkle alcohol, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.
  • the pharmaceutically acceptable form is a tautomer.
  • tautomer is a type of isomer that includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa).
  • Tautomerization includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.
  • Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order.
  • Tautomerizations i.e., the reaction providing a tautomeric pair
  • exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(a different) enamine tautomerizations.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, or the replacement or enrichment of a carbon by 13 C or 14 C at one or more atoms in the molecule are within the scope of this disclosure.
  • isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium.
  • isotopically labeled compounds having one or more carbon atoms replaced or enriched by 13 C. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 14 C.
  • the disclosure also embraces isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that may be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can allow for ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • provided herein are compounds that can also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. All isotopic variations of the compounds as disclosed herein, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • polymorph may be used herein to describe a crystalline material, e.g., a crystalline form.
  • polymorph as used herein are also meant to include all crystalline and amorphous forms of a compound or a salt thereof, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms of the compounds or a salt thereof, as well as mixtures thereof.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • a “phosphoinositide 3-kinase (PI3K) inhibitor” or “PI3K inhibitor” refers to an inhibitor of any PI3K.
  • PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3′-OH group on phosphatidylinositols or phosphoinositides.
  • the PI3K family includes kinases with distinct substrate specificities, expression patterns, and modes of regulation (see, e.g., Katso et al., 2001 , Annu. Rev. Cell Dev. Biol. 17, 615-675; Foster, F. M. et al., 2003 , J Cell Sci 116, 3037-3040).
  • the class I PI3Ks are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIPS, which engages downstream mediators such as those in the Akt/PDK1 pathway, mTOR, the Tec family kinases, and the Rho family GTPases.
  • the class II PI3Ks e.g., PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇
  • III PI3Ks e.g., Vps34
  • Specific exemplary PI3K inhibitors are disclosed herein.
  • the class I PI3Ks comprise a p110 catalytic subunit and a regulatory adapter subunit. See, e.g., Cantrell, D. A. (2001) Journal of Cell Science 114: 1439-1445.
  • Four isoforms of the p110 subunit including PI3K- ⁇ (alpha), PI3K- ⁇ (beta), PI3K- ⁇ (gamma), and PI3K- ⁇ (delta) isoforms
  • Class I PI3K ⁇ is involved, for example, in insulin signaling, and has been found to be mutated in solid tumors.
  • Class I PI3K- ⁇ is involved, for example, in platelet activation and insulin signaling.
  • Class I PI3K- ⁇ plays a role in mast cell activation, innate immune function, and immune cell trafficking (chemokines). Class I PI3K- ⁇ is involved, for example, in B-cell and T-cell activation and function and in Fc receptor signaling in mast cells.
  • the PI3K inhibitor is a class I PI3K inhibitor.
  • the PI3K inhibitor inhibits a PI3K- ⁇ (alpha), PI3K- ⁇ (beta), PI3K- ⁇ (gamma), or PI3K- ⁇ (delta) isoform, or a combination thereof.
  • Downstream mediators of PI3K signal transduction include Akt and mammalian target of rapamycin (mTOR).
  • Akt possesses a pleckstrin homology (PH) domain that binds PIPS, leading to Akt kinase activation.
  • PH pleckstrin homology
  • Akt phosphorylates many substrates and is a central downstream effector of PI3K for diverse cellular responses.
  • One important function of Akt is to augment the activity of mTOR, through phosphorylation of TSC2 and other mechanisms.
  • mTOR is a serine-threonine kinase related to the lipid kinases of the PI3K family.
  • B-cell lymphoma 2 (Bcl-2) is a family of proteins that regulates cell death, e.g., by controlling the regulation of mitochondrial membrane and the release of cytochrome c from mitochondria during apoptosis. Bcl-2 plays an important survival role for many cancers, and the overexpression of the Bcl-2 proteins has been associated with tumor initiation, progression, and resistance to certain anticancer therapies.
  • Bcl-2 Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, and a possible cause of schizophrenia and autoimmunity. It is also a cause of resistance to cancer treatments.
  • Over-expression of anti-apoptotic Bcl-2 members such as Bcl-2, Bcl-xL, and Mcl-1, occurs frequently in cancers, particularly hematological malignancies such as acute myelogenous leukemia (AML), resulting in defective apoptosis leading to enhanced cell survival and drug resistance.
  • AML acute myelogenous leukemia
  • ABT-263 a clinical derivative of ABT-737 is currently undergoing phase I and II clinical evaluation in various tumor types including leukemia.
  • this disclosure provides experiments indicating that treating a patient with a PI3K inhibitor induces an apoptotic cascade characterized by up-regulation of the pro-apoptotic factors BMF, BIK, Bcl2L11 (also called BIM), PMAIP1 (also called NOXA), BBC3 (also called PUMA), and HRK (see Example 2). These factors are upstream of, and negatively regulate, the anti-apoptotic factor Bcl-2.
  • Bcl-2 levels rise in some patients treated with a PI3K inhibitor (see Example 2). Taken together, these data indicate that elevated levels of Bcl-2 can prevent the pro-apoptotic factors from successfully initiating apoptosis.
  • a PI3K inhibitor can be administered to a patient (e.g., as a monotherapy) until rising Bcl-2 levels reduce its efficacy. At that point, a Bcl-2 inhibitor can be administered to counteract the resistance mechanism. In other embodiments, a PI3K inhibitor and a Bcl-2 inhibitor can be administered over the same period, so that Bcl-2 activity can be kept low, thereby preventing resistance from developing.
  • PI3K inhibitors and Bcl-2 inhibitor show synergistic efficacy indicates that administering both drugs at normal (e.g., monotherapy) levels produces greater efficacy than either agent alone.
  • PI3K inhibitors and Bcl-2 inhibitor show synergistic efficacy suggests that one can lower the dose, frequency, or dose and frequency of one or both of the inhibitors, and still maintain efficacy. Lowering the dose and/or frequency of administration can lower side effects.
  • compositions comprising a PI3K inhibitor, or a pharmaceutically acceptable form thereof, in combination with a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof.
  • the combination is in a therapeutically effective amount.
  • the combination is in a synergistically therapeutically effective amount.
  • the combination is synergistic.
  • the combination has a synergistic effect.
  • the combination has a synergistic anti-cancer effect.
  • the combination has a synergistic therapeutic effect.
  • Also provided herein are methods of treating (e.g., inhibiting, managing, or preventing) a cancer in a subject comprising administering to the subject a PI3K inhibitor, or a pharmaceutically acceptable form thereof, in combination with a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof.
  • the combination is synergistic.
  • the combination has a synergistic effect.
  • the combination has a synergistic anti-cancer effect.
  • the combination has a synergistic therapeutic effect.
  • the combination is administered in a therapeutically effective amount.
  • the combination is administered in a synergistically therapeutically effective amount.
  • compositions and methods provided herein are utilized where a monotherapy of one of the therapeutic agents is becoming less effective due to drug resistance or where the relatively high dosage of monotherapy lead to undesirable side effects.
  • PI3K inhibitors down-regulate Mcl-1, an event that plays an important role in transformed cell lethality. Balakrishnan et al. (ASH Annual Meeting). 2013; No. 4167. Furthermore, Mcl-1, as well as Bim, which is also regulated by the PI3K pathway, play important roles in determining ABT-737 sensitivity. Merino et al. Blood 2012 (119) 24; 5807-5816. In addition, PI3K activity can lead to inhibition of apoptosis and therefore antagonize the effects of Bcl-2 inhibitors.
  • PI3K inhibitors that can be used in the compositions and methods provided herein include, but are not limited to, those described in, e.g., WO 09/088990, WO 09/088086, WO 2011/008302, WO 2010/036380, WO 2010/006086, WO 09/114870, WO 05/113556, WO2014072937, WO2014071125; US 2009/0312310, and US 2011/0046165, the entirety of each incorporated herein by reference.
  • Additional PI3K inhibitors that can be used in the compositions and methods provided herein include, but are not limited to, AMG-319, GSK 2126458 (2,4-Difluoro-N- ⁇ 2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl ⁇ benzenesulfonamide), GSK 1059615 (5Z-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), GDC-0032 (4-[5,6-dihydro-2-[3-methyl-1-(1-methylethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-d][1,4]benzoxazepin-9-yl]- ⁇ , ⁇ -dimethyl-1H-Pyrazole-1-acetamide), GDC-0980 ((S)-1-(4-((2-(2-a
  • the PI3K inhibitor is Idelalisib (GS1101), CAL-130, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, PF-4691502, GDC-0980, GSK 2126458, PF-05212384, XL765, or XL147.
  • a PI3K inhibitor is a compound that inhibits one or more PI3K isoforms, e.g., alpha, beta, delta, or gamma isoform.
  • a PI3K inhibitor is a compound that inhibits one or more PI3K isoforms with an IC 50 of less than about 1000 nM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM.
  • the PI3K inhibitor is a compound that inhibits alpha, beta, delta and gamma isoforms. In another embodiment, the PI3K inhibitor is a compound that inhibits beta, delta, and gamma isoforms. In another embodiment, the PI3K inhibitor is a compound that inhibits the delta and gamma isoforms.
  • the PI3K inhibitor is a PI3K isoform selective inhibitor. In one embodiment, the PI3K inhibitor is a PI3K alpha selective inhibitor. In another embodiment, the PI3K inhibitor is a PI3K beta selective inhibitor.
  • the PI3K inhibitor is a PI3K delta selective inhibitor.
  • the PI3K delta selective inhibitor selectively inhibits PI3K delta isoform over PI3K gamma isoform.
  • the PI3K delta selective inhibitor has a gamma/delta selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000.
  • the PI3K delta selective inhibitor has a gamma/delta selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850. In one embodiment, the gamma/delta selectivity ratio is determined by dividing the inhibitor's IC 50 against PI3K gamma isoform by the inhibitor's IC 50 against PI3K delta isoform.
  • the PI3K inhibitor is a PI3K delta selective inhibitor.
  • the PI3K delta selective inhibitor selectively inhibits PI3K delta isoform over PI3K alpha isoform.
  • the PI3K delta selective inhibitor has an alpha/delta selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000.
  • the PI3K delta selective inhibitor has an alpha/delta selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850. In one embodiment, the alpha/delta selectivity ratio is determined by dividing the inhibitor's IC 50 against PI3K alpha isoform by the inhibitor's IC 50 against PI3K delta isoform.
  • the PI3K inhibitor is a PI3K delta selective inhibitor.
  • the PI3K delta selective inhibitor selectively inhibits PI3K delta isoform over PI3K beta isoform.
  • the PI3K delta selective inhibitor has a beta/delta selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000.
  • the PI3K delta selective inhibitor has a beta/delta selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850.
  • the beta/delta selectivity ratio is determined by dividing the inhibitor's IC 50 against PI3K beta isoform by the inhibitor's IC 50 against PI3K delta isoform.
  • the PI3K inhibitor is selective for both gamma and delta. In one embodiment, the PI3K gamma and delta selective inhibitor selectively inhibits PI3K gamma and delta isoforms over PI3K beta isoform.
  • the PI3K gamma and delta selective inhibitor has a beta/delta selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000 and a beta/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000.
  • the PI3K delta selective inhibitor has a beta/delta selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850 and a beta/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850.
  • the beta/delta selectivity ratio is determined by dividing the inhibitor's IC 50 against PI3K beta isoform by the inhibitor's IC 50 against PI3K delta isoform and the beta/gamma selectivity ratio is determined by dividing the inhibitor's IC 50 against PI3K beta isoform by the inhibitor's IC 50 against PI3K gamma isoform.
  • PI3K delta inhibitors that can be used in the compositions and methods provided herein include, but are not limited to, GSK-2269557 (2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole), GS-9820, GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG319, or TGR-1202 (((S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one)), or a mixture thereof.
  • the PI3K inhibitor is a PI3K inhibitor as described in WO 2005/113556, the entirety of which is incorporated herein by reference. In one embodiment, the PI3K inhibitor is Compound Nos. 113 or 107 as described in WO2005/113556.
  • the PI3K inhibitor is a PI3K inhibitor as described in WO2014/006572, the entirety of which is incorporated herein by reference. In one embodiment, the PI3K inhibitor is Compound Nos. A1, A2, B, B1, or B2 as described in WO2014/006572.
  • the PI3K inhibitor is a PI3K delta/gamma dual inhibitor.
  • the PI3K delta/gamma dual inhibitor has an IC 50 value against PI3K alpha that is at least 5 ⁇ , 10 ⁇ , 20 ⁇ , 50 ⁇ , 100 ⁇ , 200 ⁇ , 500 ⁇ , or 1000 ⁇ higher than its IC 50 values against delta and gamma.
  • the PI3K inhibitor is Compound 1A of the structure:
  • the PI3K inhibitor is Compound 1 of the structure:
  • Compound 1A has a chemical name of 3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one.
  • Compound 1 has a chemical name of (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one.
  • An exemplary method for synthesizing Compound 1A and Compound 1 has been previously described in U.S. Pat. No. 8,193,182, which is incorporated by reference in its entirety.
  • Compound 1 is a PI3K- ⁇ , - ⁇ inhibitor and can be used to treat cancers. See U.S. Pat. No. 8,193,182.
  • Compound 1 provided herein contains one chiral center, and can exist as a mixture of enantiomers, e.g., a racemic mixture.
  • This application encompasses the use of stereomerically pure forms of such a compound, as well as the use of mixtures of those forms.
  • mixtures comprising equal or unequal amounts of the enantiomers of Compound 1 provided herein may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S.
  • the PI3K inhibitor provided herein is a mixture of Compound 1 and its (R)-enantiomer. In one embodiment, the PI3K inhibitor provided herein is a racemic mixture of Compound 1 and its (R)-enantiomer. In other embodiments, the compound mixture has an (S)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more.
  • the compound mixture has an (S)-enantiomeric purity of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
  • the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more.
  • the compound mixture has an (R)-enantiomeric purity of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
  • Compound 1 also refers to any crystal form or polymorph of (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one.
  • a polymorph of Compound 1, or a pharmaceutically form thereof, disclosed herein is used. Exemplary polymorphs are disclosed in U.S. Patent Publication No. 2012/0184568, which is hereby incorporated by reference in its entirety.
  • the compound is Form A of Compound 1.
  • the compound is Form B of Compound 1.
  • the compound is Form C of Compound 1.
  • the compound is Form D of Compound 1.
  • the compound is Form E of Compound 1. In one embodiment, the compound is Form F of Compound 1. In one embodiment, the compound is Form G of Compound 1. In one embodiment, the compound is Form H of Compound 1. In one embodiment, the compound is Form I of Compound 1. In one embodiment, the compound is Form J of Compound 1. In one embodiment, the compound is a mixture of solid forms (e.g., polymorphs and/or amorphous forms) of Compound 1 disclosed herein.
  • any of the compounds disclosed herein can be in the form of pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, isotopically labeled derivatives, or mixtures thereof.
  • Bcl-2 inhibitors that can be used in the compositions and methods provided herein include, but are not limited to ABT-199, ABT-263, ABT-737, G3139 (genasense or oblimersen), GX15-070 (obatoclax mesylate), HA14-1, TW-37, sabutoclax, Gossypol (AT-101), antimycin A, and apogossypol.
  • Bcl-2 inhibitors that can be used in the compositions and methods provided herein include, but are not limited to, those described in, e.g., WO2006/009869, WO2007075387, WO2008024337, WO2008060569, or WO2013110890, the entirety of each incorporated herein by reference.
  • ABT-737 has the chemical name of (4-[4-[(4′-chloro[1,1′-biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide).
  • G3139 (genasense or oblimersen) is an 18-mer phosphorothioate oligodeoxyribonucleotide.
  • GX15-070 (obatoclax mesylate) has a chemical name of (Z)-2-(5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-4-methoxy-5H-pyrrol-2-yl)-1H-indole mesylate).
  • HA14-1 has a chemical name of ((R)-ethyl 2-amino-6-bromo-4-((R)-1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate.
  • TW-37 has the chemical name of [4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide).
  • Sabutoclax has the chemical name of ((1R)-[2,2′-Binaphthalene]-5,5′-dicarboxamide, 1,1′,6,6′,7,7′-hexahydroxy-3,3′-dimethyl-N5,N5′-bis[(2R)-2-phenylpropyl]).
  • Gossypol (AT-101) has the chemical name of 2,2′-bis-(Formyl-1,6,7-trihydroxy-5-isopropyl-3-methylnaphthalene).
  • S44563 has the chemical name (R)-3-((4′-chloro-[1,1′-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxamide.
  • Antimycin A has the chemical name of ((2 ⁇ R ⁇ ,3 ⁇ S ⁇ ,6 ⁇ S ⁇ ,7 ⁇ R ⁇ ,8 ⁇ R ⁇ )-3-[(3-formamido-2-hydroxybenzoyl)amino]-8-hexyl-2,6-dimethyl-4,9-dioxo-1,5-dioxonan-7-yl 3-methylbutanoate).
  • the Bcl-2 inhibitor is ABT-199.
  • ABT-199 has a chemical name of 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide, and is of the structure:
  • the Bcl-2 inhibitor is ABT-263.
  • ABT-263 has a chemical name of (R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide and is of the structure:
  • a pharmaceutical composition comprising a therapeutically effective amount of a PI3K delta selective inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof.
  • the PI3K delta selective inhibitor is GS1101 (CAL-101).
  • the Bcl-2 inhibitor is ABT-199, ABT-263, ABT-737, G3139 (genasense or oblimersen), GX15-070 (obatoclax mesylate), HA14-1, TW-37, sabutoclax, Gossypol (AT-101), antimycin A, apogossypol, or a mixture thereof.
  • the Bcl-2 inhibitor is ABT-199. In another embodiment, the Bcl-2 inhibitor is ABT-263. In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of GS1101, or a pharmaceutically acceptable form thereof, and ABT-199, or a pharmaceutically acceptable form thereof. In another embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of GS1101, or a pharmaceutically acceptable form thereof, and ABT-263, or a pharmaceutically acceptable form thereof.
  • the molar ratio of the PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, to a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about 30:1 to about 1:30, from about 20:1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5.
  • a Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the PI3K delta inhibitor is GS1101 and the Bcl-2 inhibitor is ABT-199
  • the molar ratio of the PI3K delta inhibitor to the Bcl-2 inhibitor is from about 10:1 to about 1:500, from about 1:1 to about 1:50, from about 1:2 to about 1:10, from about 1:3 to about 1:5, from about 1:3 to about 1:1, from about 1:2 to about 1:1, from about 5:1 to about 1:1, from about 2:1 to about 1:1, about 2:1, or about 1.5:1.
  • the PI3K delta inhibitor (e.g., GS1101) is administered at an amount to reach maximum plasma concentration at steady state (Cmaxss) at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, about 1400 ng/mL to about 2300 ng/mL, about 2000 ng/mL to about 2300 ng/mL, or about 2200 ng/mL; and
  • the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) is administered at an amount to reach Cmaxss at about 0.1 ⁇ g/mL to about 1000 ⁇ g/mL, about 0.1 ⁇ g/mL to about 500 ⁇ g/mL, about 0.1 ⁇ g/mL to about 250 ⁇ g/mL, about 1 ⁇ g/mL to about 100 ⁇ g/mL, about 1 ⁇ g/mL to about 50 ⁇ g/mL, about 1 ⁇ g/mL to about 25 ⁇ g/mL, about 1 ⁇ g/mL to about 20 ⁇ g/mL, about 1 ⁇ g/mL to about 10 ⁇ g/mL, about 4 ⁇ g/mL, or about 3 ⁇ g/mL.
  • the PI3K delta inhibitor (e.g., GS1101) is administered at an amount to reach maximum plasma concentration at steady state (Cmaxss) at less than about 5000 ng/mL, less than about 4000 ng/mL, less than about 3000 ng/mL, less than about 2000 ng/mL, less than about 1500 ng/mL, less than about 1000 ng/mL, less than about 500 ng/mL, less than about 100 ng/mL, less than about 50 ng/mL, less than about 25 ng/mL, less than about 10 ng/mL, or less than about 1 ng/mL.
  • Cmaxss maximum plasma concentration at steady state
  • the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) is administered at an amount to reach Cmaxss less than about 1000 ⁇ g/mL, less than about 500 ⁇ g/mL, less than about 100 ⁇ g/mL, less than about 50 ⁇ g/mL, less than about 10 ⁇ g/mL, less than about 5 ⁇ g/mL, less than about 4 ⁇ g/mL, less than about 3 ⁇ g/mL, less than about 2 ⁇ g/mL, less than about 1 ⁇ g/mL, less than about 0.5 ⁇ g/mL, or less than about 0.1 ⁇ g/mL.
  • Cmaxss less than about 1000 ⁇ g/mL, less than about 500 ⁇ g/mL, less than about 100 ⁇ g/mL, less than about 50 ⁇ g/mL, less than about 10 ⁇ g/mL, less than about 5 ⁇ g/mL, less than about 4 ⁇ g/mL, less than about
  • the PI3K delta inhibitor (e.g., GS1101) is administered at an amount to reach an area under the plasma concentration-time curve at steady-state (AUCss) at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 8000 ng/mL*hr, about 6500 ng/mL*hr to about 7500 ng/mL*hr, or about 7000 ng/mL*hr; and
  • the Bcl-2 inhibitor e.g., ABT-199 or ABT-263 is administered at an amount to reach an AUCss at about 0.1 ng/mL*hr to about 10000 ng/mL*hr, about 1 ng/mL*hr to about 10000 ng/mL*hr, or about 100 ng/mL*hr to about 5000 ng/mL*hr.
  • the PI3K delta inhibitor (e.g., GS1101) is administered at an amount to reach an area under the plasma concentration-time curve at steady-state (AUCss) at less than about 10000 ng/mL*hr, less than about 9500 ng/mL*hr, less than about 9000 ng/mL*hr, less than about 8500 ng/mL*hr, less than about 8000 ng/mL*hr, less than about 7000 ng/mL*hr, less than about 6000 ng/mL*hr, less than about 5000 ng/mL*hr, less than about 4000 ng/mL*hr, less than about 3000 ng/mL*hr, less than about 2000 ng/mL*hr, less than about 1000 ng/mL*hr, less than about 500 ng/mL*hr, less than about 100 ng/mL*hr, less than about 10 ng/mL*hr, or less
  • the composition comprises the PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 500 mg, from about 1 mg to about 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 400 mg, from about 200 mg to about 400 mg, from about 250 mg to about 350 mg, or about 300 mg.
  • the PI3K delta inhibitor e.g., GS1101
  • a pharmaceutically acceptable form thereof at an amount in the range of from about 0.1 mg to about 500 mg, from about 1 mg to about 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 400 mg, from about 200 mg to about 400 mg, from about 250 mg to about 350 mg, or about 300 mg.
  • the composition comprises the PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg.
  • the PI3K delta inhibitor e.g., GS1101
  • a pharmaceutically acceptable form thereof at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg.
  • the composition comprises the PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, at an amount of less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg.
  • the PI3K delta inhibitor e.g., GS1101
  • a pharmaceutical composition comprising a therapeutically effective amount of a PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof.
  • the Bcl-2 inhibitor is ABT-199, ABT-263, ABT-737, G3139 (genasense or oblimersen), GX15-070 (obatoclax mesylate), HA14-1, TW-37, sabutoclax, Gossypol (AT-101), antimycin A, apogossypol, or a mixture thereof.
  • the Bcl-2 inhibitor is ABT-199.
  • the Bcl-2 inhibitor is ABT-263.
  • the molar ratio of the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, to a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about 30:1 to about 1:30, from about 20:1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5.
  • a Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the PI3K delta/gamma dual inhibitor is Compound 1 and the Bcl-2 inhibitor is ABT-199, and the molar ratio of the PI3K delta/gamma dual inhibitor to the Bcl-2 inhibitor is from about 10:1 to about 1:100, from about 1:1 to about 1:20, from about 1:2 to about 1:5, from about 1:3.5 to about 1:4.5, or about 1:4.
  • the PI3K delta/gamma dual inhibitor is Compound 1 and the Bcl-2 inhibitor is ABT-263, and the molar ratio of the PI3K delta/gamma dual inhibitor to the Bcl-2 inhibitor is from about 10:1 to about 1:100, from about 1:1 to about 1:20, from about 1:2 to about 1:5, from about 1:3.5 to about 1:4.5, about 1:3, or about 1:4.
  • the PI3K delta/gamma dual inhibitor (e.g., Compound 1) is administered at an amount to reach maximum plasma concentration at steady state (Cmaxss) at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, about 1400 ng/mL to about 2000 ng/mL, about 1400 ng/mL to about 1500 ng/mL, or about 1487 ng/mL; and
  • the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) is administered at an amount to reach Cmaxss at about 0.1 ⁇ g/mL to about 1000 ⁇ g/mL, about 0.1 ⁇ g/mL to about 500 ⁇ g/mL, about 0.1 ⁇ g/mL to about 250 ⁇ g/mL, about 1 ⁇ g/mL to about 100 ⁇ g/mL, about 1 ⁇ g/mL to about 50 ⁇ g/mL, about 1 ⁇ g/mL to about 25 ⁇ g/mL, about 1 ⁇ g/mL to about 20 ⁇ g/mL, about 1 ⁇ g/mL to about 10 ⁇ g/mL, about 4 ⁇ g/mL, or about 3 ⁇ g/mL.
  • the PI3K delta/gamma dual inhibitor (e.g., Compound 1) is administered at an amount to reach maximum plasma concentration at steady state (Cmaxss) at less than about 5000 ng/mL, less than about 4000 ng/mL, less than about 3000 ng/mL, less than about 2000 ng/mL, less than about 1500 ng/mL, less than about 1000 ng/mL, less than about 500 ng/mL, less than about 100 ng/mL, less than about 50 ng/mL, less than about 25 ng/mL, less than about 10 ng/mL, or less than about 1 ng/mL.
  • Cmaxss maximum plasma concentration at steady state
  • the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) is administered at an amount to reach Cmaxss less than about 1000 ⁇ g/mL, less than about 500 ⁇ g/mL, less than about 100 ⁇ g/mL, less than about 50 ⁇ g/mL, less than about 10 ⁇ g/mL, less than about 5 ⁇ g/mL, less than about 4 ⁇ g/mL, less than about 3 ⁇ g/mL, less than about 2 ⁇ g/mL, less than about 1 ⁇ g/mL, less than about 0.5 ⁇ g/mL, or less than about 0.1 ⁇ g/mL.
  • Cmaxss less than about 1000 ⁇ g/mL, less than about 500 ⁇ g/mL, less than about 100 ⁇ g/mL, less than about 50 ⁇ g/mL, less than about 10 ⁇ g/mL, less than about 5 ⁇ g/mL, less than about 4 ⁇ g/mL, less than about
  • the PI3K delta/gamma dual inhibitor (e.g., Compound 1) is administered at an amount to reach an area under the plasma concentration-time curve at steady-state (AUCss) at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr to about 9000 ng/mL*hr, about 8000 ng/mL*hr to about 9000 ng/mL*hr, or about 8787 ng/mL*hr; and
  • the Bcl-2 inhibitor e.g., ABT-199 or ABT-263 is administered at an amount to reach an AUCss at about 0.1 ng/mL*hr to about 10000 ng/mL*hr, about 1 ng/mL*hr to about 10000 ng/mL*hr, or about 100 ng/mL*hr to about 5000 ng/mL*hr.
  • the PI3K delta/gamma dual inhibitor (e.g., Compound 1) is administered at an amount to reach an area under the plasma concentration-time curve at steady-state (AUCss) at less than about 10000 ng/mL*hr, less than about 9500 ng/mL*hr, less than about 9000 ng/mL*hr, less than about 8500 ng/mL*hr, less than about 8000 ng/mL*hr, less than about 7000 ng/mL*hr, less than about 6000 ng/mL*hr, less than about 5000 ng/mL*hr, less than about 4000 ng/mL*hr, less than about 3000 ng/mL*hr, less than about 2000 ng/mL*hr, less than about 1000 ng/mL*hr, less than about 500 ng/mL*hr, less than about 100 ng/mL*hr, less than about 10 ng/mL*h
  • the PI3K delta/gamma dual inhibitor (e.g., Compound 1) is administered at an amount that is decreased by about 1.5 fold to about 50 fold of the amount when administered alone and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) is administered at an amount that is decreased by about 1.1 fold to about 50 fold of the amount when administered alone.
  • the Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the PI3K delta/gamma dual inhibitor (e.g., Compound 1) is administered at an amount that is decreased by about 1.5 fold to about 50 fold, about 1.5 fold to about 25 fold, about 1.5 fold to about 20 fold, about 1.5 fold to about 15 fold, about 1.5 fold to about 10 fold, about 2 fold to about 10 fold, about 2 fold to about 8 fold, about 4 fold to about 6 fold, or about 5 fold of the amount when administered alone; and
  • the Bcl-2 inhibitor e.g., ABT-199 or ABT-263 is administered at an amount that is decreased by about 1.1 fold to about 50 fold, about 1.1 fold to about 40 fold, about 1.1 fold to about 30 fold, about 1.1 fold to about 25 fold, about 1.1 fold to about 20 fold, about 1.1 fold to about 15 fold, about 1.1 fold to about 10 fold of the amount when administered alone.
  • the composition comprises the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg.
  • the composition comprises the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, at an amount of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg.
  • composition comprising a Compound 1:
  • the combination is synergistic. In certain embodiments, the combination has a synergistic effect. In certain embodiments, the combination has a synergistic anti-cancer effect. In certain embodiments, the combination has a synergistic therapeutic effect. In certain embodiments, the combination is in a therapeutically effective amount. In certain embodiments, the combination is in a synergistically therapeutically effective amount.
  • the Bcl-2 inhibitor is ABT-199, ABT-263, ABT-737, G3139 (genasense or oblimersen), GX15-070 (obatoclax mesylate), HA14-1, TW-37, sabutoclax, Gossypol (AT-101), antimycin A, apogossypol, S44563, or a mixture thereof.
  • the Bcl-2 inhibitor is ABT-199.
  • the Bcl-2 inhibitor is ABT-263.
  • provided herein is a method of treating (e.g., inhibiting, managing, or preventing) a cancer in a subject comprising administering to the subject Compound 1:
  • the combination is synergistic. In certain embodiments, the combination has a synergistic effect. In certain embodiments, the combination has a synergistic anti-cancer effect. In certain embodiments, the combination has a synergistic therapeutic effect. In certain embodiments, the combination is in a therapeutically effective amount. In certain embodiments, the combination is in a synergistically therapeutically effective amount.
  • the Bcl-2 inhibitor is ABT-199, ABT-263, ABT-737, G3139 (genasense or oblimersen), GX15-070 (obatoclax mesylate), HA14-1, TW-37, sabutoclax, Gossypol (AT-101), antimycin A, apogossypol, S44563, or a mixture thereof.
  • the Bcl-2 inhibitor is ABT-199.
  • the Bcl-2 inhibitor is ABT-263.
  • Compound 1 is used in combination with a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, at certain molar ratios.
  • a Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • a pharmaceutical composition comprising Compound 1:
  • a Bcl-2 inhibitor or a pharmaceutically acceptable form thereof, wherein the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, is in the range of from about 1000:1 to about 1:1000.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to a Bcl-2 inhibitor is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about 30:1 to about 1:30, from about 20:1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5.
  • a Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to a Bcl-2 inhibitor is in the range of from about 1:3 to about 1:7 or from about 1:5 to about 1:6.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to a Bcl-2 inhibitor is from about 10:1 to about 1:100, from about 1:1 to about 1:20, from about 1:2 to about 1:5, from about 1:3.5 to about 1:4.5, about 1:3, or about 1:4.
  • the molar ratio of Compound 1, or a pharmaceutically acceptable form thereof, to a Bcl-2 inhibitor is about 1:3, about 1:4, about 1:5, about 1:6, or about 1:7.
  • the weight ratio of Compound 1, or a pharmaceutically acceptable form thereof, to ABT-199, or a pharmaceutically acceptable form thereof is in the range of from about 7.5-37.5 of Compound 1 to from 40-200 of ABT-199. In one embodiment, the weight ratio is in the range of from about 1:1.1 to about 1:27. In one embodiment, the weight ratio is in the range of from about 1:2.2 to about 1:13.5. In one embodiment, the weight ratio is in the range of from about 1:3.3 to about 1:9.
  • the weight ratio of Compound 1, or a pharmaceutically acceptable form thereof, to ABT-263, or a pharmaceutically acceptable form thereof is in the range of from about 7.5-37.5 of Compound 1 to from 32.5-162.5 of ABT-263. In one embodiment, the weight ratio is in the range of from about 1.2:1 to about 1:21. In one embodiment, the weight ratio is in the range of from about 1:1.7 to about 1:10.5. In one embodiment, the weight ratio is in the range of from about 1:2.5 to about 1:7.
  • Compound 1 is administered at an amount to reach maximum plasma concentration at steady state (Cmaxss) at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, about 1400 ng/mL to about 2000 ng/mL, about 1400 ng/mL to about 1500 ng/mL, or about 1487 ng/mL; and
  • ABT-199 or ABT-263 is administered at an amount to reach Cmaxss at about 0.1 ⁇ g/mL to about 1000 ⁇ g/mL, about 0.1 ⁇ g/mL to about 500 ⁇ g/mL, about 0.1 ⁇ g/mL to about 250 ⁇ g/mL, about 1 ⁇ g/mL to about 100 ⁇ g/mL, about 1 ⁇ g/mL to about 50 ⁇ g/mL, about 1 ⁇ g/mL to about 25 ⁇ g/mL, about 1 ⁇ g/mL to about 20 ⁇ g/mL, about 1 ⁇ g/mL to about 10 ⁇ g/mL, about 4 ⁇ g/mL, or about 3 ⁇ g/mL.
  • Compound 1 is administered at an amount to reach an area under the plasma concentration-time curve at steady-state (AUCss) at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr to about 9000 ng/mL*hr, about 8000 ng/mL*hr to about 9000 ng/mL*hr, or about 8787 ng/mL*hr; and
  • ABT-199 or ABT-263 is administered at an amount to reach an AUCss at about 0.1 ng/mL*hr to about 10000 ng/mL*hr, about 1 ng/mL*hr to about 10000 ng/mL*hr, or about 100 ng/mL*hr to about 5000 ng/mL*hr.
  • the composition comprises Compound 1, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, at certain amounts.
  • the composition comprises Compound 1, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.01 mg to about 75 mg and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, at an amount of in the range of from about 0.01 mg to about 1100 mg.
  • the composition comprises Compound 1, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg.
  • the composition comprises Compound 1, or a pharmaceutically acceptable form thereof, at an amount of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg.
  • the composition comprises the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 800 mg, from about 0.1 mg to about 750 mg, from about 0.1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 400 mg, from about 10 mg to about 300 mg, from about 50 mg to about 250 mg, from about 50 mg to about 200 mg, from about 50 mg to about 150 mg, from about 50 mg to about 100 mg, from about 50 mg to about 90 mg, or from about 50 mg to about 80 mg.
  • Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • a pharmaceutically acceptable form thereof at an amount in the range of from about 0.1 mg to about 800 mg, from about 0.1 mg to about 750 mg, from about 0.1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 400 mg, from about 10 mg to about 300 mg, from about 50 mg
  • the composition comprises the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, at an amount of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg.
  • Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg.
  • the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 400 mg.
  • the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 325 mg.
  • the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 250 mg. In one embodiment, the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 150 mg. In one embodiment, the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 100 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, or about 5 mg. In one embodiment, the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 85 mg. In one embodiment, the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 75 mg. In one embodiment, the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 50 mg.
  • the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg.
  • the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of about 325 mg.
  • the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of about 250 mg.
  • the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of about 150 mg. In one embodiment, the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of about 100 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, or about 5 mg. In one embodiment, the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of about 85 mg. In one embodiment, the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of about 75 mg. In one embodiment, the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of about 50 mg.
  • the PI3K inhibitor e.g., Compound 1 or GS1101
  • the Bcl-2 inhibitor, or pharmaceutically acceptable form thereof are in a single dosage form.
  • the PI3K inhibitor, or pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor, or pharmaceutically acceptable form thereof are in separate dosage forms.
  • the PI3K inhibitor e.g., Compound 1
  • the Bcl-2 inhibitor or pharmaceutically acceptable form thereof
  • the compositions and methods provided herein comprise or use at least one more therapeutically active ingredient, e.g., a third agent, e.g., an anti-CD20 antibody.
  • a method described herein further comprises administration of an anti-CD20 antibody.
  • a pharmaceutical composition described herein further comprises an anti-CD20 antibody.
  • the anti-CD20 antibody is included in the same dosage form as the PI3K inhibitor and/or second agent.
  • the anti-CD20 antibody is in a separate dosage form as the PI3K inhibitor and/or second agent.
  • the anti-CD20 antibody can be administered before, after, or concurrent with the PI3K inhibitor and/or second agent.
  • the anti-CD20 antibody is selected from one or more of rituximab, ofatumumab and obinotuzumab.
  • Subjects that can be treated with a pharmaceutical composition as provided herein, according to the methods as provided herein include, but are not limited to, patients that have been diagnosed as having breast cancer such as a ductal carcinoma, lobular carcinoma, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarcinoma that has migrated to the bone; pancreatic cancer such as epitheliod carcinoma in the pancreatic duct tissue and an adenocarcinoma in a pancreatic
  • the cancer or disease that may be treated (e.g., inhibited or prevented) by methods, compositions, or kits provided herein includes a blood disorder or a hematologic malignancy.
  • the cancer or disease that may be treated is an acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medul
  • Lignin Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leukemia (e.g., acute lymphocytic leukemia (ALL), which includes B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HCL) and Waldenstrom's macroglobulinemia (WM); peripheral T cell lymphomas (PTCL), adult T cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), large granular lymphocytic leukemia (LGF), Hodgkin's disease and Reed-Stemberg disease; acute myelocytic leukemia (AML), chronic myeloc
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), Paget's disease of the vulva, Paget's disease of the penis, papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)), pine
  • the cancer or disease being treated or prevented such as a blood disorder or hematologic malignancy, has a high expression level of one or more PI3K isoform(s) (e.g., PI3K- ⁇ , PI3K- ⁇ , PI3K- ⁇ , or PI3K- ⁇ , or a combination thereof).
  • PI3K isoform(s) e.g., PI3K- ⁇ , PI3K- ⁇ , PI3K- ⁇ , or PI3K- ⁇ , or a combination thereof.
  • the cancer or disease that may be treated or prevented by methods, compositions, or kits provided herein includes a blood disorder or a hematologic malignancy, including, but not limited to, myeloid disorder, lymphoid disorder, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), mast cell disorder, and myeloma (e.g., multiple myeloma), among others.
  • myeloid disorder including, but not limited to, myeloid disorder, lymphoid disorder, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), mast cell disorder, and myeloma (e.g., multiple myeloma), among others.
  • the blood disorder or the hematologic malignancy includes, but is not limited to, acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL), B-cell ALL (B-ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), blast phase CML, small lymphocytic lymphoma (SLL), CLL/SLL, blast phase CLL, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), B-cell NHL, T-cell NHL, indolent NHL (iNHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), aggressive B-cell NHL, B-cell lymphoma (BCL), Richter's syndrome (RS), T-cell lymphoma (TCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), transformed mycos
  • the cancer is a T-cell lymphoma (e.g., peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL)).
  • T-cell lymphoma e.g., peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL)
  • the cancer is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • the cancer has a high level of Bcl-2 expression.
  • the cancer is a large cell lymphoma with a high level of Bcl-2 expression.
  • the hematologic malignancy is relapsed. In one embodiment, the hematologic malignancy is refractory.
  • the cancer or disease is in a pediatric patient (including an infantile patient). In one embodiment, the cancer or disease is in an adult patient. Additional embodiments of a cancer or disease being treated or prevented by methods, compositions, or kits provided herein are described herein elsewhere.
  • the cancer or hematologic malignancy is CLL. In exemplary embodiments, the cancer or hematologic malignancy is CLL/SLL. In exemplary embodiments, the cancer or hematologic malignancy is blast phase CLL. In exemplary embodiments, the cancer or hematologic malignancy is SLL.
  • the cancer or hematologic malignancy is iNHL. In exemplary embodiments, the cancer or hematologic malignancy is DLBCL. In exemplary embodiments, the cancer or hematologic malignancy is B-cell NHL (e.g., aggressive B-cell NHL). In exemplary embodiments, the cancer or hematologic malignancy is MCL. In exemplary embodiments, the cancer or hematologic malignancy is RS. In exemplary embodiments, the cancer or hematologic malignancy is AML. In exemplary embodiments, the cancer or hematologic malignancy is MM. In exemplary embodiments, the cancer or hematologic malignancy is ALL.
  • B-cell NHL e.g., aggressive B-cell NHL
  • MCL e.g., aggressive B-cell NHL
  • the cancer or hematologic malignancy is MCL.
  • the cancer or hematologic malignancy is RS.
  • the cancer or hematologic malignancy is AML.
  • the cancer or hematologic malignancy is T-ALL. In exemplary embodiments, the cancer or hematologic malignancy is B-ALL. In exemplary embodiments, the cancer or hematologic malignancy is TCL. In exemplary embodiments, the cancer or hematologic malignancy is ALCL. In exemplary embodiments, the cancer or hematologic malignancy is leukemia. In exemplary embodiments, the cancer or hematologic malignancy is lymphoma. In exemplary embodiments, the cancer or hematologic malignancy is T-cell lymphoma. In exemplary embodiments, the cancer or hematologic malignancy is MDS (e.g., low grade MDS).
  • MDS e.g., low grade MDS
  • the cancer or hematologic malignancy is MPD. In exemplary embodiments, the cancer or hematologic malignancy is a mast cell disorder. In exemplary embodiments, the cancer or hematologic malignancy is Hodgkin lymphoma (HL). In exemplary embodiments, the cancer or hematologic malignancy is non-Hodgkin lymphoma. In exemplary embodiments, the cancer or hematologic malignancy is PTCL. In exemplary embodiments, the cancer or hematologic malignancy is CTCL (e.g., mycosis fungoides or Sezary syndrome). In exemplary embodiments, the cancer or hematologic malignancy is WM.
  • HL Hodgkin lymphoma
  • CTCL e.g., mycosis fungoides or Sezary syndrome
  • the cancer or hematologic malignancy is WM.
  • the cancer or hematologic malignancy is CML. In exemplary embodiments, the cancer or hematologic malignancy is FL. In exemplary embodiments, the cancer or hematologic malignancy is transformed mycosis fungoides. In exemplary embodiments, the cancer or hematologic malignancy is Sezary syndrome. In exemplary embodiments, the cancer or hematologic malignancy is acute T-cell leukemia. In exemplary embodiments, the cancer or hematologic malignancy is acute B-cell leukemia. In exemplary embodiments, the cancer or hematologic malignancy is Burkitt lymphoma.
  • the cancer or hematologic malignancy is myeloproliferative neoplasms. In exemplary embodiments, the cancer or hematologic malignancy is splenic marginal zone. In exemplary embodiments, the cancer or hematologic malignancy is nodal marginal zone. In exemplary embodiments, the cancer or hematologic malignancy is extranodal marginal zone.
  • the cancer or hematologic malignancy is a B cell lymphoma.
  • a method of treating or managing a B cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof.
  • a method of treating or lessening one or more of the symptoms associated with a B cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof.
  • the B cell lymphoma is iNHL.
  • the B cell lymphoma is follicular lymphoma. In another embodiment, the B cell lymphoma is Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma). In another embodiment, the B cell lymphoma is marginal zone lymphoma (MZL) In another embodiment, the B cell lymphoma is MCL. In another embodiment, the B cell lymphoma is HL. In another embodiment, the B cell lymphoma is aNHL. In another embodiment, the B cell lymphoma is DLBCL. In another embodiment, the B cell lymphoma is Richters lymphoma.
  • MZL marginal zone lymphoma
  • the cancer or hematologic malignancy is a T cell lymphoma.
  • a method of treating e.g., inhibiting, preventing or managing
  • a T cell lymphoma comprising administering to a patient a composition described herein.
  • a method of treating e.g., lessening one or more of the symptoms associated with
  • a T cell lymphoma comprising administering to a patient a composition described herein.
  • the T cell lymphoma is peripheral T cell lymphoma (PTCL).
  • the T cell lymphoma is cutaneous T cell lymphoma (CTCL).
  • the cancer or hematologic malignancy is Sezary syndrome.
  • a method of treating e.g., inhibiting, preventing or managing
  • Sezary syndrome comprising administering to a patient a composition described herein.
  • a method of treating e.g., lessening one or more of the symptoms associated with
  • Sezary syndrome comprising administering to a patient a therapeutically effective amount of a composition described herein.
  • the dosage (e.g., the therapeutically effective dosage) of Compound 1 included in the combination is about 25 mg to 75 mg of Compound 1, administered twice daily.
  • the dosage is from about 50 mg to about 75 mg, from about 30 mg to about 65 mg, from about 45 mg to about 60 mg, from about 30 mg to about 50 mg, or from about 55 mg to about 65 mg.
  • this dosage is administered twice daily.
  • the dosage is about 60 mg, administered twice daily.
  • the present invention also provides a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, comprising: assessing the level of a prognosis-positive biomarker expressed by a tumor cell; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein high expression levels of tumor cell prognosis-positive biomarkers correlate with high sensitivity to inhibition by a PI3K inhibitor, or wherein low expression levels of said tumor cell prognosis-positive biomarker correlate with low sensitivity to inhibition by PI3K inhibitors, and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor (e.g., if the tumor is predicted to have a low sensitivity to a PI3K inhibitor alone).
  • the present invention also provides a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, comprising: assessing the level of a prognosis-negative biomarker expressed by a tumor cell; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein high expression levels of tumor cell prognosis-negative biomarkers correlate with low sensitivity to inhibition by PI3K inhibitors, or wherein low expression levels of said tumor cell prognosis-negative biomarker correlates with high sensitivity to inhibition by a PI3K inhibitor, and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor (e.g., if the tumor is predicted to have a low sensitivity to a PI3K inhibitor alone).
  • the present invention further provides a method for treating a tumor in a patient, comprising the step of administering to the patient a PI3K inhibitor and a Bcl-2 inhibitor, wherein the patient possesses a tumor that has been determined as having high sensitivity to tumor cell growth inhibition by a PI3K inhibitor by assessing the level of at least one prognosis-positive biomarker expressed by a tumor cell from said tumor; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein high expression levels of said tumor cell prognosis-positive biomarker correlate with high sensitivity to inhibition by a PI3K inhibitor; or
  • the range of expression level between tumor cells that are relatively insensitive to PI3K inhibitors and those that are sensitive can readily be assessed by one of skill in the art, for example by testing on a panel of tumor cells as described herein, or by testing in tumor biopsies from patients whose tumors display a range of sensitivities to a PI3K inhibitor.
  • this invention also provides additional methods wherein simultaneous assessment of the expression level in tumor cells of more than one biomarker level is utilized.
  • the present invention provides a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, comprising: assessing the level of at least one (or a panel of) prognosis-positive biomarkers expressed by a tumor cell; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein simultaneous high expression levels of all of the assessed tumor cell prognosis-positive biomarkers correlates with high sensitivity to inhibition by a PI3K inhibitor, and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor (e.g., if the tumor is predicted to have a low sensitivity to a PI3K inhibitor alone).
  • the present invention also provides a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, comprising: assessing the level of one or more (or a panel of) prognosis-negative biomarkers expressed by a tumor cell; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein simultaneous low or undetectable expression levels of all of the assessed tumor cell prognosis-negative biomarkers correlates with high sensitivity to inhibition by a PI3K inhibitor, and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor (e.g., if the tumor is predicted to have a low sensitivity to a PI3K inhibitor alone).
  • the present invention also provides a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, comprising: assessing the level of one or more prognosis-positive biomarker expressed by a tumor cell; assessing the level of one or more prognosis-negative biomarker expressed by a tumor cell; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein a high ratio of prognosis-positive to prognosis-negative biomarker expression levels correlates with high sensitivity to inhibition by a PI3K inhibitor and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor (e.g., if the tumor is predicted to have a low sensitivity to a PI3K inhibitor alone).
  • a high ratio of prognosis-positive to prognosis-negative biomarker expression levels means greater than 1:1, preferably greater than 1.1:1, preferably greater than 1.5:1, more preferably greater than 2:1, more preferably greater than 5:1, more preferably greater than 10:1, even more preferably greater than 100:1, or greater than 1,000:1.
  • biomarker expression level can be assessed relative to the biomarker level in non-tumor cells of the same tissue, or another cell or tissue source used as an assay reference.
  • the expression level of a biomarker is considered high if expression level relative to a suitable reference is greater than 1:1, preferably greater than 1.1:1, preferably greater than 1.5:1, more preferably greater than 2:1, more preferably greater than 5:1, more preferably greater than 10:1, even more preferably greater than 100:1, even more preferably greater than 1,000:1, even more preferably greater than 10,000:1, even more preferably greater than 1,000,000:1.
  • the expression level of a biomarker is considered low if expression level relative to a suitable reference is less than 1:1, preferably less than 1:1.1, preferably less than 1:1.5, more preferably less than 1:2, more preferably less than 1:5, more preferably less than 1:10, even more preferably less than 1:100, even more preferably less than 1:1,000, even more preferably less than 1:10,000, even more preferably less than 1:1,000,000.
  • the present invention further provides a method of predicting the likelihood that a tumor will progress to a more aggressive tumor wherein the tumor is treatable with a PI3K inhibitor, comprising: assessing the level of at least one progression-positive biomarker expressed by a tumor cell from said tumor; and predicting the likelihood that the tumor cell will progress to a more aggressive tumor, wherein high expression levels of said tumor cell progression-positive biomarker correlate with high likelihood that the tumor cell will progress to a more aggressive tumor or wherein low expression levels of said tumor cell progression-positive biomarker correlate with low likelihood that the tumor cell will progress to a more aggressive tumor and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor (e.g., if it is determined that there is a high likelihood that the tumor cell will progress to a more aggressive tumor if treated with a PI3K inhibitor alone).
  • the PI3K inhibitor is selected from Compound 1, GS1101, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, PF-4691502, GDC-0980, GSK 2126458, PF-05212384, XL765, or XL147.
  • the PI3K inhibitor is selected from Compound 1 and GS1101.
  • the PI3K inhibitor is Compound 1.
  • the tumor or tumor cell is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and adult T-cell lymphoma. In certain embodiments, the tumor is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma and diffuse large B-cell lymphoma.
  • the PI3K inhibitor is Compound 1 and the tumor or tumor cell is indolent non-Hodgkin lymphoma.
  • the progression-positive biomarker is a genomic alteration in one or more gene in the 6q deletion region.
  • the progression-positive biomarker is a genomic alteration in an NF- ⁇ B pathway gene. In one embodiment, the progression-positive biomarker is a del(6q13-16) or a del(6q23-24). In one embodiment the progression-positive biomarker is a TNFAIP3 mutation or copy number loss. In one embodiment the progression-positive biomarker is an EPHA7 mutation or copy number loss.
  • the present invention also provides a method of predicting the likelihood that a tumor cell from a tumor will progress to a more aggressive tumor wherein the tumor is treatable with a PI3K inhibitor, comprising: assessing the level of at least one progression-negative biomarker expressed by a tumor cell; and predicting the likelihood that the tumor cell will progress to a more aggressive tumor, wherein high expression levels of said tumor cell progression-negative biomarker correlate with low likelihood that the tumor cell will progress to a more aggressive tumor, or wherein low expression levels of said tumor cell progression-negative biomarker correlates with high sensitivity to inhibition by a PI3K inhibitor and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor (e.g., if it is determined that there is a high likelihood that the tumor cell will progress to a more aggressive tumor if treated with a PI3K inhibitor alone).
  • the PI3K inhibitor is selected from Compound 1, GS1101, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, PF-4691502, GDC-0980, GSK 2126458, PF-05212384, XL765, or XL147.
  • the PI3K inhibitor is selected from Compound 1 and GS1101.
  • the PI3K inhibitor is Compound 1.
  • the tumor or tumor cell is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and adult T-cell lymphoma. In some embodiments, the tumor is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma and diffuse large B-cell lymphoma.
  • the PI3K inhibitor is Compound 1 and the tumor or tumor cell is indolent non-Hodgkin lymphoma.
  • the progression-positive biomarker is a genomic alteration in one or more gene in the 6q deletion region.
  • the progression-positive biomarker is a genomic alteration in an NF- ⁇ B pathway gene. In one embodiment, the progression-positive biomarker is a del(6q13-16) or a del(6q23-24). In one embodiment the progression-positive biomarker is a TNFAIP3 mutation or copy number loss. In one embodiment the progression-positive biomarker is an EPHA7 mutation or copy number loss.
  • the present invention provides a method for treating a tumor in a patient, comprising the step of administering to the patient a PI3K inhibitor and a Bcl-2 inhibitor, wherein there is a high likelihood that the patient will develop a more aggressive tumor and wherein said likelihood has been determined by:
  • the PI3K inhibitor is selected from Compound 1, GS1101, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, PF-4691502, GDC-0980, GSK 2126458, PF-05212384, XL765, or XL147.
  • the PI3K inhibitor is selected from Compound 1 and GS1101.
  • the PI3K inhibitor is Compound 1.
  • the tumor or tumor cell is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and adult T-cell lymphoma. In some embodiments, the tumor is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma and diffuse large B-cell lymphoma.
  • the PI3K inhibitor is Compound 1 and the tumor or tumor cell is indolent non-Hodgkin lymphoma.
  • the progression-positive biomarker is a genomic alteration in one or more gene in the 6q deletion region.
  • the progression-positive biomarker is a genomic alteration in an NF- ⁇ B pathway gene. In one embodiment, the progression-positive biomarker is a del(6q13-16) or a del(6q23-24). In one embodiment the progression-positive biomarker is a TNFAIP3 mutation or copy number loss. In one embodiment the progression-positive biomarker is an EPHA7 mutation or copy number loss.
  • the level of a prognosis-positive or prognosis-negative biomarker expressed by a tumor cell can be assessed by using any of the standard bioassay procedures known in the art for determination of the level of expression of a gene, including for example ELISA, RIA, immunoprecipitation, immunoblotting, immunofluorescence microscopy, RT-PCR, in situ hybridization, cDNA microarray, or the like, as described in more detail below.
  • the expression level of a tumor cell prognosis-positive biomarker or prognosis-negative biomarker is preferably assessed by assaying a tumor biopsy.
  • expression level of the tumor cell biomarker can be assessed in bodily fluids or excretions containing detectable levels of biomarkers originating from the tumor or tumor cells.
  • Bodily fluids or excretions useful in the present invention include blood, urine, saliva, stool, pleural fluid, lymphatic fluid, sputum, ascites, prostatic fluid, cerebrospinal fluid (CSF), or any other bodily secretion or derivative thereof.
  • blood it is meant to include whole blood, plasma, serum or any derivative of blood.
  • Assessment of tumor prognosis-positive or prognosis-negative biomarkers in such bodily fluids or excretions can sometimes be preferred in circumstances where an invasive sampling method is inappropriate or inconvenient.
  • an example of such a sample can be a tumor biopsy.
  • the biomarkers provided herein include, but are not limited to, a target biomarker, a signaling pathway biomarker, a protein mutation biomarker, a protein expression biomarker, a gene mutation biomarker, a copy number alteration (CNA) biomarker, a gene expression biomarker, a cytokine biomarker, a chemokine biomarker, a matrix metalloproteinase biomarker, or a biomarker for particular cancer cells.
  • the biomarker can be used to evaluate the prognosis, and/or sensitivity to a treatment agent, of a particular type of cancer or disease, or of a particular patient or group of patients.
  • the prognosis-positive or prognosis-negative biomarker is a genomic alteration.
  • the genomic alteration is a gene mutation or a copy number alteration.
  • the gene mutation is a non-dbSNP mutation.
  • the gene mutation is a single nucleotide polymorphism (SNP) mutation.
  • the prognosis-negative biomarker is associated with a mutation in one or more of the following genes: ALK, SF3B1, TP53, NOTCH1, MYD88, ATM, XPO1, POT1, NRAS, BCOR, KRAS, MED12, DDX3X, FBXW7, BTK and PLCG2.
  • the prognosis-negative biomarker is associated with a mutation in one or more of the following genes: SF3B1, TP53, NOTCH1, MYD88, ATM, XPO1, MED12, and FBXW7. In one embodiment, the prognosis-negative biomarker is associated with a chromosome deletion.
  • the prognosis-negative biomarker is associated with one or more genomic alterations selected from the group consisting of del(11q21), del(13q14), trisomy 12, del(11q22-23), del(17p13), del(8p), TP53 mutation, TP53 pathway mutation, MAPK pathway mutation, TP53 copy number loss, STK11 copy number loss, TSC1 copy number loss, and TSC2 copy number loss.
  • the prognosis-negative biomarker is copy number loss in one or more of STK11, TSC1, and TSC2.
  • the prognosis-negative biomarker is copy number loss in STK11.
  • the prognosis-negative biomarker is copy number loss in TSC1. In one embodiment, the prognosis-negative biomarker is copy number loss in TSC2. In one embodiment, the prognosis-negative biomarker is copy number loss in STK11 and TSC1. In one embodiment, the prognosis-negative biomarker is copy number loss in STK11 and TSC2. In one embodiment, the prognosis-negative biomarker is TP53 pathway mutation or MAPK pathway mutation or both. In one embodiment, the prognosis-negative biomarker is TP53 pathway and MAPK pathway dual mutation. In one embodiment, the prognosis-negative biomarker is TP53 C141Y mutation. In another embodiment, the prognosis-negative biomarker is ALK E1028D mutation.
  • the prognosis-negative biomarker is associated with one or more (e.g., 2, 3, 4, 5, or all) genomic alterations selected from the group consisting of del(11q21), del(13q14), trisomy 12, del(11q22-23), del(17p13), and del(8p).
  • one or more genomic alterations selected from the group consisting of del(11q21), del(13q14), trisomy 12, del(11q22-23), del(17p13), and del(8p).
  • the prognosis-negative biomarker is one or more genomic alterations selected from the group consisting of BRAF copy number gain, CTNNB1 copy number gain, FHIT copy number gain, IRF4 copy number gain, MITF copy number gain, MN1 copy number gain, NF2 copy number gain, NF2 copy number loss, RET copy number loss, STK11 copy number loss, TSC2 copy number loss, RB1 loss of heterozygosity.
  • the prognosis-positive biomarker is one or more of RANBP17 copy number gain, FGFR3 loss of heterozygosity, GMPS loss of heterozygosity, and WHSC1 loss of heterozygosity.
  • the progression-positive or progression-negative biomarker is a genomic alteration.
  • the genomic alteration is a gene mutation or a copy number alteration.
  • the gene mutation is a non-dbSNP mutation.
  • the gene mutation is a single nucleotide polymorphism (SNP) mutation.
  • the progression-positive biomarker is a genomic alteration in one or more gene in the 6q deletion region.
  • the progression-positive biomarker is a genomic alteration in an NF- ⁇ B pathway gene.
  • the progression-positive biomarker is a del(6q13-16) or a del(6q23-24).
  • the progression-positive biomarker is a TNFAIP3 mutation or copy number loss.
  • the progression-positive biomarker is an EPHA7 mutation or copy number loss.
  • a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor comprising: assessing the level of at least one prognosis-positive biomarker expressed by a tumor cell; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein high levels of a prognosis-positive biomarker expression by the tumor cells correlates with high sensitivity to inhibition by a PI3K inhibitor, or wherein low expression levels of said tumor cell prognosis-positive biomarker correlate with low sensitivity to inhibition by PI3K inhibitors, and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor.
  • a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor comprising: assessing the level of at least one prognosis-negative biomarker expressed by a tumor cell; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein high levels of prognosis-negative biomarker expression by the tumor cell correlates with low sensitivity to inhibition by a PI3K inhibitor, or wherein low expression levels of said tumor cell prognosis-negative biomarker correlates with high sensitivity to inhibition by a PI3K inhibitor, and treating the tumor with a PI3K inhibitor and a Bcl-2 inhibitor.
  • a method for treating a tumor in a patient comprising the step of administering to the patient a PI3K inhibitor, wherein the patient possesses a tumor that has been determined as having high sensitivity to tumor cell growth inhibition by a PI3K inhibitor by (a) assessing the level of at least one prognosis-positive biomarker expressed by a tumor cell from said tumor; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein high expression levels of said tumor cell prognosis-positive biomarker correlate with high sensitivity to inhibition by a PI3K inhibitor; or (b) assessing the level of at least one prognosis-negative biomarker expressed by a tumor cell from said tumor; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein low expression levels of said tumor cell prognosis-negative biomarker correlate with high sensitivity to inhibition by a PI3K inhibitor, and treating the tumor with a PI3K inhibitor and a
  • a method for treating a tumor in a patient comprising the step of administering to the patient a PI3K inhibitor as a first-line therapy, wherein the patient possesses a tumor that has been determined as having high sensitivity to tumor cell growth inhibition by a PI3K inhibitor by (a) assessing the level of at least one prognosis-positive biomarker expressed by a tumor cell from said tumor; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein high expression levels of said tumor cell prognosis-positive biomarker correlate with high sensitivity to inhibition by a PI3K inhibitor; or (b) assessing the level of at least one prognosis-negative biomarker expressed by a tumor cell from said tumor; and predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor, wherein low expression levels of said tumor cell prognosis-negative biomarker correlate with high sensitivity to inhibition by a PI3K inhibitor, and treating the tumor with a
  • the PI3K inhibitor can be selected from Compound 1, GS1101, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, PF-4691502, GDC-0980, GSK 2126458, PF-05212384, XL765, or XL147.
  • the PI3K inhibitor is selected from Compound 1 and GS1101.
  • the tumor is an acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma, benign monoclonal gammopathy, biliary cancer bladder cancer, breast cancer, brain cancer, bronchus cancer, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer, epithelial carcinoma, ependymoma, endotheliosarcoma, endometrial cancer, esophageal cancer, Ewing sarcoma, familiar hypereosinophilia, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cancer, heavy chain disease, hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer, liver cancer, malignant hepatoma, lung cancer, leiomyosarcoma (LMS), mastocytosis, multiple myectheli
  • the tumor is a myeloid disorder, lymphoid disorder, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), mast cell disorder, or a myeloma.
  • myeloid disorder lymphoid disorder, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), mast cell disorder, or a myeloma.
  • the tumor is selected from acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia, blast phase chronic myelogenous leukemia, small lymphocytic lymphoma (SLL), CLL/SLL, blast phase CLL, Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), B-cell NHL, T-cell NHL, indolent NHL, diffuse large B-cell lymphoma, mantle cell lymphoma, aggressive B-cell NHL, B-cell lymphoma, Richter's syndrome, T-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, transformed mycosis fungoides, Sezary syndrome, anaplastic large-cell lymphoma, follicular lymphoma, Waldenström macroglobul
  • the tumor is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma (e.g., indolent Non-Hodgkin lymphoma), diffuse large B-cell lymphoma, mantle cell lymphoma, and adult T-cell lymphoma.
  • non-Hodgkin lymphoma e.g., indolent Non-Hodgkin lymphoma
  • diffuse large B-cell lymphoma e.g., mantle cell lymphoma
  • mantle cell lymphoma e.g., indolent Non-Hodgkin lymphoma
  • adult T-cell lymphoma e.g., adult T-cell lymphoma
  • the prognosis-positive or prognosis-negative biomarker is a genomic alteration.
  • the prognosis-positive or prognosis-negative biomarker is selected from a gene mutation, a copy number alteration, a non-dbSNP mutation or an single nucleotide polymorphism (SNP) mutation.
  • the prognosis-positive biomarker is associated with a mutation in a gene selected from RANBP17 copy number gain, FGFR3 loss of heterozygosity, GMPS loss of heterozygosity and WHSC1 loss of heterozygosity.
  • the prognosis-negative biomarker is associated with a genomic alteration selected from the group consisting of del(11q21), del(13q14), del(8p), trisomy 12, del(11q22-23), del(17p13), TP53 mutation, TP53 pathway mutation, MAPK pathway mutation, TP53 copy number loss, STK11 copy number loss, TSC1 copy number loss, and TSC2 copy number loss.
  • the prognosis-negative biomarker is associated with a mutation in a gene selected from SF3B1, TP53, NOTCH1, MYD88, ATM, XPO1, POT1, NRAS, BCOR, KRAS, MED12, DDX3X, FBXW7, BTK and PLCG2.
  • the prognosis-negative biomarker is associated with an STK11 copy number loss, a TSC1 or a TSC2 copy number loss.
  • a method of predicting the likelihood that a tumor will progress to a more aggressive tumor wherein the tumor is treatable with a PI3K inhibitor and a Bcl-2 inhibitor, said method comprising the steps of: assessing the level of at least one progression-positive biomarker expressed by a tumor cell from said tumor; and predicting the likelihood that the tumor cell will progress to a more aggressive tumor, wherein high expression levels of said tumor cell progression-positive biomarker correlate with high likelihood that the tumor cell will progress to a more aggressive tumor or wherein low expression levels of said tumor cell progression-positive biomarker correlate with low likelihood that the tumor cell will progress to a more aggressive tumor.
  • a method of predicting the likelihood that a tumor will progress to a more aggressive tumor wherein the tumor is treatable with a PI3K inhibitor and a Bcl-2 inhibitor, said method comprising the steps of: assessing the level of at least one progression-negative biomarker expressed by a tumor cell from said tumor; and predicting the likelihood that the tumor cell will progress to a more aggressive tumor, wherein high expression levels of said tumor cell progression-negative biomarker correlate with low likelihood that the tumor cell will progress to a more aggressive tumor or wherein low expression levels of said tumor cell progression-positive biomarker correlate with low likelihood that the tumor cell will progress to a more aggressive tumor.
  • a method of treating a tumor in a patient comprising the step of administering to the patient a PI3K inhibitor and a Bcl-2 inhibitor, wherein there is a high likelihood that the patient will develop a more aggressive tumor and wherein said likelihood has been determined by: (a) assessing the level of at least one progression-positive biomarker expressed by a tumor cell from said tumor; and predicting the likelihood that the tumor cell will progress to a more aggressive tumor, wherein high expression levels of said tumor cell progression-positive biomarker correlate with high likelihood that the tumor cell will progress to a more aggressive tumor; or (b) assessing the level of at least one progression-negative biomarker expressed by a tumor cell from said tumor; and predicting the likelihood that the tumor cell will progress to a more aggressive tumor, wherein low expression levels of said tumor cell progression-negative biomarker correlate with high likelihood that the tumor cell will progress to a more aggressive tumor.
  • the PI3K inhibitor is selected from Compound 1, GS1101, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, PF-4691502, GDC-0980, GSK 2126458, PF-05212384, XL765, or XL147.
  • the tumor is an acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma, benign monoclonal gammopathy, biliary cancer bladder cancer, breast cancer, brain cancer, bronchus cancer, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer, epithelial carcinoma, ependymoma, endotheliosarcoma, endometrial cancer, esophageal cancer, Ewing sarcoma, familiar hypereosinophilia, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cancer, heavy chain disease, hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer, liver cancer, malignant hepatoma, lung cancer, leiomyosarcoma (LM
  • the tumor is a myeloid disorder, lymphoid disorder, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), mast cell disorder, or a myeloma.
  • MDS myelodysplastic syndrome
  • MPD myeloproliferative disease
  • mast cell disorder or a myeloma.
  • the tumor is indolent.
  • the tumor is selected from acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia, blast phase chronic myelogenous leukemia, small lymphocytic lymphoma (SLL), CLL/SLL, blast phase CLL, Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), B-cell NHL, T-cell NHL, indolent NHL, diffuse large B-cell lymphoma, mantle cell lymphoma, aggressive B-cell NHL, B-cell lymphoma, Richter's syndrome, T-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, transformed mycosis fungoides, Sezary syndrome, anaplastic large-cell lymphoma, follicular lymphoma, Waldenström macroglobul
  • the tumor is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma (e.g., indolent non-Hodgkin lymphoma), diffuse large B-cell lymphoma, mantle cell lymphoma, and adult T-cell lymphoma.
  • non-Hodgkin lymphoma e.g., indolent non-Hodgkin lymphoma
  • diffuse large B-cell lymphoma e.g., mantle cell lymphoma
  • mantle cell lymphoma e.g., mantle cell lymphoma
  • adult T-cell lymphoma e.g., adult T-cell lymphoma
  • the progression-positive or progression-negative biomarker is a genomic alteration.
  • the progression-positive or progression-negative biomarker is selected from a gene mutation, a copy number alteration, a non-dbSNP mutation or an single nucleotide polymorphism (SNP) mutation.
  • the progression-positive biomarker is associated with a mutation in a gene in the 6q deletion region.
  • the progression-positive biomarker is a genomic alteration in an NF- ⁇ B pathway gene.
  • the progression-positive biomarker is a del(6q13-16) or a del(6q23-24).
  • the progression-positive biomarker is a TNFAIP3 mutation or copy number loss.
  • the progression-positive biomarker is an EPHA7 mutation or copy number loss.
  • the disclosure provides a method of treating a patient, comprising (i) administering a first treatment comprising a first PI3K inhibitor to the subject (ii) acquiring information regarding an alteration in a biomarker by comparing an assessment of the biomarker in a first sample taken from the subject before the first treatment is administered with an assessment of the biomarker in a second sample taken from the subject after the first treatment is administered, wherein the biomarker is selected from STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, MAP2K4, or EGFR, and (iii) continuing administration of the first treatment if the alteration is absent, or administering a second treatment if the alteration is present, wherein the second treatment includes administration of a Bcl-2 inhibitor.
  • the present disclosure provides a method of determining the further course of treatment for a subject who has undergone a first treatment with a first PI3K inhibitor, the method comprising: (i) acquiring information regarding the presence or absence of an alteration in one or more of STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, MAP2K4, or EGFR in one or more samples from the subject; and (ii) selecting the subject for continuation of the first treatment with the first PI3K inhibitor if the alteration is absent and selecting the subject for a second treatment if the alteration is present, wherein the second treatment includes administration of a Bcl-2 inhibitor.
  • the disclosure provides a method of determining decreased responsiveness, or resistance, of a subject to a first treatment comprising a first PI3K inhibitor, the method comprising (i) acquiring information regarding the presence or absence of an alteration in one or more of STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, MAP2K4, or EGFR in one or more samples from the subject; and (ii) determining that the subject shows decreased responsiveness or resistance to the first treatment if the alteration is present, wherein the second treatment includes administration of a Bcl-2 inhibitor.
  • the PI3K inhibitor can be selected from: Compound 1, AMG-319, GSK 2126458, GSK 1059615, GDC-0032, GDC-0980, GDC-0941, XL147, XL499, XL765, BKM 120 GS1101, CAL 263, SF1126, PX-866, BEZ235, CAL-120, BYL719, RP6503, RP6530, TGR1202, INK1117, PX-886, BAY 80-6946, IC87114, Palomid 529, ZSTK474, PWT33597, TG100-115, GNE-477, CUDC-907, AEZS-136, BGT-226, PF-05212384, LY3023414, PI-103, LY294002, INCB-040093, CAL-130 and wortmannin.
  • the present invention also provides, at least in part, methods (e.g., diagnostic and prognostic methods) for evaluating, e.g., predicting, the responsiveness to a treatment of a cancer with a B-cell receptor (BCR) pathway inhibitor (e.g., a PI3K inhibitor).
  • BCR B-cell receptor pathway inhibitor
  • STK11 copy number loss (with or without copy number loss of TSC1, TSC2, or both) is associated with, or is predictive of, decreased responsiveness (e.g., acquired resistance) of a cancer (e.g., chronic lymphocytic leukemia (CLL)) to a PI3K inhibitor (e.g., Compound 1).
  • CLL chronic lymphocytic leukemia
  • compositions, methods, and kits for evaluating responsiveness (e.g., acquisition of resistance) to, or monitor, therapy involving PI3K inhibition (including combination therapies); stratify patient populations; identify subjects likely to benefit from such agents, predict a time course of disease or a probability of a significant event in the disease for such subjects, and/or more effectively monitor, treat or prevent a cancer are disclosed.
  • the methods further comprise treating the subject with a PI3K inhibitor and a Bcl-2 inhibitor.
  • STK11 copy number loss is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • a dual alteration in the MAPK/P53 pathway is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • copy number loss of STK11 combined with copy number loss of TSC1, TSC2, or both is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • a cancer e.g., a CLL
  • a PI3K inhibitor e.g., Compound 1
  • TSC2 copy number loss was associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • Copy number gain in each of BRAF, CTNNB1, FHIT, IRF4, MITF, MN1, and NF2 was associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • Copy number loss in each of NF2 and RET was associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • Loss of heterozygosity in RB1 was associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • Copy number gain in RANBP17 was associated with responsiveness or lack of resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • Loss of heterozygosity in each of FGFR3, GMPS, and WHSC1 is associated with or predictive of responsiveness or lack of resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • a cancer e.g., a CLL
  • a PI3K inhibitor e.g., Compound 1
  • the present invention further provides a method for treating cancer in a subject, e.g., a patient, comprising the step of administering to the subject a PI3K inhibitor and a Bcl-2 inhibitor, wherein the subject possesses a cancer that has been determined as having high sensitivity to cancer or tumor cell growth inhibition by a PI3K inhibitor by assessing the level of at least one prognosis-positive biomarker in a cancer or tumor cell from said cancer or tumor; and predicting the sensitivity of cancer or tumor cell growth to inhibition by a PI3K inhibitor, wherein detection or an elevated level of said prognosis-positive biomarker correlate with high sensitivity to inhibition by a PI3K inhibitor; or assessing the level of at least one prognosis-negative biomarker in
  • a further aspect of the invention is a method of treating a cancer or tumor or a metastasis thereof in a subject, comprising the step of administering to the subject a PI3K inhibitor, e.g., as a first-line therapy, wherein the subject possesses a cancer or tumor that has been determined as having high sensitivity to cancer or tumor cell growth inhibition by a PI3K inhibitor by assessing the level of at least one prognosis-positive biomarker by one of the following: assessing the level of at least one prognosis-positive biomarker expressed by a cancer cell from said cancer or tumor; and predicting the sensitivity of cancer or tumor cell growth to inhibition by a PI3K inhibitor, wherein detection or an elevated level of said prognosis-positive biomarker correlate with high sensitivity to inhibition by a PI3K inhibitor; or assessing the presence or an alteration at least one prognosis-negative biomarker in a cancer or tumor cell from said cancer or tumor; and predicting the sensitivity of cancer or tumor cell growth to
  • the present invention provides a method for treating a cancer or tumor in a subject, e.g., a patient, comprising administering to the subject a PI3K inhibitor and a Bcl-2 inhibitor, wherein there is a high likelihood that the patient will develop a more aggressive tumor and wherein said likelihood has been determined by assessing the level of at least one progression-positive biomarker expressed by a tumor cell from said tumor; and predicting the likelihood that the tumor cell will progress to a more aggressive tumor, wherein high expression levels of said tumor cell progression-positive biomarker correlate with high likelihood that the tumor cell will progress to a more aggressive tumor; or assessing the level of at least one progression-negative biomarker expressed by a tumor cell from said tumor; and predicting the likelihood that the tumor cell will progress to a more aggressive tumor, wherein low expression levels of said tumor cell progression-negative biomarker correlate with high likelihood that the tumor cell will progress to a more aggressive tumor.
  • the invention features a method of evaluating the responsiveness of a cancer or tumor, or a subject having a cancer or tumor, to a treatment with a BCR pathway inhibitor (e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination).
  • a BCR pathway inhibitor e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination.
  • responsiveness to a PI3K inhibitor is evaluated.
  • the method includes: acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of an alteration or biomarker chosen from one, two, three, four or all of: an STK11 copy number, TSC1 copy number, TSC2 copy number, a p53 pathway mutation (e.g., a mutation disclosed in Table 20), or MAPK pathway mutation (e.g., a mutation disclosed in Table 18), or any combination thereof (e.g., a dual MAPK/p53 pathway mutation, e.g., a mutation disclosed in Table 18 and a mutation disclosed in Table 20).
  • the method further comprises administering a PI3K inhibitor and a Bcl-2 inhibitor to the subject.
  • the invention features a method of monitoring a treatment of a subject with a BCR pathway inhibitor (e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination).
  • a BCR pathway inhibitor e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination.
  • treatment with a PI3K inhibitor is monitored.
  • the method includes: acquiring, at two or more time intervals, a value (e.g., determining one or more of: the presence, absence, amount or level) of an alteration or biomarker chosen from one, two, three, four or all of: an STK11 copy number, TSC1 copy number, TSC2 copy number, a p53 pathway mutation (e.g., a mutation disclosed in Table 20), or MAPK pathway mutation (e.g., a mutation disclosed in Table 18), or any combination thereof (e.g., a dual MAPK/p53 mutation, e.g., a mutation disclosed in Table 18 and a mutation disclosed in Table 20).
  • the method further comprises administering a PI3K inhibitor and a Bcl-2 inhibitor to the subject.
  • the invention features a method of treating (e.g., inhibiting, reducing, ameliorating, managing, or preventing) a cancer or tumor in a subject.
  • the method includes: acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of an alteration or biomarker chosen from one, two, three, four or all of: an STK11 copy number, TSC1 copy number, TSC2 copy number, a p53 pathway mutation (e.g., a mutation disclosed in Table 20), or MAPK pathway mutation (e.g., a mutation disclosed in Table 18), or any combination thereof (e.g., a dual MAPK/p53 mutation, e.g., a mutation disclosed in Table 18 and a mutation disclosed in Table 20), and responsive to said value, administering to the subject a BCR pathway inhibitor, e.g., a PI3K inhibitor (e.g., one or more PI3K inhibitors) and a Bcl-2 inhibitor.
  • the invention features a method of treating a subject, comprising (i) administering a first treatment comprising a first PI3K inhibitor to the subject (ii) acquiring information regarding the presence or absence of an alteration in a biomarker in one or more samples from the subject, wherein the biomarker is selected from STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, MAP2K4, or EGFR; and (iii) continuing administration of the first treatment if the alteration is absent, or administering a second treatment if the alteration is present, wherein the second treatment includes administration of a Bcl-2 inhibitor.
  • the alteration is an STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, or MAP2K4 copy number loss (e.g., single copy loss).
  • the STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, or MAP2K4 copy number in a sample taken from the subject after the first treatment is lower than a corresponding STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, MAP2K4 copy number in a sample taken from the subject before the first treatment (e.g., there is an STK11 single copy loss).
  • the present disclosure provides a method of evaluating the responsiveness of a cancer or tumor, or a subject having a cancer or tumor, to a treatment with a BCR pathway inhibitor (e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination).
  • a BCR pathway inhibitor e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination.
  • responsiveness to a PI3K inhibitor is evaluated.
  • the method includes: acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of an anti-apoptotic factor such as Bcl-2.
  • the invention features a method of monitoring a treatment of a subject with a BCR pathway inhibitor (e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination).
  • a BCR pathway inhibitor e.g., a treatment with an inhibitor of PI3K, BTK or SYK, alone or in combination.
  • treatment with a PI3K inhibitor is monitored.
  • the method includes: acquiring, at two or more time intervals, a value (e.g., determining one or more of: the presence, absence, amount or level) of an anti-apoptotic factor such as Bcl-2.
  • the invention features a method of treating (e.g., inhibiting, reducing, ameliorating, managing, or preventing) a cancer or tumor in a subject.
  • the method includes: acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of an anti-apoptotic factor such as Bcl-2.
  • the methods that include acquiring a value of Bcl-2 also include acquiring a value (e.g., determining one or more of: the presence, absence, amount or level) of a pro-apoptotic factor or anti-apoptotic factor.
  • the pro-apoptotic factor can be, e.g., one or more of (e.g., 2, 3, 4, or all of) BMF, BIK, BIM, NOXA, PUMA, and HRK.
  • an elevated level of Bch 2 indicates that the cancer is resistant to a PI3K inhibitor.
  • a normal or reduced level of Bcl-2 indicates that the cancer is responsive to a PI3K inhibitor.
  • an elevated level of one or more pro-apoptotic factors indicates that the cancer is more responsive to a PI3K inhibitor (optionally in combination with a Bcl-2 inhibitor) than a cancer with normal or lowered levels of the pro-apoptotic factor.
  • the methods involve administering a Bcl-2 inhibitor (e.g., in combination with a PI3K inhibitor) to a subject having elevated Bcl-2 levels.
  • the methods involve administering a PI3K inhibitor as a monotherapy to a subject having normal or low Bcl-2 levels.
  • the elevated, normal, or reduced levels of a biomarker are determined with reference to a non-cancerous control value.
  • acquiring a value comprises acquiring information regarding the presence or absence of an alteration described herein.
  • the methods herein comprise comparing an assessment of a biomarker in a first sample taken from the subject before the first treatment is administered with an assessment of the biomarker in a second sample taken from the subject after the first treatment is administered.
  • the method comprises determining the further course of treatment for the subject.
  • the method comprises a method of determining decreased responsiveness, or resistance, of the subject to the first treatment.
  • the methods herein comprise administering a first treatment comprising a first PI3K inhibitor to the subject and continuing administration of the first treatment if an alteration is absent, or administering a second treatment including a Bcl-2 inhibitor, if the alteration is present.
  • the methods herein comprise determining the further course of treatment for a subject, e.g., selecting the subject for continuation of the first treatment with the first PI3K inhibitor if the alteration is absent and selecting the subject for a second treatment if the alteration is present, wherein the second treatment includes administration of a Bcl-2 inhibitor.
  • the methods comprise determining decreased responsiveness, or resistance, of a subject to a first treatment comprising a first PI3K inhibitor.
  • the methods comprise determining that the subject shows decreased responsiveness or resistance to the first treatment if the alteration is present, wherein the second treatment includes administration of a Bcl-2 inhibitor.
  • the alteration is an STK11 copy number loss (e.g., single copy loss).
  • the STK11 copy number in a sample taken from the subject after the first treatment is lower than the STK11 copy number in a sample taken from the subject before the first treatment (e.g., there is an STK11 single copy loss).
  • the first treatment with the first PI3K inhibitor e.g., Compound 1 is a monotherapy in which the first PI3K inhibitor is the only component of the first treatment known to have a substantial therapeutic activity.
  • a prognosis-negative biomarker is chosen from one, two, three or all of the following:
  • a p53 pathway mutation e.g., TP53 C141Y;
  • a prognosis-negative biomarker is a copy number loss of STK11.
  • detection of copy number loss of STK11 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • a prognosis-negative biomarker is a dual MAPK/p53 mutation.
  • detection of the dual MAPK/p53 mutation is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • a prognosis-negative biomarker is a copy number loss of STK11 in combination with a copy number loss of TSC1, TSC2, or both.
  • detection of copy number loss of STK11 in combination with a copy number loss of TSC1 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of STK11 in combination with a copy number loss of TSC2 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of STK11 in combination with a copy number loss of TSC1 and TSC2 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • the alteration is a prognosis-negative biomarker or a progression-positive biomarker, or both.
  • detection of a prognosis-negative biomarker or a progression-positive biomarker, or both is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • the BCR pathway mutation is a mutation disclosed in Table 19.
  • the p53 pathway mutation is a mutation disclosed in Table 20.
  • the MAPK pathway mutation is a mutation disclosed in Table 18.
  • the combination thereof is a dual MAPK/p53 mutation of which a mutation is disclosed in Table 18 and a mutation is disclosed in Table 20.
  • one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, or all of the following is indicative of decreased responsiveness of the cancer, or the subject, to the treatment:
  • a p53 pathway mutation e.g., a mutation listed in Table 20 (e.g., TP53 C141Y); or
  • a MAPK pathway mutation e.g., a mutation listed in Table 18.
  • the alteration or biomarker is a copy number loss (e.g., a single copy loss) of STK11. In one embodiment, detection of copy number loss of STK11 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment. In some embodiments of any of the above aspects, the alteration or biomarker is a dual MAPK/p53 pathway mutation. In one embodiment the dual mutation includes a mutation listed in Table 18 and/or Table 20. In one embodiment, detection of the dual MAPK/p53 pathway mutation is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment. In some embodiments of any of the above aspects, the alteration or biomarker is a BCR pathway mutation.
  • detection of a BCR pathway mutation is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of TP53 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of PTEN is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of CBFAT2T3 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of YWHAE is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of PER1 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of GAS7 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of FSTL3 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of USP6 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of MAP2K4 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of EGFR is indicative of increased responsiveness of the cancer or tumor, or the subject, to the treatment; or wherein detection of copy number gain of EGFR is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment, or both.
  • detection of copy number loss of EGFR is indicative of increased responsiveness of the cancer or tumor, or the subject, to the treatment, and wherein increased responsiveness is determined using nodal criteria.
  • the alteration or biomarker is a copy number loss of STK11 in combination with a copy number loss of TSC1, TSC2, or both.
  • detection of copy number loss of STK11 in combination with a copy number loss of TSC1 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of STK11 in combination with a copy number loss of TSC2 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • detection of copy number loss of STK11 in combination with a copy number loss of TSC1 and TSC2 is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • no detectable copy number loss of STK11, TSC1, TSC2, TP53, PTEN, CBFA2T3, YWHAE, PER1, GAS7, FSTL3, USP6, or MAP2K4, or no detectable dual MAPK/p53 pathway mutation, or no detectable BCR pathway mutation is indicative of continued responsiveness to the treatment.
  • the alteration is a prognosis-negative biomarker or a progression-positive biomarker, or both.
  • detection of a prognosis-negative biomarker or a progression-positive biomarker, or both is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment.
  • no detectable copy number loss of STK11, or no detectable dual MAPK/p53 pathway mutation is indicative of continued responsiveness to the treatment.
  • the subject is evaluated prior to undergoing, while undergoing, or after undergoing, treatment with the BCR pathway inhibitor, e.g., the PI3K inhibitor.
  • the subject is evaluated at at least two time intervals, e.g., prior to undergoing and while undergoing the treatment.
  • the subject is evaluated at at least three time points, e.g., prior to undergoing, while undergoing the treatment, and after undergoing the treatment.
  • decreased responsiveness of the cancer or tumor, or the subject to the treatment is indicative of increased resistance (e.g., acquired resistance) to the treatment, e.g., the PI3K inhibitor.
  • increased resistance e.g., acquired resistance
  • the treatment is continued.
  • the treatment is altered or discontinued, thereby having a first and second treatment.
  • the method responsive to a determination of the value of the alteration or biomarker, the method further includes one, two, three, four, five, six, seven, eight, nine or all of the following:
  • identifying the subject as being in need of a treatment e.g., treatment with a PI3K inhibitor (e.g., a first treatment or a second (alternative) treatment);
  • identifying the subject as having an increased or a decreased responsiveness to the treatment e.g., the treatment with the PI3K inhibitor (e.g., a monotherapy with Compound 1);
  • identifying the subject as being a responder to the treatment e.g., identifying the subjects as being in complete remission (CR) or partial cancer remission (PR) (e.g., CR or PR subjects as described herein);
  • identifying the subject as being a non-responder to the treatment e.g., identifying the subjects as having a progressive disease (PD) or stable disease (SD) (e.g., PD or SD subjects as described herein);
  • PD progressive disease
  • SD stable disease
  • identifying the subject as having developed resistance e.g., partial or complete, acquired resistance
  • the treatment e.g., the PI3K inhibitor (e.g., Compound 1);
  • determining a treatment e.g., selecting or altering the course of, a treatment (e.g., a first treatment), a dose, a treatment schedule or time course, and/or the use of an alternative, second treatment); and/or
  • the subject is identified as having decreased responsiveness to the treatment by having at least one progression-positive biomarker.
  • the progression-positive biomarker is a genomic alteration in an NF- ⁇ B pathway gene.
  • the progression-positive biomarker is a 6q deletion region, e.g., a del(6q13-16) or a del(6q23-24).
  • the progression-positive biomarker is a TNFAIP3 mutation or copy number loss.
  • the progression-positive biomarker is an EPHA7 mutation or copy number loss.
  • the subject is a mammal, e.g., a human. In one embodiment, the subject is at risk or suffers from a cancer or tumor, e.g., a cancer or tumor described herein.
  • the subject shows decreased responsiveness to a PI3K inhibitor (e.g., is resistant or refractive to treatment with a PI3K inhibitor, e.g., Compound 1).
  • a PI3K inhibitor e.g., is resistant or refractive to treatment with a PI3K inhibitor, e.g., Compound 1).
  • the subject is identified as developing resistance (e.g., acquired resistance) to the monotherapy.
  • the subject is identified as having a decreased responsiveness (e.g., being resistance or having acquired resistance) to a monotherapy treatment with a PI3K inhibitor (e.g., Compound 1 or GS1101) (referred herein to a “first PI3K inhibitor treatment”).
  • a PI3K inhibitor e.g., Compound 1 or GS1101
  • the subject is identified as having a decreased responsiveness (e.g., being resistance or having acquired resistance) to a monotherapy treatment of a PI3K inhibitor (e.g., Compound 1).
  • the subject is identified as having an increased responsiveness to a second treatment, e.g., a treatment comprising a reduced dose of the PI3K inhibitor, or a treatment comprising a combination of the PI3K inhibitor and a Bcl-2 inhibitor.
  • a second treatment e.g., a treatment comprising a reduced dose of the PI3K inhibitor, or a treatment comprising a combination of the PI3K inhibitor and a Bcl-2 inhibitor.
  • the dose of the PI3K inhibitor, the Bcl-2 inhibitor, or both is reduced, e.g., at least 20%, at least 30%, at least 40%, or at least 50%, than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the method further includes altering a treatment (e.g., a first treatment), a dose, a treatment schedule or time course, and/or the use of an alternative, second treatment.
  • a treatment e.g., a first treatment
  • a dose e.g., a dose
  • a treatment schedule or time course e.g., a treatment schedule or time course
  • the method further includes administering the treatment (e.g., the first treatment or a second (alternative) treatment) to the subject.
  • the treatment e.g., the first treatment or a second (alternative) treatment
  • the method further includes administering a combination of the PI3K inhibitor and a Bcl-2 inhibitor in an amount sufficient to treat the cancer, in the subject, e.g., for treatment of a cancer described herein.
  • the genomic alteration biomarkers provided herein can be detected by the methods known in the art to detect genomic alterations.
  • the gene mutations or copy number alterations are detected by methods such as CytoScan Microarray (pre- and post-treatment), targeted exome sequencing (pre- and post-treatment), and Sanger sequencing.
  • the mutation or copy number alteration of STK11 is detected by STK11 FISH Probe or qPCR.
  • the biomarkers provided herein can be used to identify, diagnose, predict efficacy, predict long term clinical outcome, predict prognosis, and/or select patients for a treatment described herein. In one embodiment, the biomarkers provided herein can be used for subsets of patients with different prognostic factors.
  • Expression of a biomarkers described in this invention may be assessed by any of a wide variety of well known methods for detecting expression of a transcribed nucleic acid or protein.
  • Non-limiting examples of such methods include immunological methods for detection of secreted, cell-surface, cytoplasmic, or nuclear proteins, protein purification methods, protein function or activity assays, nucleic acid hybridization methods, nucleic acid reverse transcription methods, and nucleic acid amplification methods.
  • expression of a biomarker is assessed using an antibody (e.g. a radio-labeled, chromophore-labeled, fluorophore-labeled, or enzyme-labeled antibody), an antibody derivative (e.g. an antibody conjugated with a substrate or with the protein or ligand of a protein-ligand pair ⁇ e.g. biotin-streptavidin ⁇ ), or an antibody fragment (e.g. a single-chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically with a biomarker protein or fragment thereof, including a biomarker protein which has undergone either all or a portion of post-translational modifications to which it is normally subjected in the tumor cell (e.g. glycosylation, phosphorylation, methylation etc.).
  • an antibody e.g. a radio-labeled, chromophore-labeled, fluorophore-labeled, or enzyme-labeled antibody
  • an antibody derivative
  • expression of a biomarker is assessed by preparing mRNA/cDNA (i.e. a transcribed polynucleotide) from cells in a patient sample, and by hybridizing the mRNA/cDNA with a reference polynucleotide which is a complement of a biomarker nucleic acid, or a fragment thereof.
  • cDNA can, optionally, be amplified using any of a variety of polymerase chain reaction methods prior to hybridization with the reference polynucleotide.
  • Expression of one or more biomarkers can likewise be detected using quantitative PCR to assess the level of expression of the biomarker(s).
  • the expression level of a biomarker can be determined with reference to the effect on biomarker expression caused by a mutation or variant in a gene associated with said biomarker. Accordingly, for example, the consequences of a genomic alteration on the expression level of biomarkers referred to in the methods of the invention may be inferred directly from identification of the genomic alteration in the genome of a patient.
  • the mutation can be a point mutation, e.g. SNP, an insertion, a deletion, an amplification, a deletion, a chromosomal translocation, an interstitial deletion, a chromosomal inversion or a loss of heterozygosity.
  • a mixture of transcribed polynucleotides obtained from the sample is contacted with a substrate having fixed thereto a polynucleotide complementary to or homologous with at least a portion (e.g. at least 7, 10, 15, 20, 25, 30, 40, 50, 100, 500, or more nucleotide residues) of a biomarker nucleic acid. If polynucleotides complementary to or homologous with are differentially detectable on the substrate (e.g. detectable using different chromophores or fluorophores, or fixed to different selected positions), then the levels of expression of a plurality of biomarkers can be assessed simultaneously using a single substrate (e.g.
  • the level of expression of each biomarker in a patient sample can be compared with the normal level of expression of each of the plurality of biomarkers in non-cancerous samples of the same type, either in a single reaction mixture (i.e. using reagents, such as different fluorescent probes, for each biomarker) or in individual reaction mixtures corresponding to one or more of the biomarkers.
  • the level of expression of a biomarker in normal (i.e. non-cancerous) human tissue can be assessed in a variety of ways.
  • this normal level of expression is assessed by assessing the level of expression of the biomarker in a portion of cells which appears to be non-cancerous, and then comparing this normal level of expression with the level of expression in a portion of the tumor cells.
  • population-average values for normal expression of the biomarkers of the invention may be used.
  • the ‘normal’ level of expression of a biomarker may be determined by assessing expression of the biomarker in a patient sample obtained from a non-cancer-afflicted patient, from a patient sample obtained from a patient before the suspected onset of cancer in the patient, from archived patient samples, and the like.
  • An exemplary method for detecting the presence or absence of a biomarker protein or nucleic acid in a biological sample involves obtaining a biological sample (e.g. a tumor-associated body fluid) from a test patient and contacting the biological sample with a compound or an agent capable of detecting the polypeptide or nucleic acid (e.g., mRNA, genomic DNA, or cDNA).
  • a biological sample e.g. a tumor-associated body fluid
  • a compound or an agent capable of detecting the polypeptide or nucleic acid e.g., mRNA, genomic DNA, or cDNA.
  • the detection methods of the invention can thus be used to detect mRNA, protein, cDNA, or genomic DNA, for example, in a biological sample in vitro as well as in vivo.
  • in vitro techniques for detection of mRNA include Northern hybridizations and in situ hybridizations.
  • In vitro techniques for detection of a biomarker protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence.
  • In vitro techniques for detection of genomic DNA include Southern hybridizations.
  • In vivo techniques for detection of mRNA include polymerase chain reaction (PCR), Northern hybridizations and in situ hybridizations.
  • in vivo techniques for detection of a biomarker protein include introducing into a patient a labeled antibody directed against the protein or fragment thereof.
  • the antibody can be labeled with a radioactive marker whose presence and location in a patient can be detected by standard imaging techniques.
  • a general principle of such diagnostic and prognostic assays involves preparing a sample or reaction mixture that may contain a biomarker, and a probe, under appropriate conditions and for a time sufficient to allow the biomarker and probe to interact and bind, thus forming a complex that can be removed and/or detected in the reaction mixture.
  • These assays can be conducted in a variety of ways.
  • one method to conduct such an assay would involve anchoring the biomarker or probe onto a solid phase support, also referred to as a substrate, and detecting target biomarker/probe complexes anchored on the solid phase at the end of the reaction.
  • a sample from a patient which is to be assayed for presence and/or concentration of biomarker, can be anchored onto a carrier or solid phase support.
  • the reverse situation is possible, in which the probe can be anchored to a solid phase and a sample from a patient can be allowed to react as an unanchored component of the assay.
  • biomarker or probe molecules which are immobilized through conjugation of biotin and streptavidin.
  • biotinylated assay components can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical).
  • the surfaces with immobilized assay components can be prepared in advance and stored.
  • suitable carriers or solid phase supports for such assays include any material capable of binding the class of molecule to which the biomarker or probe belongs.
  • Well-known supports or carriers include, but are not limited to, glass, polystyrene, nylon, polypropylene, nylon, polyethylene, dextran, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.
  • the non-immobilized component is added to the solid phase upon which the second component is anchored.
  • uncomplexed components may be removed (e.g., by washing) under conditions such that any complexes formed will remain immobilized upon the solid phase.
  • the detection of biomarker/probe complexes anchored to the solid phase can be accomplished in a number of methods outlined herein.
  • the probe when it is the unanchored assay component, can be labeled for the purpose of detection and readout of the assay, either directly or indirectly, with detectable labels discussed herein and which are well-known to one skilled in the art.
  • biomarker/probe complex formation without further manipulation or labeling of either component (biomarker or probe), for example by utilizing the technique of fluorescence energy transfer (i.e. FET, see for example, Lakowicz et al., U.S. Pat. No. 5,631,169; Stavrianopoulos, et al., U.S. Pat. No. 4,868,103).
  • FET fluorescence energy transfer
  • a fluorophore label on the first, ‘donor’ molecule is selected such that, upon excitation with incident light of appropriate wavelength, its emitted fluorescent energy will be absorbed by a fluorescent label on a second ‘acceptor’ molecule, which in turn is able to fluoresce due to the absorbed energy.
  • the ‘donor’ protein molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the ‘acceptor’ molecule label may be differentiated from that of the ‘donor’. Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, spatial relationships between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the ‘acceptor’ molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter).
  • determination of the ability of a probe to recognize a biomarker can be accomplished without labeling either assay component (probe or biomarker) by utilizing a technology such as real-time Biomolecular Interaction Analysis (BIA) (see, e.g., Sjolander, S. and Urbaniczky, C., 1991, Anal. Chem. 63:2338-2345 and Szabo et al., 1995, Curr. Opin. Struct. Biol. 5:699-705).
  • BIOA Biomolecular Interaction Analysis
  • surface plasmon resonance is a technology for studying biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore).
  • analogous diagnostic and prognostic assays can be conducted with biomarker and probe as solutes in a liquid phase.
  • the complexed biomarker and probe are separated from uncomplexed components by any of a number of standard techniques, including but not limited to: differential centrifugation, chromatography, electrophoresis and immunoprecipitation.
  • differential centrifugation biomarker/probe complexes may be separated from uncomplexed assay components through a series of centrifugal steps, due to the different sedimentation equilibria of complexes based on their different sizes and densities (see, for example, Rivas, G., and Minton, A.
  • Standard chromatographic techniques may also be utilized to separate complexed molecules from uncomplexed ones.
  • gel filtration chromatography separates molecules based on size, and through the utilization of an appropriate gel filtration resin in a column format, for example, the relatively larger complex may be separated from the relatively smaller uncomplexed components.
  • the relatively different charge properties of the biomarker/probe complex as compared to the uncomplexed components may be exploited to differentiate the complex from uncomplexed components, for example through the utilization of ion-exchange chromatography resins.
  • Such resins and chromatographic techniques are well known to one skilled in the art (see, e.g., Heegaard, N.
  • Gel electrophoresis may also be employed to separate complexed assay components from unbound components (see, e.g., Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, New York, 1987-1999). In this technique, protein or nucleic acid complexes are separated based on size or charge, for example. In order to maintain the binding interaction during the electrophoretic process, non-denaturing gel matrix materials and conditions in the absence of reducing agent are typically preferred. Appropriate conditions to the particular assay and components thereof will be well known to one skilled in the art.
  • the level of biomarker mRNA can be determined both by in situ and by in vitro formats in a biological sample using methods known in the art.
  • biological sample is intended to include tissues, cells, biological fluids and isolates thereof, isolated from a patient, as well as tissues, cells and fluids present within a patient.
  • Many expression detection methods use isolated RNA.
  • any RNA isolation technique that does not select against the isolation of mRNA can be utilized for the purification of RNA from tumor cells (see, e.g., Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, New York 1987-1999).
  • large numbers of tissue samples can readily be processed using techniques well known to those of skill in the art, such as, for example, the single-step RNA isolation process of Chomczynski (1989, U.S. Pat. No. 4,843,155).
  • the isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses and probe arrays.
  • One preferred diagnostic method for the detection of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to the mRNA encoded by the gene being detected.
  • the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to a mRNA or genomic DNA encoding a biomarker of the present invention.
  • Other suitable probes for use in the diagnostic assays of the invention are described herein. Hybridization of an mRNA with the probe indicates that the biomarker in question is being expressed.
  • the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose.
  • the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in an Affymetrix gene chip array.
  • a skilled artisan can readily adapt known mRNA detection methods for use in detecting the level of mRNA encoded by the biomarkers of the present invention.
  • An alternative method for determining the level of mRNA biomarker in a sample involves the process of nucleic acid amplification, e.g., by RT-PCR (the experimental embodiment set forth in Mullis, 1987, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany, 1991, Proc. Natl. Acad. Sci. USA, 88:189-193), self sustained sequence replication (Guatelli et al., 1990, Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh et al., 1989, Proc. Natl. Acad. Sci.
  • RT-PCR the experimental embodiment set forth in Mullis, 1987, U.S. Pat. No. 4,683,202
  • ligase chain reaction Barany, 1991, Proc. Natl. Acad. Sci. USA, 88:189-193
  • self sustained sequence replication (Guatelli et al., 1990, Proc. Natl.
  • amplification primers are defined as being a pair of nucleic acid molecules that can anneal to 5′ or 3′ regions of a gene (plus and minus strands, respectively, or vice-versa) and contain a short region in between.
  • amplification primers are from about 10 to 30 nucleotides in length and flank a region from about 50 to 200 nucleotides in length. Under appropriate conditions and with appropriate reagents, such primers permit the amplification of a nucleic acid molecule comprising the nucleotide sequence flanked by the primers.
  • mRNA does not need to be isolated from the tumor cells prior to detection.
  • a cell or tissue sample is prepared/processed using known histological methods. The sample is then immobilized on a support, typically a glass slide, and then contacted with a probe that can hybridize to mRNA that encodes the biomarker.
  • An alternative method for determining the level of mRNA biomarker in a sample involves deep sequencing of cDNA generated from RNA.
  • mRNA is isolated from tumor cells, fragmented, and converted into cDNA libraries, and quantified using next generation sequencing.
  • determinations may be based on the normalized expression level of the biomarker.
  • Expression levels are normalized by correcting the absolute expression level of a biomarker by comparing its expression to the expression of a gene that is not a biomarker, e.g., a housekeeping gene that is constitutively expressed. Suitable genes for normalization include housekeeping genes such as the actin gene, or prognosis-positive cell-specific genes. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, e.g., a non-tumor sample, or between samples from different sources.
  • the expression level can be provided as a relative expression level.
  • a biomarker e.g. a prognosis-negative biomarker
  • the level of expression of the biomarker is determined for 10 or more samples of normal versus cancer cell isolates, preferably 50 or more samples, prior to the determination of the expression level for the sample in question.
  • the mean expression level of each of the genes assayed in the larger number of samples is determined and this is used as a baseline expression level for the biomarker.
  • the expression level of the biomarker determined for the test sample absolute level of expression
  • a biomarker protein is detected.
  • One agent for detecting biomarker protein of the invention is an antibody capable of binding to such a protein or a fragment thereof, preferably an antibody with a detectable label.
  • Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment or derivative thereof (e.g., Fab or F(ab′)2 can be used.
  • the term “labeled”, with regard to the probe or antibody is intended to encompass direct labeling of the probe or antibody by coupling (e.g., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin.
  • Proteins from tumor cells can be isolated using techniques that are well known to those of skill in the art.
  • the protein isolation methods employed can, for example, be such as those described in Harlow and Lane (Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).
  • a variety of formats can be employed to determine whether a sample contains a protein that binds to a given antibody.
  • formats include, but are not limited to, enzyme immunoassay (EIA), radioimmunoassay (RIA), Western blot analysis and enzyme linked immunoabsorbant assay (ELISA).
  • EIA enzyme immunoassay
  • RIA radioimmunoassay
  • ELISA enzyme linked immunoabsorbant assay
  • antibodies, or antibody fragments or derivatives can be used in methods such as Western blots or immunofluorescence techniques to detect the expressed proteins.
  • Suitable solid phase supports or carriers include any support capable of binding an antigen or an antibody.
  • Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.
  • protein isolated from tumor cells can be run on a polyacrylamide gel electrophoresis and immobilized onto a solid phase support such as nitrocellulose.
  • the support can then be washed with suitable buffers followed by treatment with the detectably labeled antibody.
  • the solid phase support can then be washed with the buffer a second time to remove unbound antibody.
  • the amount of bound label on the solid support can then be detected by conventional means.
  • specific binding pairs can be of the immune or non-immune type.
  • Immune specific binding pairs are exemplified by antigen-antibody systems or hapten/anti-hapten systems. There can be mentioned fluorescein/anti-fluorescein, dinitrophenyl/anti-dinitrophenyl, biotin/anti-biotin, peptide/anti-peptide and the like.
  • the antibody member of the specific binding pair can be produced by customary methods familiar to those skilled in the art. Such methods involve immunizing an animal with the antigen member of the specific binding pair.
  • Non-immune binding pairs include systems wherein the two components share a natural affinity for each other but are not antibodies.
  • Exemplary non-immune pairs are biotin-streptavidin, intrinsic factor-vitamin B12, folic acid-folate binding protein and the like.
  • Biotin can be covalently coupled to antibodies by utilizing commercially available active derivatives. Some of these are biotin-N-hydroxy-succinimide which binds to amine groups on proteins; biotin hydrazide which binds to carbohydrate moieties, aldehydes and carboxyl groups via a carbodiimide coupling; and biotin maleimide and iodoacetyl biotin which bind to sulfhydryl groups.
  • Fluorescein can be coupled to protein amine groups using fluorescein isothiocyanate. Dinitrophenyl groups can be coupled to protein amine groups using 2,4-dinitrobenzene sulfate or 2,4-dinitrofluorobenzene.
  • Other standard methods of conjugation can be employed to couple monoclonal antibodies to a member of a specific binding pair including dialdehyde, carbodiimide coupling, homofunctional crosslinking, and heterobifunctional crosslinking
  • Carbodiimide coupling is an effective method of coupling carboxyl groups on one substance to amine groups on another. Carbodiimide coupling is facilitated by using the commercially available reagent 1-ethyl-3-(dimethyl-aminopropyl)-carbodiimide (EDAC).
  • Homobifunctional crosslinkers including the bifunctional imidoesters and bifunctional N-hydroxysuccinimide esters, are commercially available and are employed for coupling amine groups on one substance to amine groups on another.
  • Heterobifunctional crosslinkers are reagents which possess different functional groups.
  • the most common commercially available heterobifunctional crosslinkers have an amine reactive N-hydroxysuccinimide ester as one functional group, and a sulfhydryl reactive group as the second functional group.
  • the most common sulfhydryl reactive groups are maleimides, pyridyl disulfides and active halogens.
  • One of the functional groups can be a photoactive aryl nitrene, which upon irradiation reacts with a variety of groups.
  • the detectably-labeled antibody or detectably-labeled member of the specific binding pair is prepared by coupling to a reporter, which can be a radioactive isotope, enzyme, fluorogenic, chemiluminescent or electrochemical materials.
  • a reporter can be a radioactive isotope, enzyme, fluorogenic, chemiluminescent or electrochemical materials.
  • Two commonly used radioactive isotopes are 125I and 3H.
  • Standard radioactive isotopic labeling procedures include the chloramine T, lactoperoxidase and Bolton-Hunter methods for 125I and reductive methylation for 3H.
  • detectably-labeled refers to a molecule labeled in such a way that it can be readily detected by the intrinsic enzymatic activity of the label or by the binding to the label of another component, which can itself be readily detected.
  • Enzymes suitable for use in this invention include, but are not limited to, horseradish peroxidase, alkaline phosphatase, ⁇ -galactosidase, glucose oxidase, luciferases, including firefly and renilla, ⁇ -lactamase, urease, green fluorescent protein (GFP) and lysozyme.
  • Enzyme labeling is facilitated by using dialdehyde, carbodiimide coupling, homobifunctional crosslinkers and heterobifunctional crosslinkers as described above for coupling an antibody with a member of a specific binding pair.
  • the labeling method chosen depends on the functional groups available on the enzyme and the material to be labeled, and the tolerance of both to the conjugation conditions.
  • the labeling method used in the present invention can be one of, but not limited to, any conventional methods currently employed including those described by Engvall and Pearlmann, Immunochemistry 8, 871 (1971), Avrameas and Ternynck, Immunochemistry 8, 1175 (1975), Ishikawa et al., J. Immunoassay 4(3):209-327 (1983) and Jablonski, Anal. Biochem. 148:199 (1985).
  • Labeling can be accomplished by indirect methods such as using spacers or other members of specific binding pairs.
  • An example of this is the detection of a biotinylated antibody with unlabeled streptavidin and biotinylated enzyme, with streptavidin and biotinylated enzyme being added either sequentially or simultaneously.
  • the antibody used to detect can be detectably-labeled directly with a reporter or indirectly with a first member of a specific binding pair.
  • detection is effected by reacting the antibody-first member of a specific binding complex with the second member of the binding pair that is labeled or unlabeled as mentioned above.
  • the unlabeled detector antibody can be detected by reacting the unlabeled antibody with a labeled antibody specific for the unlabeled antibody.
  • detectably-labeled as used above is taken to mean containing an epitope by which an antibody specific for the unlabeled antibody can bind.
  • an anti-antibody can be labeled directly or indirectly using any of the approaches discussed above.
  • the anti-antibody can be coupled to biotin which is detected by reacting with the streptavidin-horseradish peroxidase system discussed above.
  • biotin is utilized.
  • the biotinylated antibody is in turn reacted with streptavidin-horseradish peroxidase complex.
  • Orthophenylenediamine, 4-chloro-naphthol, tetramethylbenzidine (TMB), ABTS, BTS or ASA can be used to effect chromogenic detection.
  • a forward sandwich assay is used in which the capture reagent has been immobilized, using conventional techniques, on the surface of a support.
  • Suitable supports used in assays include synthetic polymer supports, such as polypropylene, polystyrene, substituted polystyrene, e.g. aminated or carboxylated polystyrene, polyacrylamides, polyamides, polyvinylchloride, glass beads, agarose, or nitrocellulose.
  • kits for detecting the presence of a biomarker protein or nucleic acid in a biological sample can be used to determine if a patient is suffering from or is at increased risk of developing a tumor that is less susceptible to inhibition by PI3K inhibitors.
  • the kit can comprise a labeled compound or agent capable of detecting a biomarker protein or nucleic acid in a biological sample and means for determining the amount of the protein or mRNA in the sample (e.g., an antibody which binds the protein or a fragment thereof, or an oligonucleotide probe which binds to DNA or mRNA encoding the protein).
  • Kits can also include instructions for interpreting the results obtained using the kit.
  • the kit can comprise, for example: (1) a first antibody (e.g., attached to a solid support) which binds to a biomarker protein; and, optionally, (2) a second, different antibody which binds to either the protein or the first antibody and is conjugated to a detectable label.
  • a first antibody e.g., attached to a solid support
  • a second, different antibody which binds to either the protein or the first antibody and is conjugated to a detectable label.
  • the kit can comprise, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a biomarker protein or (2) a pair of primers useful for amplifying a biomarker nucleic acid molecule.
  • the kit can also comprise, e.g., a buffering agent, a preservative, or a protein stabilizing agent.
  • the kit can further comprise components necessary for detecting the detectable label (e.g., an enzyme or a substrate).
  • the kit can also contain a control sample or a series of control samples which can be assayed and compared to the test sample.
  • Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of at an amount of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg daily.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of about 325 mg daily.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of about 250 mg daily.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of about 150 mg daily. In one embodiment, ABT-199, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 100 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, or about 5 mg daily. In one embodiment, ABT-199, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 85 mg daily. In one embodiment, ABT-199, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 75 mg daily. In one embodiment, ABT-199, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 50 mg daily.
  • ABT-263, or a pharmaceutically acceptable form thereof is administered at a dosage of at an amount of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg daily.
  • ABT-263, or a pharmaceutically acceptable form thereof is administered at a dosage of about 325 mg daily.
  • ABT-263, or a pharmaceutically acceptable form thereof is administered at a dosage of about 250 mg daily.
  • ABT-263, or a pharmaceutically acceptable form thereof is administered at a dosage of about 150 mg daily. In one embodiment, ABT-263, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 100 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, or about 5 mg daily. In one embodiment, ABT-263, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 85 mg daily. In one embodiment, ABT-263, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 75 mg daily. In one embodiment, ABT-263, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 50 mg daily.
  • a method of treating e.g., inhibiting, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of a PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof.
  • a PI3K delta selective inhibitor e.g., GS1101
  • Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the cancer is diffuse large B-cell lymphoma (activated B-cell-like), diffuse large B-cell lymphoma (germinal center B-cell-like), follicular lymphoma, T-cell lymphoma, mantle cell lymphoma, multiple myeloma.
  • the PI3K delta inhibitor e.g., GS1101
  • the Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the PI3K delta inhibitor are administered at certain dosages.
  • a method of treating, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of a PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, wherein the PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.
  • a PI3K delta inhibitor e.g., GS1101
  • Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 500 mg, from about 1 mg to about 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 400 mg, from about 200 mg to about 400 mg, from about 250 mg to about 350 mg, or about 300 mg.
  • the composition comprises the PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg daily.
  • the PI3K delta inhibitor e.g., GS1101
  • a pharmaceutically acceptable form thereof at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg daily.
  • the PI3K delta inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, less than about 30 mg, less than, less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily.
  • a method of treating, managing, or preventing a cancer in a subject comprising administering to the subject a PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, in combination with a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, wherein the cancer is diffuse large B-cell lymphoma (activated B-cell-like), diffuse large B-cell lymphoma (germinal center B-cell-like), follicular lymphoma, T-cell lymphoma, mantle cell lymphoma, or multiple myeloma.
  • a Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the cancer is diffuse large B-cell lymphoma (activated B-cell-like), diffuse large B-cell lymphoma (germinal center B-cell-like), follicular lymphoma, T-cell lymphoma, mantle cell lymphoma,
  • the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, are administered at certain dosages.
  • a method of treating e.g., inhibiting, managing, or preventing a cancer in a subject comprising administering to the subject a PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, wherein the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.
  • the Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the PI3K delta/gamma dual inhibitor is administered at a dosage of in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg daily.
  • the PI3K delta/gamma dual inhibitor is administered at a dosage of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily.
  • a method of treating e.g., inhibiting, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, wherein the cancer is Diffuse large B-cell lymphoma (activated B-cell-like), Diffuse large B-cell lymphoma (germinal center B-cell-like), Follicular lymphoma, T-cell lymphoma, Mantle cell lymphoma, Multiple myeloma.
  • the Bcl-2 inhibitor is ABT-199.
  • the Bcl-2 inhibitor is ABT-263.
  • Compound 1, or a pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof are administered at certain dosages.
  • a method of treating, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of Compound 1:
  • Bcl-2 inhibitor or a pharmaceutically acceptable form thereof, wherein Compound 1, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.
  • Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • Compound 1, or a pharmaceutically acceptable form thereof is administered at a dosage of in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg daily.
  • Compound 1, or a pharmaceutically acceptable form thereof is administered at a dosage of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily.
  • the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 800 mg, from about 0.1 mg to about 750 mg, from about 0.1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 400 mg, from about 10 mg to about 300 mg, or from about 50 mg to about 250 mg daily.
  • the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg daily.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg daily.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of about 325 mg daily.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of about 400 mg daily.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of about 250 mg daily. In one embodiment, ABT-199, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 150 mg daily. In one embodiment, ABT-199, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 100 mg daily, about 90 mg daily, about 85 mg daily, about 80 mg daily, about 75 mg daily, about 70 mg daily, about 65 mg, about 60 mg daily, about 55 mg daily, about 50 mg daily, about 45 mg daily, about 40 mg daily, about 35 mg daily, about 30 mg daily, about 25 mg daily, about 20 mg daily, about 15 mg daily, about 10 mg daily, or about 5 mg daily.
  • ABT-199, or a pharmaceutically acceptable form thereof is administered at a dosage of about 75 mg daily. In one embodiment, the composition comprises ABT-199, or a pharmaceutically acceptable form thereof, at an amount of about 55 mg. In one embodiment, ABT-199, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 50 mg daily.
  • ABT-263, or a pharmaceutically acceptable form thereof is administered at a dosage of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 325 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg daily.
  • ABT-263, or a pharmaceutically acceptable form thereof is administered at a dosage of about 325 mg daily.
  • ABT-263, or a pharmaceutically acceptable form thereof is administered at a dosage of about 250 mg daily.
  • ABT-263, or a pharmaceutically acceptable form thereof is administered at a dosage of about 150 mg daily. In one embodiment, ABT-263, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 100 mg daily, about 90 mg daily, about 85 mg daily, about 80 mg daily, about 75 mg daily, about 70 mg daily, about 65 mg, about 60 mg daily, about 55 mg daily, about 50 mg daily, about 45 mg daily, about 40 mg daily, about 35 mg daily, about 30 mg daily, about 25 mg daily, about 20 mg daily, about 15 mg daily, about 10 mg daily, or about 5 mg daily. In one embodiment, ABT-263, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 75 mg daily. In one embodiment, the composition comprises ABT-263, or a pharmaceutically acceptable form thereof, at an amount of about 55 mg. In one embodiment, ABT-263, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 50 mg daily.
  • a daily dosage can be achieved by a single administration of the targeted dosage amount or multiple administrations of smaller dosage amount(s).
  • a 150 mg daily dosage can be achieved by a single administration of 150 mg of the therapeutic agent per day, two administrations of 75 mg of the therapeutic agent per day, or three administrations of 50 mg of the therapeutic agent per day.
  • the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, is administered to the subject at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, is administered.
  • the PI3K inhibitor e.g., Compound 1
  • the Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the PI3K inhibitor e.g., Compound 1
  • the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), or a pharmaceutically acceptable form thereof, is administered to the subject at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, is administered.
  • the Bcl-2 inhibitor is ABT-199.
  • the Bcl-2 inhibitor is ABT-263.
  • the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263), are administered via a same route, e.g., both are administered orally.
  • the PI3K inhibitor (e.g., Compound 1), or a pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) are administered via different routes, e.g., one is administered orally and the other is administered intravenously.
  • the PI3K inhibitor (e.g., Compound 1) is administered orally once per day and ABT-199 is administered orally once per day.
  • the PI3K inhibitor (e.g., Compound 1) is administered orally once per day and ABT-263 is administered orally once per day.
  • MRD minimal residual disease negativity
  • compositions and methods described herein are effective to reduce MRD.
  • the methods described herein include selecting a subject for treatment with the combination of a PI3K inhibitor and a Bcl-2 inhibitor.
  • the subject e.g., a patient with a cancer, e.g., a cancer described herein
  • the selection is based on the presence of an MRD above a preselected level (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells).
  • the methods described herein further comprise monitoring the MRD in a subject, e.g., evaluating MRD at at least one, two, three, four, five, six, nine months after initiating, continuing or ceasing treatment (e.g., PI3K inhibitor monotherapy or Bcl-2 inhibitor monotherapy, or a combination therapy disclosed herein).
  • monitoring the MRD in a subject e.g., evaluating MRD at at least one, two, three, four, five, six, nine months after initiating, continuing or ceasing treatment (e.g., PI3K inhibitor monotherapy or Bcl-2 inhibitor monotherapy, or a combination therapy disclosed herein).
  • the combination of a PI3K inhibitor (e.g. a PI3K inhibitor described herein) and a Bcl-2 inhibitor (e.g., a Bcl-2 inhibitor described herein) is effective to reduce the MRD in the subject, e.g., below a level previously measured in the subject (e.g., the level measured before the combination treatment).
  • the combination of a PI3K inhibitor and a Bcl-2 inhibitor is effective to reduce the MRD in the subject below the level observed during or after treatment with a monotherapy, e.g., a monotherapy comprising either the PI3K inhibitor or the Bcl-2 inhibitor.
  • the MRD is decreased below the level observed during treatment with a monotherapy comprising the PI3K inhibitor.
  • the combination is effective to reduce the MRD below a preselected cutoff value (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells).
  • a preselected cutoff value e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells.
  • the preselected cutoff value is 1 malignant cell in 1000 normal cells.
  • the treatment e.g., PI3K inhibitor monotherapy or Bcl-2 inhibitor monotherapy, or a combination therapy disclosed herein
  • the treatment e.g., PI3K inhibitor monotherapy or Bcl-2 inhibitor monotherapy, or a combination therapy disclosed herein
  • a second treatment can be initiated (e.g., PI3K inhibitor monotherapy or Bcl-2 inhibitor monotherapy, a combination therapy disclosed herein, or a combination with a third agent).
  • a method of treating cancer in a subject comprising (i) administering to the subject a monotherapy (e.g., a monotherapy comprising a PI3K inhibitor or a second therapeutic agent as described herein) and monitoring the MRD in the subject, and (ii) if the MRD increases above a preselected cutoff value (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells), administering to the subject a PI3K inhibitor in combination with a Bcl-2 inhibitor.
  • the combination is effective to reduce the MRD, e.g. to reduce the MRD below the cutoff value.
  • the preselected cutoff value is 1 malignant cell in 1000 or 10,000 normal cells.
  • a method of increasing the depth of response resulting in minimal residual disease (MRD) negativity in a subject diagnosed with a cancer comprising: (a) administering to the subject a therapeutically effective amount of a PI3K inhibitor (e.g., Compound 1), and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof; (b) monitoring the amount of MRD negativity in the subject, e.g., by methods such as flow cytometry, sequencing, or PCR, and administering a monotherapy comprising the PI3K inhibitor, or a pharmaceutically acceptable form thereof, to the subject if the amount of MRD negativity in the subject represents greater than 1 malignant cell in 1000 normal cells; and (c) monitoring the amount of MRD negativity, e.g., by methods such as flow cytometry, sequencing, or PCR in the subject receiving the monotherapy, and administering a second combination therapy comprising the PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor
  • the Bcl-2 inhibitor is ABT-199, ABT-263, ABT-737, G3139 (genasense or oblimersen), GX15-070 (obatoclax mesylate), HA14-1, TW-37, sabutoclax, Gossypol (AT-101), antimycin A, apogossypol to the subject if the amount of MRD negativity in the subject is at least 0.001%.
  • the combination therapy provided herein leads to the reduction or diminishment of one or more undesirable side effects associated with the monotherapy of either the PI3K inhibitor or the Bcl-2 inhibitor.
  • monotherapy of a Bcl-2 inhibitor e.g., ABT-199 at a dose such as 1200 mg
  • a dose reduction of ABT-199 can diminish the undesirable side effects associated with monotherapy of a Bcl-2 inhibitor.
  • a PI3K inhibitor and a Bcl-2 inhibitor can have synergistic effects.
  • the synergistic effect can be measured by timing, e.g., by a delay in the development of resistance, to at least one of the agents, or an increased in the period of remission.
  • the synergistic effect can also be measured in the quality of remission, e.g., the synergistic effect can be a reduction in resistance (e.g., a decrease in a measure of resistance or a decreased likelihood of developing resistance), an increased likelihood of experiencing complete remission, or a reduction in the levels of MRD (e.g., to below detectable levels).
  • PI3K inhibitor e.g., Compound 1 or CAL-101
  • Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the method comprises administering a combination of a PI3K inhibitor (e.g., Compound 1 or CAL-101) and a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263).
  • Both agents may be administered to the subject before the subject develops resistance to one or both of the PI3K inhibitor or the Bcl-2 inhibitor, or after the subject develops resistance to the PI3K inhibitor or the Bcl-2 inhibitor.
  • a first agent e.g., the PI3K inhibitor or Bcl-2 inhibitor
  • the first agent is withdrawn.
  • a first agent e.g., the PI3K inhibitor of Bcl-2 inhibitor
  • the patient has elevated Bcl-2 levels, e.g., in the cancer cell.
  • the patient has elevated levels of a Bcl-2 family members such as NOXA, BMF, BIM, PUMA, and HRK, e.g., in the cancer cell.
  • Increased levels of Bcl-2 or its family member may be measured, e.g., by measuring DNA copy number, RNA levels or protein levels.
  • the level of Bcl-2 or its family member are increased by at least 25%, 50%, 75%, 2-fold, 3-fold, 5-fold, or 10-fold over levels before treatment began (e.g., treatment with the PI3K inhibitor).
  • the subject is not resistant to a PI3K inhibitor (e.g., Compound 1 or CAL-101). In some embodiments, the subject is not resistant to a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263). In certain embodiments, the subject has previously been administered a PI3K inhibitor (e.g., Compound 1 or CAL-101) as a monotherapy or in combination with an agent other than a Bcl-2 inhibitor. In some embodiments, the subject has previously been administered a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) as a monotherapy or in combination with an agent other than a PI3K inhibitor.
  • a PI3K inhibitor e.g., Compound 1 or CAL-101
  • Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the subject has a cancer, e.g., a cancer described herein.
  • resistance is delayed compared to the time in which resistance generally develops when the subject is treated with any of the agents or inhibitors alone as monotherapy.
  • the resistance is delayed by at least 2 weeks, e.g., at least 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months, 1 year, 2 years, 4 years, 6 years, 8 years, or more.
  • remission e.g., complete remission or partial remission
  • remission is prolonged compared to the time in which remission generally lasts when the subject is treated with any of the agents or inhibitors alone as monotherapy.
  • remission is prolonged by at least 2 weeks, e.g., at least 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months, 1 year, 2 years, 4 years, 6 years, 8 years, or more.
  • a method of reducing e.g., overcoming resistance of a subject to a PI3K inhibitor (e.g., Compound 1 or CAL-101), comprising administering the PI3K inhibitor as a monotherapy to the subject until development of resistance in the subject to the PI3K inhibitor, and subsequently administering a Bcl-2 inhibitor (e.g., ABT-199 or ABT-263) to the subject.
  • the method comprises continuing administration of the PI3K inhibitor (e.g., at the same dosage, lower dosage, or higher dosage) to the subject in combination with the Bcl-2 inhibitor.
  • the method comprises discontinuing administration of the PI3K inhibitor upon commencing administration of the Bcl-2 inhibitor. For example the administration of the PI3K inhibitor is stopped before administration of the Bcl-2 inhibitor commences. In other examples, the dosage of the PI3K inhibitor is decreased, e.g., gradually, upon commencing administration of the Bcl-2 inhibitor.
  • the formulations or compositions described herein can include a PI3K inhibitor (e.g., one or more PI3K inhibitors as described herein) and/or one or more additional agents (e.g., a Bcl-2 inhibitor, e.g., one or more Bcl-2 inhibitors) as described herein.
  • a PI3K inhibitor e.g., one or more PI3K inhibitors as described herein
  • additional agents e.g., a Bcl-2 inhibitor, e.g., one or more Bcl-2 inhibitors
  • the PI3K inhibitor and the additional agent(s) are included in the same dosage form.
  • the PI3K inhibitor e.g., one or more PI3K inhibitors as described herein
  • the second agent e.g., a Bcl-2 inhibitor, e.g., one or more Bcl-2 inhibitors
  • the PI3K inhibitor and the second agent are included in separate dosage forms.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), capsules, boluses, powders, granules, pastes for application to the tongue, and intraduodenal routes; parenteral administration, including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; intravaginally or intrarectally, for example, as a pessary, cream, stent or foam; sublingually; ocularly; pulmonarily; local delivery by catheter or stent; intrathecally, or nasally.
  • oral administration for example
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants.
  • adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants.
  • Prevention of the action of microorganisms upon the compounds described herein may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound described herein and/or the chemotherapeutic with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound as disclosed herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the concentration of the PI3K inhibitor e.g., one or more PI3K inhibitors, e.g., Compound 1 and/or GS1101 or another agent (e.g., the Bcl 2 inhibitor, e.g., one or more Bcl 2 inhibitors as described herein) provided a pharmaceutical composition disclosed herein or administered in a method disclosed herein is less than about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about
  • the concentration of the PI3K inhibitor e.g., one or more PI3K inhibitors, e.g., Compound 1 and/or GS1101
  • another agent e.g., the Bcl 2 inhibitor, e.g., one or more Bcl 2 inhibitors as described herein
  • a pharmaceutical composition disclosed herein or administered in a method disclosed herein is greater than about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%, about 19.50%, about 19.25%, about 19%, about 18.75%, about 18.50%, about 18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%, about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about 15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about 14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%,
  • the concentration of the PI3K inhibitor e.g., one or more PI3K inhibitors, e.g., Compound 1 and/or GS1101
  • another agent e.g., the Bcl 2 inhibitor, e.g., one or more Bcl 2 inhibitors as described herein
  • a pharmaceutical composition disclosed herein or administered in a method disclosed herein is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0. 0.
  • the concentration of the PI3K inhibitor e.g., one or more PI3K inhibitors, e.g., Compound 1 and/or GS1101 or another agent (e.g., the Bcl 2 inhibitor, e.g., one or more Bcl 2 inhibitors as described herein) provided a pharmaceutical composition disclosed herein or administered in a method disclosed herein is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, or approximately 0.1% to approximately 0.9%, w/w, w/v or v/v.
  • the concentration of the PI3K inhibitor e.g., one or more PI3K inhibitors, e.g., Compound 1 and/or GS110
  • the amount of Compound 1 or one or more of the therapeutic agent disclosed herein is equal to or less than about 10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g, about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about 3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2 g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08
  • the concentration of the PI3K inhibitor e.g., one or more PI3K inhibitors, e.g., Compound 1 and/or GS1101) or another agent (e.g., the Bcl 2 inhibitor, e.g., one or more Bcl 2 inhibitors as described herein) provided a pharmaceutical composition disclosed herein or administered in a method disclosed herein is more than about 0.0001 g, about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about 0.0065 g, about 0.007 g
  • the amount of Compound 1 or one or more of the therapeutic agent disclosed herein is in the range of about 0.0001 to about 10 g, about 0.0005 to about 9 g, about 0.001 to about 8 g, about 0.005 to about 7 g, about 0.01 to about 6 g, about 0.05 to about 5 g, about 0.1 to about 4 g, about 0.5 to about 4 g, or about 1 to about 3 g.
  • PI3K inhibitor e.g., one or more PI3K inhibitors
  • another agent e.g., the Bcl-2 inhibitor, e.g., one or more Bcl-2 inhibitors as described herein
  • PI3K inhibitor e.g., Compound 1
  • another agent e.g., the Bcl-2 inhibitor, e.g., one or more Bcl-2 inhibitors as described herein
  • is formulated for oral administration is formulated for oral administration.
  • compositions for oral administration containing a compound as disclosed herein, and a pharmaceutical excipient suitable for oral administration.
  • pharmaceutical compositions for oral administration containing: (i) an effective amount of a disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for oral administration.
  • the pharmaceutical composition further contains: (iv) an effective amount of a third agent.
  • the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption.
  • Pharmaceutical compositions suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the present disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds.
  • water can be added (e.g., about 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • pharmaceutical compositions and dosage forms which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous pharmaceutical compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations. In some embodiments, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia , sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia , sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • talc calcium carbonate
  • microcrystalline cellulose e.g., powdere., powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants can be used in the pharmaceutical compositions as provided herein to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant can produce tablets which can disintegrate in the bottle. Too little can be insufficient for disintegration to occur and can thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) can be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary based upon the type of formulation and mode of administration, and can be readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the active ingredient therein can be combined with various sweetening or flavoring agents, coloring matter or dyes and, for example, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactant which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be employed, a mixture of lipophilic surfactants can be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.
  • a suitable hydrophilic surfactant can generally have an HLB value of at least about 10, while suitable lipophilic surfactants can generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value).
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants can be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures
  • ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants can be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate,
  • Hydrophilic non-ionic surfactants can include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and an
  • hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl oleate
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • non-limiting examples of lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the pharmaceutical composition can include a solubilizer to ensure good solubilization and/or dissolution of a compound as provided herein and to minimize precipitation of the compound. This can be especially important for pharmaceutical compositions for non-oral use, e.g., pharmaceutical compositions for injection.
  • a solubilizer can also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ⁇ -caprolactam
  • solubilizers can also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer can be limited to a bioacceptable amount, which can be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of about 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients.
  • solubilizer can also be used, such as about 5%, 2%, 1% or even less.
  • the solubilizer can be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
  • the pharmaceutical composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, oils, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • Exemplary preservatives can include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid monohydrate disodium edetate
  • dipotassium edetate dipotassium edetate
  • edetic acid fumaric acid, malic acid
  • phosphoric acid sodium edetate
  • tartaric acid tartaric acid
  • trisodium edetate trisodium edetate.
  • antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus , evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba , macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, s
  • oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • an acid or a base can be incorporated into the pharmaceutical composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples can include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic
  • the therapeutic agent e.g., Compound 1 or Bcl-2 inhibitor
  • the Bcl-2 inhibitor e.g., ABT-199 or ABT-263
  • the formulation can comprise of 60% phosal 50 propylene glycol (PG), 30% polyethylene glycol (PEG) 400 and 10% ethanol.
  • the PI3K inhibitor (e.g., Compound 1 or GS1101) or another agent (e.g., a Bcl-2 inhibitor) disclosed herein may be delivered in the form of pharmaceutically acceptable compositions which comprise the PI3K inhibitor (e.g., (e.g., Compound 1 or GS1101) described herein and/or one or more additional therapeutic agents, formulated together with one or more pharmaceutically acceptable excipients.
  • the PI3K inhibitor (e.g., Compound 1 or GS1101) or one or more of the other agents are administered in separate pharmaceutical compositions and may (e.g., because of different physical and/or chemical characteristics) be administered by different routes (e.g., one therapeutic is administered orally, while the other is administered intravenously).
  • the PI3K inhibitor e.g., Compound 1 or GS1101
  • the PI3K inhibitor e.g., Compound 1 or GS1101
  • the PI3K inhibitor e.g., Compound 1 or GS1101
  • the other agents disclosed herein may be administered in the same pharmaceutical composition.
  • the selected dosage level will depend upon a variety of factors including, for example, the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a suitable daily dose of Compound 1 described herein and/or a therapeutic agent will be that amount of the compound which, in some embodiments, may be the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described herein. Generally, doses of Compound 1 or the therapeutic agent described herein for a patient, when used for the indicated effects, will range from about 0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg per day, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about 100 mg per day, or about 0.0001 mg to about 500 mg per day, or about 0.001 mg to about 500 mg per day, or about 0.01 mg to 1000 mg, or about 0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg per day, or about 1 mg to 50 mg per day, or about 5 mg to 40 mg per day.
  • An exemplary dosage is about 10 to 30 mg per day.
  • a suitable dose would be about 0.05 to about 7 g/day, such as about 0.05 to about 2.5 g/day.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • the compounds may be administered daily, every other day, three times a week, twice a week, weekly, or bi-weekly.
  • the dosing schedule can include a “drug holiday,” e.g., the drug may be administered for two weeks on, one week off, or three weeks on, one week off, or four weeks on, one week off, etc., or continuously, without a drug holiday.
  • the compounds may be administered orally, intravenously, intraperitoneally, topically, transdermally, intramuscularly, subcutaneously, intranasally, sublingually, or by any other route.
  • Compound 1 or the therapeutic agent described herein may be administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, about once every two weeks, about once a week, or about once every other day. In another embodiment, Compound 1 as disclosed herein and another therapeutic agent are administered together from about once per day to about 6 times per day. In another embodiment, the administration of Compound 1 as provided herein and a therapeutic agent continues for less than about 7 days. In yet another embodiment, the administration continues for more than about 6 days, about 10 days, about 14 days, about 28 days, about two months, about six months, or about one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • an agent as disclosed herein is administered for more than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 14, or about 28 days. In some embodiments, an agent as disclosed herein is administered for less than about 28, about 14, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 day. In some embodiments, a therapeutic agent as disclosed herein is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • Compound 1 described herein may be administered in combination with one or more therapeutic agent, the doses of each agent or therapy may be lower than the corresponding dose for single-agent therapy.
  • the dose for single-agent therapy can range from, for example, about 0.0001 to about 200 mg, or about 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1 to about 100 mg, or about 1 to about 50 mg per kilogram of body weight per day.
  • Compound 1 provided herein is administered in a pharmaceutical composition that comprises one or more therapeutic agents, and the agent has a shorter half-life than Compound 1, unit dose forms of the agent and Compound 1 may be adjusted accordingly.
  • kits may include a pharmaceutical composition as described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like.
  • kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the pharmaceutical composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider.
  • information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
  • a memory aid is provided with the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.
  • a “daily dose” may be a single tablet or capsule or several tablets or capsules to be taken on a given day.
  • the kit may contain a PI3K inhibitor (e.g., one or more PI3K inhibitors, e.g., Compound 1 or GS1101) in combination with another agent (e.g., a Bcl-1 inhibitor, e.g., one or more Bcl-1 inhibitors as described herein).
  • a PI3K inhibitor and the other agent are provided as separate pharmaceutical compositions in separate containers within the kit.
  • the PI3K inhibitor as disclosed herein and the other agent are provided as a single pharmaceutical composition within a container in the kit.
  • Suitable packaging and additional articles for use are known in the art and may be included in the kit.
  • kits may further comprise devices that are used to administer the active agents.
  • devices include, but are not limited to, syringes, drip bags, patches, and inhalers. Kits described herein may be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits can also, in some embodiments, be marketed directly to the consumer.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. The strength of the sheet is such that the tablets or capsules may be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • Kits may further comprise pharmaceutically acceptable vehicles that may be used to administer one or more active agents.
  • the kit can comprise a sealed container of a suitable vehicle in which the active agent may be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as, but not limited to, ethyl alcohol
  • the present disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds.
  • water may be added (e.g., about 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms may be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • pharmaceutical compositions and dosage forms which contain lactose may be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous pharmaceutical compositions may be packaged using materials known to prevent exposure to water such that they may be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • the method is described as follows. Cells are thawed from a liquid nitrogen preserved state. Once cells have been expanded and divide at their expected doubling times, screening begins. Cells are seeded in growth media in either black 1536-well or 384-well tissue culture treated plates. Cells are then equilibrated in assay plates via centrifugation and placed in incubators attached to the Dosing Modules at 37° C. for 24 hours before treatment. At the time of treatment, a set of assay plates (which do not receive treatment) are collected and ATP levels are measured by adding ATPLite (Perkin Elmer). These Tzero (T 0 ) plates are read using ultra-sensitive luminescence on Envision plate readers (Perkin Elmer).
  • Treated assay plates are incubated with compound for 72 hours. After 72 hours, plates are developed for endpoint analysis using ATPLite. All data points are collected via automated processes, quality controlled and analyzed using Zalicus software. Assay plates are accepted if they pass the following quality control standards: relative luciferase values are consistent throughout the entire experiment, Z-factor scores are greater than 0.6, untreated/vehicle controls behave consistently on the plate.
  • Inhibition (I) is defined as
  • T is treated cell count and V is untreated (vehicle) cell count (at 72 hours).
  • the measure of effect in the experiment can be the inhibition of cellular response relative to the untreated level (vehicle alone).
  • GI Growth Inhibition
  • T0 time of dosing
  • T72 72 hours
  • a GI reading of 0% represents no growth inhibition—T72 compound-treated and T72 vehicle signals are matched.
  • a GI reading of 100% represents complete growth inhibition—T72 compound-treated and T0 vehicle signals are matched.
  • Cell numbers have not increased during the treatment period in wells with GI 100% and may suggest a cytostatic effect for compounds reaching a plateau at this effect level.
  • a GI reading of 200% represents complete death of all cells in the culture well. Compounds reaching an activity plateau of GI 200% are considered cytotoxic.
  • GI is calculated by applying the following test and equation:
  • T is the signal measure for a test article
  • V is the vehicle-treated control measure
  • V 0 is the vehicle control measure at time zero. This formula is derived from the Growth Inhibition calculation used in the National Cancer Institute's NCI-60 high-throughput screen.
  • Potency shifting was evaluated using an isobologram, which demonstrates how much less drug is required in combination to achieve a desired effect level, when compared to the single agent doses needed to reach that effect.
  • the isobologram was drawn by identifying the locus of concentrations that correspond to crossing the indicated inhibition level. This is done by finding the crossing point for each single agent concentration in a dose matrix across the concentrations of the other single agent. Practically, each vertical concentration C Y is held fixed while a bisection algorithm is used to identify the horizontal concentration C X in combination with that vertical dose that gives the chosen effect level in the response surface Z(C X ,C Y ). These concentrations are then connected by linear interpolation to generate the isobologram display.
  • the isobologram contour fall below the additivity threshold and approaches the origin, and an antagonistic interaction would lie above the additivity threshold.
  • the error bars represent the uncertainty arising from the individual data points used to generate the isobologram.
  • the uncertainty for each crossing point is estimated from the response errors using bisection to find the concentrations where Z ⁇ Z (C X ,C Y ) and Z+ ⁇ Z (C X ,C Y ) cross I cut , where ⁇ Z is the standard deviation of the residual error on the effect scale.
  • Synergy Score a scalar measure to characterize the strength of synergistic interaction termed the Synergy Score. The Synergy Score is calculated as:
  • the fractional inhibition for each component agent and combination point in the matrix is calculated relative to the median of all vehicle-treated control wells.
  • the Synergy Score equation integrates the experimentally-observed activity volume at each point in the matrix in excess of a model surface numerically derived from the activity of the component agents using the Loewe model for additivity. Additional terms in the Synergy Score equation (above) are used to normalize for various dilution factors used for individual agents and to allow for comparison of synergy scores across an entire experiment.
  • the inclusion of positive inhibition gating or an I data multiplier removes noise near the zero effect level, and biases results for synergistic interactions at that occur at high activity levels.
  • Synergy Score measure was used for the self-cross analysis. Synergy Scores of self-crosses are expected to be additive by definition and, therefore, maintain a synergy score of zero. However, while some self-cross synergy scores are near zero, many are greater suggesting that experimental noise or non-optimal curve fitting of the single agent dose responses are contributing to the slight perturbations in the score. This strategy was cell line-centric, focusing on self-cross behavior in each cell line versus a global review of cell line panel activity.
  • Loewe Volume (Loewe Vol) is used to assess the overall magnitude of the combination interaction in excess of the Loewe additivity model. Loewe Volume is particularly useful when distinguishing synergistic increases in a phenotypic activity (positive Loewe Volume) versus synergistic antagonisms (negative Loewe Volume). When antagonisms are observed, as in the current dataset, the Loewe Volume should be assessed to examine if there is any correlation between antagonism and a particular drug target-activity or cellular genotype. This model defines additivity as a non-synergistic combination interaction where the combination dose matrix surface should be indistinguishable from either drug crossed with itself. The calculation for Loewe additivity is:
  • XI and YI are the single agent effective concentrations for the observed combination effect I.
  • XI and YI are the single agent effective concentrations for the observed combination effect I.
  • a combination of 0.5 ⁇ M of A and 0.5 ⁇ M of B should also inhibit by 50%.
  • the types of cell lines tested are diffuse large B-cell lymphoma (DLBCL) activated B-cell-like (ABC), DLBCL germinal center B-cell-like (GCB), follicular lymphoma, mantle cell lymphoma, multiple myeloma, and T-cell lymphoma.
  • DLBCL diffuse large B-cell lymphoma
  • ABSC B-cell-like
  • GCB DLBCL germinal center B-cell-like
  • follicular lymphoma mantle cell lymphoma
  • multiple myeloma multiple myeloma
  • T-cell lymphoma T-cell lymphoma
  • Synergy score CI 50 Synergy therapeutic growth growth score CI 50 agent Cell Line inhibition inhibition inhibition inhibition ABT-199 HBL-1 A3 T A2 U ABT-199 OCI-Ly3 A3 S A2 T ABT-199 U-2932 A3 S A2 S ABT-199 TMD8 A3 S A3 S ABT-263 OCI-Ly3 A3 U A1 W ABT-263 HBL-1 A3 S A2 U ABT-263 U-2932 A3 T A2 T ABT-263 TMD8 A3 S A2 T
  • FIG. 1 shows isobolograms depicting the synergistic effect of the combination of Compound 1 and ABT-199 in SU-DHL-4 and DoHH-2 cell lines, respectively. The results are shown in Table 2 below.
  • Synergy score CI 50 Synergy therapeutic growth growth score CI 50 agent Cell Line inhibition inhibition inhibition inhibition ABT-199 OCI-Ly7 A1 A1 ABT-199 SU-DHL- A1 W A1 W 10-epst ABT-199 Farage A2 W A1 ABT-199 DOHH-2 A4 S A3 S ABT-199 SU-DHL- A4 S A3 S 4-epst ABT-263 OCI-Ly7 A1 W A1 ABT-263 Farage A3 T A2 T ABT-263 SU-DHL- A3 U A2 U 10-epst ABT-263 SU-DHL- A4 T A3 S 4-epst ABT-263 DOHH-2 A4 S A3 S
  • FIG. 3 shows an isobologram depicting the synergistic effect of the combination of Compound 1 and ABT-199 in WSU-NHL cell line. The results are shown in Table 3 below.
  • Synergy score CI 50 Synergy therapeutic growth growth score CI 50 agent Cell Line inhibition inhibition inhibition inhibition ABT-199 RL A3 U A1 W ABT-199 KARPAS- A3 T A2 U 422 ABT-199 WSU- A3 T A2 S NHL ABT-263 RL A3 U A1 U ABT-263 WSU- A4 T A3 S NHL ABT-263 KARPAS- A4 S A3 T 422
  • Cell lines related to T-cell lymphoma were exposed to a combination of Compound 1 and a Bcl-2 inhibitor.
  • the cell line includes HH and Karpas-299. The results are shown in Table 4 below.
  • Synergy score CI 50 Synergy therapeutic Cell growth growth score CI 50 agent Line inhibition inhibition inhibition inhibition ABT-199 KARPAS-299 A1 A1 ABT-199 HH A2 S A1 T ABT-263 KARPAS-299 A1 A1 ABT-263 HH A3 U A2 S
  • FIG. 2 shows an isobologram depicting the synergistic effect of the combination of Compound 1 and ABT-199 in Mino cell line. The results are shown in Table 5 below.
  • Synergy score CI 50 Synergy therapeutic Cell growth growth score CI 50 agent Line inhibition inhibition inhibition inhibition ABT-199 GRANTA-519 A2 T A1 W ABT-199 Jeko-1 A2 S A2 S ABT-199 Mino A4 S A3 S ABT-263 GRANTA-519 A3 S A1 W ABT-263 Mino A3 S A2 T ABT-263 Jeko-1 A3 S A3 S
  • Cell lines related to multiple myeloma were exposed to a combination of Compound 1 and a Bcl-2 inhibitor. These cell lines include NCI-H929, OMP-2, and RPMI-8226. The results are shown in Table 6 below.
  • Synergy score CI 50 Synergy therapeutic Cell growth growth score CI 50 agent Line inhibition inhibition inhibition inhibition ABT-199 NCI-H929 A2 U A1 U ABT-199 RPMI-8226 A2 W A1 ABT-199 OPM-2 A2 U A1 ABT-263 NCI-H929 A2 U A2 T ABT-263 OPM-2 A3 T A2 U ABT-263 RPMI-8226 A3 T A2 U
  • RNAseq technology was used to measure gene expression changes in peripheral blood in patients treated with Compound 1.
  • the patients were treated as part of a clinical trial (identifier NCT01476657) which is a phase 1 study in patients with advanced hematologic malignancies. Briefly, RNA was extracted from 200 ul of blood using TRI reagent, followed by RNA purification using a Zymo-Spin column. Timepoints were taken at baseline and cycle 1 day 8 (C1D8), which is 7 days of Compound 1 treatment. Expression was quantified using both FPKM and VOOM methods. Filters were used to prioritize genes identified during this analysis.
  • FIGS. 5A , 5 B, and 5 C show expression levels of selected genes from this study.
  • FIG. 6 uses a graph format to visualize several apoptotic genes examined in the study, and illustrates increased levels of at least NOXA, BMF, BIM, Bcl-22, PUMA, and HRK after 8 and 28 days after treatment with Compound 1.
  • this experiment provides a rationale for a combination treatment with a PI3K inhibitor such as Compound 1 with a Bcl-2 inhibitor.
  • a PI3K inhibitor such as Compound 1 with a Bcl-2 inhibitor.
  • increased expression of the pro-survival protein Bcl-2 can contribute to resistance to PI3K inhibitor treatment. Accordingly, administering a Bcl-2 inhibitor can overcome this resistance mechanism by allowing the cell to enter the apoptosis pathway.
  • cancer cells respond to Compound 1 treatment by upregulating at least five pro-apoptotic genes, e.g., inhibitors of Bcl-2, e.g., BIM, BMF, HRK, NOXA, and PUMA.
  • pro-apoptotic genes e.g., inhibitors of Bcl-2, e.g., BIM, BMF, HRK, NOXA, and PUMA.
  • Bcl-2 e.g., BIM, BMF, HRK, NOXA, and PUMA.
  • pro-apoptotic factors suggests that Compound 1-treated cells would be more sensitive than untreated cells to a pro-apoptotic therapeutic such as a Bcl-2 inhibitor. Consequently, a combination therapy with a PI3K-inhibitor such as Compound 1 and a Bcl-2 inhibitor can produce unexpectedly high efficacy by acting in concert with high levels of pro-apoptotic signaling factors, to trigger apoptosis.
  • the methods of treatment described herein comprise administering a combination of a PI3K inhibitor and a modulator of, e.g., inhibitor of, the apoptotic signaling pathway.
  • a modulator of, e.g., inhibitor of, the apoptotic signaling pathway e.g., Compound 1 can enhance the expression of key pro-apoptotic factors in CLL cells, but apoptosis can be blocked. through a concomitant up-regulation of the anti-apoptotic protein, Bcl-2. Inhibition of Bcl-2 by ABT-199 in this setting can tip the balance toward apoptosis promoting tumor cell death.
  • the translational and ex-vivo experiments provided herein support that a combination of Compound 1 and ABT-199 can provide synergistic effects in subjects.
  • Example 2 described the effects of Compound 1 on a patient population including responders and non-responders, this Example focuses on cells that are resistant to compound 1.
  • SU-DHL-4 is a DLBCL cell line.
  • SU-DHL-4 cells resistant to Compound 1 were generated by culturing the cells in the presence of Compound 1 or DMSO as a control for 8 weeks. Cells were subcloned under selective pressure from the drug, seeding at densities of 3 cells per well, 1 cell per well, or 0.3 cell per well. Parental, DMSO-treated, and Compound 1-resistant clones were selected for expansion. Five clones from each group were expanded.
  • Cells were harvested for various assays, including CellTiter-Glo® assays, PD, RNA analysis, DNA analysis, and short tandem repeat (STR) fingerprinting.
  • a CTG assay was performed to confirm that cells were resistant to Compound 1 at the time of sample collection, whereas control cells (DMSO treated) were still resistant to Compound 1.
  • the gene expression pattern of Compound 1 resistant cell clones was determined by RNASeq analysis, e.g., as described in Wong et al. Nature Reviews Genetics 10.1(2009):57-63, incorporated herein by reference. Briefly, FKPM values (Fragments Per Kilobase Of Exon Per Million Fragments Mapped) were generated and filtered by processing the raw values, normalizing, and filtering the normalized values. This analysis revealed differential gene expression unique and common to Compound 1-resistant and ibrutinib-resistant clones.
  • 280 genes were differentially regulated in the Compound 1-resistant cells
  • 190 genes were differentially regulated in the ibrutinib-resistant cells
  • 98 genes were differentially regulated in both the Compound 1-resistant cells and the ibrutinib-resistant cells.
  • apoptotic pro-apoptotic genes (GeneGo Pathway ID GO:0006915) were differentially regulated in the Compound 1-resistant cells. This observation support the idea that promoting apoptosis (for instance, using a Bcl-2 inhibitor) can improve cell-killing of Compound 1-resistant cells.
  • Bcl-2 was not strongly upregulated or downregulated in the Compound 1-resistant cells. This result indicates that Bcl-2 remains a viable drug target even in Compound 1-resistant cells. Without wishing to be bound by theory, this finding supports the methods described herein involving treating a cancer, such as a PI3K-resistant cancer, with a Bcl-2 inhibitor.
  • a patient diagnosed with CLL was treated by a monotherapy of Compound 1 (25 mg bid) in a clinical trial.
  • Serum samples of the patient were collected at various points in the treatment.
  • the copy number of STK11 in the serum samples was determined by CytoScan (Affymetrix). The results are described below:
  • Genomic DNA can be profiled by one or more of CytoScan microarray analysis, targeted NexGen Sequencing and Sanger Sequencing. The protocols for these methods are described herein. CytoScan microarray analysis on genomic DNA can be used to determine copy number alterations (CNAs), such as copy number loss or gain. NexGen Sequencing on genomic DNA can be used to determine gene mutations. Sanger sequencing on genomic DNA can be used to determine IgHV mutation status. Results from genomic DNA profiling were used to assess whether genomic alterations in individuals treated with Compound 1 predict responsiveness or resistance to treatment with Compound 1 and whether genomic alterations occur with acquired resistance.
  • CNAs copy number alterations
  • NexGen Sequencing on genomic DNA can be used to determine gene mutations.
  • Sanger sequencing on genomic DNA can be used to determine IgHV mutation status. Results from genomic DNA profiling were used to assess whether genomic alterations in individuals treated with Compound 1 predict responsiveness or resistance to treatment with Compound 1 and whether genomic alterations occur with acquired resistance.
  • Peripheral whole blood samples were collected from CLL patients being treated with Compound 1. Genomic DNA was extracted from Cycle 1 Day 1 blood samples of 43 CLL patients, using QIAamp DNA Blood Midi kit (Qiagen, cat #51185) according to the manufacturer's protocol.
  • CytoScan array analysis allows for genome-wide identification of copy number changes.
  • the CytoScan HD array has 750,000 SNP probes and 1.9 million non-polymorphic probes, providing even copy number coverage across the genome.
  • the CytoScan HD array also has intragenic coverage of 36,000 RefSeq genes.
  • Genomic DNA samples were applied for hybridization to Affymetrix CytoScan HD arrays according to the manufacturer's manual.
  • CEL files were analyzed using Affymetrix software for initial quality control, followed by the use of Nexus 7.5 software (BioDiscovery, Inc.) for copy number and allelic analysis.
  • Nexus 7.5 software was used to identify the CNVs that are significantly different between patients who responded to treatment with Compound 1 and patients who did not (differential frequency>25%; p ⁇ 0.05).
  • Copy number variances were initially assessed with Nexus default setting (500 kb minimum LOH) for the first set of 43 samples. In order to efficiently utilize allele information, the segmentation window was changed to minimum LOH at 2 kb. Furthermore, gains that are not covered by an allelic event were filtered out.
  • the cancer-related genes were annotated based on the Cancer Gene Census database. Association between CNVs and clinical features were assessed by Fisher's exact test.
  • Agilent SureSelect solutions were used for the targeted DNA capture of a panel of genes. According to the manufacturer's protocol, DNA-Seq libraries were constructed and sequenced on Illumina HiSeq 2500 using 100 bp paired-end reads. FASTQ files were aligned by the OSA algorithm in Omicsoft Array Studio to generate BAM files with default parameter setting. Non-synonymous mutations including single-nucleotide variations (SNVs), insertions/deletions (InDels) and stop codon gain/loss were detected by Array Studio's mutation calling algorithm with the mutational allelic frequency (MAF) threshold set to be above 0.1.
  • SNVs single-nucleotide variations
  • InDels insertions/deletions
  • MAF mutational allelic frequency
  • SNVs were annotated with RefSeq gene model along with the Single Nucleotide Polymorphism Database (dbSNP), Catalogue Of Somatic Mutations In Cancer (COSMIC), and ClinVar databases to highlight the known germline polymorphisms and the clinically relevant somatic mutations.
  • the putative somatic mutations were determined by eliminating the SNVs that are known human single-nucleotide polymorphisms (SNPs) archived in dbSNP and ClinVar and that were detected in normal control samples.
  • KEGG and MetoCore Pathway Database was used to define the signaling pathways that are significantly enriched with the genes that have somatic mutations as detected in the CLL patients of this study (p ⁇ 0.05). Association between mutations and clinical features were assessed by Fisher's exact test.
  • the baseline mutation frequency of CLL patients in the Compound 1-treated patient population was determined, prior to treatment of the patients with Compound 1 (Table 8).
  • Many genes that were previously described in the literature as being commonly mutated in CLL were found to be mutated in the Compound 1-treated population, suggesting that the Compound 1-treated population is similar to what has been described for CLL (Landau et al. Cell 152, 714, 2013).
  • the TP53 mutation rate was twice what has been previously reported. This suggests that the Compound 1-treated population has more aggressive disease than previously published cohorts.
  • the average number of baseline mutations per patient was relatively similar among patients who show a complete or partial response to Compound 1 treatment, compared to non-responders (e.g., patients with stable disease or progressive disease).
  • the average number of baseline mutations per patient was also relatively similar among R/R and Tx-na ⁇ ve patients.
  • the difference between a mutation profile predictive of response and a mutation profile predictive of non-response seems not to be the total number of mutations, but the identity of the mutations.
  • the genes for which differences between groups were significant included BRAF, CTNNB1, FHIT, IRF4, MITF, MN1, NF2, RET, STK11, TSC2, RB1, RANBP17, FGFR3, GMPS, and WHSC1. Summaries of genetic alterations (500 kb minimum LOH) that were high in the SD/PD group or low in the SD/PD group are provided in Tables 9 and 10 respectively.
  • Table 11 shows copy number alterations for cancer genes with a higher frequency in SD/PD (i.e., non-responder) patients compared with CR/PR (i.e., responder) patients.
  • BRAF, CTNNB1, FHIT, IRF4, MITF, MN1, and NF2 had increased frequency of copy number gain in SD/PD patients relative to CR/PR patients.
  • NF2, RET, STK11, and TSC2 had increased frequency of copy number loss in SD/PD patients relative to CR/PR patients.
  • RB1 showed a higher frequency of loss of heterozygosity in SD/PD patients relative to CR/PR patients.
  • the results presented in Table 10 indicate that copy number gain in each of BRAF, CTNNB1, FHIT, IRF4, MITF, MN1, and NF2 is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • the results presented in Table 10 also indicate that copy number loss in each of NF2, RET, STK11, and TSC2 is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • Table 12 shows copy number alterations for cancer genes with a lower frequency in SD/PD patients compared with CR/PR patients.
  • Copy number gain in RANBP17 had a lower frequency in SD/PD (i.e., non-responder) patients compared with CR/PR (i.e., responder) patients.
  • loss of heterozygosity in FGFR3, GMPS, and WHSC1 had a lower frequency in SD/PD (i.e., non-responder) patients compared with CR/PR (i.e., responder) patients.
  • Table 13 shows copy number alterations for cancer genes with a higher frequency of loss in SD/PD patients compared with CR/PR patients (>25% frequency difference, p ⁇ 0.05).
  • Loss of CBFA2T3, YWHAE, TP53, PER1 and GAS7 are accompanied with an allelic event (allele imbalance or loss of heterozygosity); while only copy number loss was found in STK11, FSTL3 and USP6.
  • allelic event allele imbalance or loss of heterozygosity
  • the results presented in Table 13 indicate loss of YWHAE, STK11, TP53, FSTL3 and USP6 are associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) for all patients to a PI3K inhibitor (e.g., Compound 1).
  • the results presented in Table 13 further suggest loss of STK11, TP53, PER1, GAS7 and FSTL3 is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) among refractory or relapsed patients to a PI3K inhibitor (e.g., Compound 1).
  • Table 14 shows copy number alterations for cancer genes with a differential frequency of loss in nodal responders compared to nodal nonresponders (>25% frequency difference, p ⁇ 0.05). For these three cancer genes, copy number loss was identified without coverage of an allelic event. TSC1 and NF2 are more frequently loss in nodal nonresponders compared to nodal responders, whereas EGFR loss is found significantly frequently lost in nodal responders.
  • RNAseq e.g., as described in Wong et al. Nature Reviews Genetics 10.1(2009):57-63, incorporated herein by reference.
  • the relative expression levels of TP53, YWHAE, and STK11 are reduced in patients having a loss in copy number, compared to patients with no loss in copy number, as shown in FIGS. 13A , 13 B, and 13 C.
  • the results are shown in FIG. 8 .
  • the genes that belonged to the MAPK pathway and the p53 pathway were determined based on pathway identities from KEGG.
  • STK11 copy number loss is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • a cancer e.g., a CLL
  • a PI3K inhibitor e.g., Compound 1
  • a dual pathway alteration (a mutation in both MAPK and p53 pathways) is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • a cancer e.g., a CLL
  • a PI3K inhibitor e.g., Compound 1
  • copy number loss of STK11 combined with copy number loss of TSC1, TSC2, or both is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • TP53 Mutations in TP53 were further characterized, by determining the frequency of TP35 mutations in responders versus non-responders. Specifically, Table 15 below shows that TP53 alterations, including loss of TP53 and TP53 mutations, were more common in non-responders than responders. Thus, loss of TP53 correlated with a poorer prognosis.
  • FIGS. 9 and 10 show the results of a re-analysis of the same data that were used in the analysis presented in Example 9, except that PR patients with lymphocytosis were classified as non-responders, whereas such patients were classified as responders in Example 9.
  • the results of the re-analysis confirmed that STK11 copy number loss is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1). Furthermore, the results confirmed that a dual pathway alteration (a mutation in both MAPK and p53 pathways) and mutation of BCR pathway is associated with or predictive of nonresponsiveness or resistance (e.g., acquired resistance) of a cancer (e.g., a CLL) to a PI3K inhibitor (e.g., Compound 1).
  • FIG. 11 shows additional results of an analysis of relationships between mutations and copy number variations and responses. Correlations between CLL common CNVs and response to Compound 1 are shown in FIG. 12 .
  • FIG. 14 shows relationships between response and alterations in genes of various pathways, including the MAPK pathway p53 pathway, dual p53 and MAPK pathways, and BCR pathway.
  • PTEN is a Biomarker for Compound 1 Resistance
  • Compound 1 resistant cells were generated by culturing cells in the presence of Compound 1 or DMSO as a control for 8 weeks. Cells were subcloned under selective pressure from the drug, seeding at densities of 3 cells per well, 1 cell per well, or 0.3 cell per well. Parental, DMSO-treated, and Compound 1-resistant (also referred to as Compound 1-R) clones were selected for expansion. Five clones from each group were expanded.
  • Cells were harvested for various assays, including CTG (CellTiter-Glo, Promega, an assay that measures ATP levels as a surrogate for cell number in order to observe cell viability and changes in proliferation rate), PD (pharmacodynamic), RNA analysis, DNA analysis, and short tandem repeat (STR) fingerprinting.
  • CTG CellTiter-Glo, Promega, an assay that measures ATP levels as a surrogate for cell number in order to observe cell viability and changes in proliferation rate
  • PD pharmacodynamic
  • RNA analysis DNA analysis
  • STR short tandem repeat

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US11944631B2 (en) 2024-04-02
US11110096B2 (en) 2021-09-07

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