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WO2015059677A1 - Méthodes de traitement du cancer - Google Patents

Méthodes de traitement du cancer Download PDF

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Publication number
WO2015059677A1
WO2015059677A1 PCT/IB2014/065599 IB2014065599W WO2015059677A1 WO 2015059677 A1 WO2015059677 A1 WO 2015059677A1 IB 2014065599 W IB2014065599 W IB 2014065599W WO 2015059677 A1 WO2015059677 A1 WO 2015059677A1
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WO
WIPO (PCT)
Prior art keywords
cancer
mammal
compound
trail
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2014/065599
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English (en)
Inventor
Yuan Liu
Robert C. Gagnon
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GlaxoSmithKline Intellectual Property No 2 Ltd
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GlaxoSmithKline Intellectual Property No 2 Ltd
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Filing date
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Publication of WO2015059677A1 publication Critical patent/WO2015059677A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method of treating cancer in a mammal.
  • the method relates to methods comprising treating a human having an increased level of TRAIL comprising administering a MEK inhibitor.
  • the MEK inhibitor is: N- ⁇ 3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl;-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl ⁇ acetamide, or a pharmaceutically acceptable salt or solvate thereof to said human.
  • cancer results from the deregulation of the normal processes that control cell growth, cell division, differentiation and apoptotic cell death, among others.
  • One such process involves kinase regulation of apoptosis and cellular signaling from growth factor receptors at the cell surface to the nucleus (Crews and Erikson, Cell, 74:215-17, 1993).
  • Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the ⁇ -phosphate of the ATP-Mg 2+ complex to said amino acid side chain. These enzymes appear to control the majority of the signaling processes inside cells, thereby governing cell function, growth, differentiation and apoptosis through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases regulate many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis.
  • Raf-MEK-ERK signal transduction pathway for example, activation of Raf-MEK-ERK signal transduction pathway in cancer, particularly colorectal cancer, pancreatic cancer, lung cancer, breast cancer and the like, has been observed.
  • Figure 1 is a schematic of the MEK1 14653 NSCLC Study, an open-label, multicenter phase 2 study in patients with KRAS- and non-KRAS-mutant NSCLC, randomized 2:1 to treatment with trametinib or docetaxel.
  • Figure 2 is a Kaplan-Meier survival plot (K-M plot) using median split of TRAIL marker, to demonstrate the potential prognostic effect on OS in the trametinib arm of the MEK114653 NSCLC Study.
  • Figure 3 is a K-M plot using median split of TRAIL marker, to demonstrate the potential prognostic effect on OS in the docetaxel arm of the MEK114653 NSCLC Study.
  • Figure 4 is a K-M plot using median split of TRAIL marker in the different arms in the NSCLC study (Trametinib vs Docetaxel).
  • Figure 5 is a K-M plot using the medial split of TRAIL marker in the MEK1 13487 study in the Trametinib+Gemcitabine treatment arm.
  • Figure 6 is a K-M plot using the medial split of TRAIL marker in the MEK1 13487 study in the Gemcitabine treatment arm.
  • Figure 7 is a K-M plot using median split of TRAIL marker in the different arms of the MEK1 13487 study in pancreatic cancer (Trametinib+Gemcitabine vs Gemcitabine).
  • Figure 8 is a K-M plot using median split of TRAIL marker in the different arms in the NSCLC study to demonstrate the potential prognostic effect on PFS.
  • methods for treating a mammal having cancer comprising identifying a mammal with increased blood levels of TRAIL and treating said mammal with a pharmaceutical composition comprising at least one MEK in Structure (I):
  • the mammal is human.
  • the mammal is human.
  • the cancer may be any cancer.
  • the cancer is selected from the group consisting of melanoma, pancreatic cancer, colorectal cancer, and non-small cell lung carcinoma.
  • the cancer is selected from the group consisting of non-small cell lung carcinoma and pancreatic cancer.
  • the cancer is non-small cell lung carcinoma.
  • the cancer is pancreatic cancer.
  • the cancer is one in which an abnormal number of blast cells are present or that is diagnosed as a haematological cancer or dysplasia, such as leukemia, myeloid malignancy or myeloid dysplasia, including but not limited to, undifferentiated acute myelogenous leukemia, myeloblasts leukemia,
  • the cancer is myeloblasts leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia and megakaryoblastic leukemia.
  • the cancer is a myeloid malignancy cancer.
  • the cancer is leukemia.
  • the leukemia may be acute lymphocytic leukemia, acute non-lymphocytic leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia, chronic myelogenous (or myeloid) leukemia (CML), and chronic myelomonocytic leukemia (CMML).
  • the human has agnogenic myeloid metaplasia and/or poor-risk myelodysplasia (MDS).
  • MDS myelodysplasia
  • the cancer is relapsed or refractory. Patients may have received one or more treatments for leukemia prior to receiving Structure I.
  • Structure (I) also referred to as N- ⁇ 3-[3-cyclopropyl-5-(2- fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3- d]pyrimidin-1-yl]phenyl ⁇ acetamide, or a pharmaceutically acceptable salt or solvate thereof (hereinafter Compound A, or a pharmaceutically acceptable salt or solvate thereof) is in a sodium salt form. In another aspect, Compound A is in the form of a dimethyl sulfoxide solvate.
  • N- ⁇ 3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl ⁇ acetamide, or a pharmaceutically acceptable salt or solvate is a highly selective allosteric inhibitor of mitogen activated extracellular signal-regulated kinase 1 (MEK 1) and MEK 2.
  • MEK proteins are a node in a certain extracellular signal-related kinase ERK pathway which is commonly hyper-activated In tumor cells.
  • the present invention provides methods for treating cancer comprising administering at least one Braf inhibitor with Compound A, or a pharmaceutically ereof.
  • the Braf inhibitor is Structure (II):
  • the mammal also has a Braf mutation.
  • the Braf mutation is selected from R462I, I463S, G464V, G464E, G466A, G466E, G466V, G469A, G469E, D594V, F595L, G596R, L597V, L597R, T599I, V600E, V600D, V600K, V600R, T119S, and K601 E.
  • the BRAF mutation is detected in the same tumor cell and/or the same type of tumor cell as TRAIL expression.
  • the BRAF mutation is detected in a different sample from TRAIL expression; for example, the BRAF mutation is detected in a tumor cell whereas TRAIL expression is determined in a blood or plasma sample.
  • the amount of Structure I or a pharmaceutically acceptable salt or solvate thereof administered to said human is an amount selected from 0.125mg to 10mg. In some aspects the amount of Structure I or a pharmaceutically acceptable salt or solvate thereof administered to said human is administered daily from about 1 mg/day to about 2 mg/day.
  • the amount of BRAF inhibitor is an amount selected from 75mg to
  • the pharmaceutical composition comprises N A/- ⁇ 3-[5-(2-Amino- 4-pyrimidinyl)-2-(1 , 1-dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl ⁇ -2,6- difluorobenzenesulfonamide methanesulfonate or a pharmaceutically acceptable salt thereof, (hereinafter Compound B or a pharmaceutically acceptable salt thereof) in an amount from about 75mg to about 1 ,000mg.
  • the pharmaceutical composition comprising Structure I or a pharmaceutically acceptable salt or solvate thereof and the pharmaceutical composition comprising at least one Braf inhibitor are administered separately.
  • the pharmaceutical composition comprising Structure I or a pharmaceutically acceptable salt or solvate thereof is administered at the same time as the pharmaceutical composition comprising Structure II or a pharmaceutically acceptable salt or solvate thereof.
  • Compound A is disclosed and claimed, along with pharmaceutically acceptable salts and solvates thereof, as being useful as an inhibitor of MEK activity, particularly in treatment of cancer, in International Application No. PCT/JP2005/011082, having an International filing date of June 10, 2005; International Publication Number WO 2005/121142 and an
  • Compound A is the compound of Example 4-1.
  • Compound A can be prepared as described in International Application No. PCT/JP2005/011082.
  • Compound A can be prepared as described in United States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference.
  • Compound A is in the form of a dimethyl sulfoxide solvate.
  • Compound A is in the form of a sodium salt.
  • Compound A is in the form of a solvate selected from: hydrate, acetic acid, ethanol, nitromethane, chlorobenzene, 1- pentanci, isopropyl alcohol, ethylene glycol and 3-methyl-1-butanol.
  • Compound B is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of BRAF activity, particularly in the treatment of cancer, in PCT patent application PCT/US09/42682.
  • Compound B is embodied therein by Examples 58a through 58e of the application. This PCT application was published on 12 November 2009 as publication WO2009/137391 , and is hereby incorporated by reference.
  • the compounds of the invention may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or
  • the compounds of the invention may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute (in this invention, Compound A or a salt thereof and/or Compound B or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, dimethyl sulfoxide, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • Suitable pharmaceutically acceptable solvents include, without limitation, water, dimethyl sulfoxide, ethanol and acetic acid.
  • the solvent used is water.
  • contemplated herein is a method of treating cancer, for example in certain patient populations having certain biomarkers, for example elevated circulating TRAIL, using compound A, or a pharmaceutically acceptable salt or solvate thereof, or using a
  • compositions where Compound A, or a pharmaceutically acceptable salt or solvate thereof and/or Compound B or a pharmaceutically acceptable salt thereof.
  • methods of treating cancer for example in certain patient populations having certain biomarkers, for example elevated circulating TRAIL, where Compound A or a pharmaceutically acceptable salt or solvate thereof, and/or Compound B or a
  • pro-drugs of the compounds of the invention are readily prepared by those of skill in the art.
  • treating refers to therapeutic therapy.
  • treating means: (1) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • treating and/or treatment can be measured, quantified, or otherwise determined in a number of ways known to one of skill in the art, including RECIST
  • RECIST criteria version 1.1 is described in Eisenhauer, E.A. et al., "New Response Evaluation Criteria in Solid Tumours: Revised RECIST guideline," EUROPEAN JOURNAL OF CANCER (2009), 45, 228- 247, which is incorporated by reference in its entirety herein. Methods of evaluating non-solid cancers of the blood and specific deviations from RECIST for certain cancers such as mesothelioma are also well known in the art.
  • treating can be measured, quantified, or otherwise determined by a change in overall survival (OS), progression free survival (PFS), or both, in patients that were given a composition comprising Compound A or B or both relative to untreated patients.
  • OS overall survival
  • PFS progression free survival
  • Prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • prevention is not an absolute term.
  • the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally. Suitably, both compounds are administered orally.
  • kits as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, according to the invention. When both compounds are administered
  • the combination kit can contain Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in a single pharmaceutical composition, such as a tablet, or in separate
  • the combination kit When the compounds are not administered simultaneously, the combination kit will contain Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions.
  • the combination kit can comprise Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages.
  • Compound B or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • the combination kit comprises the following components: Compound A, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier; and
  • first container comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier
  • second container comprising Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
  • the "combination kit” can also be provided by instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
  • Compound A 2 means—Compound A, or a
  • Compound B 2 means—Compound B, or a
  • the combinations of this invention are administered within a "specified period”.
  • specified period and grammatical variations thereof, as used herein is meant the interval of time between the administration of one of Compound A 2 and
  • the specified period can include simultaneous administration. Unless otherwise defined the specified period refers to administration of Compound A 2 and Compound B 2 during a single day.
  • the compounds are administered within a "specified period" and not administered simultaneously, they are both administered within about 24 hours of each other - in this case, the specified period will be about 24 hours; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 11 hours; suitably they will both be
  • the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suitably they will both be administered within about 5 hours of each other - in this case, the specified period will be about 5 hours; suitably they will both be administered within about 4 hours of each other - in this case, the specified period will be about 4 hours; suitably they will both be administered within about 3 hours of each other - in this case, the specified period will be about 3 hours; suitably they will be administered within about 2 hours of each other - in this case, the specified period will be about 2 hours; suit
  • the compounds when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time".
  • duration of time and grammatical variations thereof, as used herein is meant that both compounds of the invention are administered for an indicated number of consecutive days. Unless otherwise defined, the number of consecutive days does not have to commence with the start of treatment or terminate with the end of treatment, it is only required that the number of consecutive days occur at some point during the course of treatment.
  • both compounds will be administered within a specified period for at least one day - in this case, the duration of time will be at least one day; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 30 consecutive days - in this case, the duration of time will be at least 30 days.
  • the compounds are not administered during a "specified period", they are administered sequentially.
  • sequential administration and derivates thereof, as used herein is meant that one of Compound A 2 and Compound B 2 is administered once a day for two or more consecutive days and the other of Compound A 2 and Compound B 2 is subsequently administered once a day for two or more consecutive days.
  • a drug holiday utilized between the sequential administration of one of Compound A 2 and Compound B 2 and the other of Compound A 2 and Compound B 2 .
  • a drug holiday is a period of days after the sequential administration of one of Compound A 2 and Compound B 2 and before the administration of the other of Compound A 2 and Compound B 2 where neither Compound A 2 nor Compound B 2 is administered.
  • the drug holiday will be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days and 14 days.
  • one of Compound A 2 and Compound B 2 is administered for from 2 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A 2 and Compound B 2 for from 2 to 30 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 2 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A 2 and Compound B 2 for from 2 to 21 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 2 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A 2 and Compound B 2 for from 2 to 30 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 2 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A 2 and Compound B 2 for from 2 to 21 consecutive days.
  • Compound B 2 is administered for from 2 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of the other of Compound A 2 and Compound B 2 for from 2 to 14 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 3 to 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of the other of Compound A 2 and Compound B 2 for from 3 to 7 consecutive days.
  • Compound B 2 will be administered first in the sequence, followed by an optional drug holiday, followed by administration of Compound A 2 .
  • Compound B 2 is administered for from 3 to 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A 2 for from 3 to 21 consecutive days.
  • Compound B 2 is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of Compound A 2 for from 3 to 21
  • Compound B 2 is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of
  • Compound A 2 for from 3 to 21 consecutive days is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A 2 for 14 consecutive days.
  • Compound B 2 is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of Compound A 2 for 14 consecutive days.
  • Compound B 2 is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound A 2 for 7 consecutive days.
  • Compound B 2 is administered for 3 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of Compound A 2 for 7 consecutive days.
  • Compound B 2 is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound A 2 for 3 consecutive days.
  • administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.
  • the amount of Compound A 2 administered as part of the combination according to the present invention will be an amount selected from about 0.125mg to about 10mg; suitably, the amount will be selected from about 0.25mg to about 9mg; suitably, the amount will be selected from about 0.25mg to about 8mg; suitably, the amount will be selected from about 0.5mg to about 8mg; suitably, the amount will be selected from about 0.5mg to about 7mg; suitably, the amount will be selected from about 1 mg to about 7mg; suitably, the amount will be about 5mg. Accordingly, the amount of Compound A
  • the amount of Compound A 2 administered as part of the combination according to the present invention will be an amount selected from about 0.125mg to about 10 mg.
  • the amount of Compound A 2 administered as part of the combination according to the present invention can be 0.125mg, 0.25mg, 0.5mg, 0.75mg, 1 mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg.
  • the amount of Compound B 2 administered as part of the combination according to the present invention will be an amount selected from about 75mg to about 1 ,000mg; suitably, the amount will be selected from about 100mg to about 900mg; suitably, the amount will be selected from about 150mg to about 850mg; suitably, the amount will be selected from about 200mg to about 800mg; suitably, the amount will be selected from about 250mg to about 750mg; suitably, the amount will be selected from about 300mg to about 6000mg; suitably, the amount will be about 450mg. Accordingly, the amount of Compound B 2 administered as part of the combination according to the present invention will be an amount selected from about 75mg to about 1 ,000mg. For example, the amount of
  • Compound B 2 administered as part of the combination according to the present invention can be 75mg, 100 mg, 125mg, 150 mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg or 1 ,000mg.
  • the invention further provides pharmaceutical compositions, which include Compound A 2 and/or Compound B 2 , and one or more pharmaceutically acceptable carriers.
  • the combinations of the present invention are as described above.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing Compound A 2 and/or Compound B 2 with one or more pharmaceutically acceptable carriers. As indicated above, such elements of the pharmaceutical combination utilized may be presented in separate pharmaceutical compositions or formulated together in one pharmaceutical formulation.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • Compound A 2 and Compound B 2 may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that Compound A 2 and Compound B 2 may be compounded together in a pharmaceutical composition/formulation.
  • routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier may include a prolonged release material, such as glyceryl
  • the preparation will suitably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • therapeutically effective amounts of the combinations of the invention are administered to a human.
  • the therapeutically effective amount of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attendant physician.
  • the combinations of the present invention are tested for efficacy, advantageous and synergistic properties according to known procedures.
  • the combinations of the invention are tested for efficacy, advantageous and synergistic properties generally according to the following combination cell proliferation assays.
  • Cells are plated in 384-well plates at 500 cells/well in culture media appropriate for each cell type, supplemented with 10% FBS and 1 % penicillin/streptomycin, and incubated overnight at 37°C, 5% C0 2 .
  • Cells are treated in a grid manner with dilution of Compound A 2 (20 dilutions, including no compound, of 2-fold dilutions starting from 1-20 ⁇ depending of compound) from left to right on 384-well plate and also treated with Compound B 2 (20 dilutions, including no compound, of 2-fold dilutions starting from 1-20 ⁇ depending of compound) from top to bottom on 384-well plate and incubated as above for a further 72 hours. In some instances compounds are added in a staggered manner and incubation time can be extended up to 7 days.
  • the cellular response is determined for each compound and/or compound combination using a 4- or 6-parameter curve fit of cell viability against concentration using the IDBS XLfit plug-in for Microsoft Excel software and determining the concentration required for 50% inhibition of cell growth (glC 50 ). Background correction is made by subtraction of values from wells containing no cells.
  • CI Combination Index
  • EHSA Excess Over Highest Single Agent
  • EOBIiss Excess Over Bliss
  • cancers that are suitable for treatment with the MEK inhibitor, the BRAF inhibitor, or both include, but are not limited to, both primary and metastatic forms of head and neck, breast, lung, colon, ovary, and prostate cancers.
  • the cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,
  • lymphoblastic T cell leukemia Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, AML, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia,
  • Erythroleukemia malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer,
  • hepatocellular cancer gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
  • examples of a cancer to be treated include Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplasia syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblast
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas,
  • glioblastoma multiforme Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from ovarian, breast, pancreatic and prostate.
  • the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
  • the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal
  • cancer As used herein, the terms "cancer,” “neoplasm,” and “tumor,” are used
  • a cancer cell refers to cells that have undergone a malignant transformation that makes them pathological to the host organism.
  • Primary cancer cells that is, cells obtained from near the site of malignant transformation
  • the definition of a cancer cell includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells.
  • a "clinically detectable" tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as CAT scan, MR imaging, X-ray, ultrasound or palpation, and/or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient.
  • Tumors may be hematopoietic tumor, for example, tumors of blood cells or the like, meaning liquid tumors.
  • Specific examples of clinical conditions based on such a tumor include leukemia such as chronic myelocytic leukemia or acute myelocytic leukemia; myeloma such as multiple myeloma; lymphoma and the like.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as
  • epipodophyllotoxins such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; receptor tyrosine kinase inhibitors; serine-threonine kinase inhibitors; non-receptor tyrosine kinase inhibitors;
  • angiogenesis inhibitors immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
  • the present invention also provides methods for treating cancer comprising administering Compound A or pharmaceutically acceptable salt thereof with or without a Braf inhibitor, including, but not limited to, Compound B or a pharmaceutically acceptable salt or solvate thereof and another anti-neoplastic agent.
  • Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with Compound A or pharmaceutically acceptable salt thereof are chemotherapeutic agents.
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anti-cancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel, 5p,20-epoxy-1 ,2 ⁇ ,4,7 ⁇ , 10 ⁇ , 13a-hexa-hydroxytax-11 -en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971), who characterized its structure by chemical and X-ray crystallographic methods.
  • TAXOL® injectable solution
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 11 1 :273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990).
  • the compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria.
  • Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide i 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
  • Docetaxel (2R,3S)- N-carboxy-3-phenylisoserine,N-te/f-butyl ester, 13-ester with 5 ⁇ - 20-epoxy-1 ,2a,4,7p, 10p, 13ot-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®.
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following.
  • Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine. Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.
  • Myelosuppression is the dose limiting side effect of vinblastine.
  • Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as
  • ONCOVIN® as an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL® an injectable solution.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin platinum, diammine [1 , 1-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through
  • nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups.
  • alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
  • Busulfan 1 ,4-butanediol dimethanesulfonate, is commercially available as
  • Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
  • Carmustine 1 ,3-[bis(2-chloroethyl)-1-nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®.
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
  • dacarbazine 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®.
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthracyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8, 11-trihydroxy-1-methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
  • Doxorubicin (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl, 7,8,9, 10-tetrahydro-6,8, 11-trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of
  • epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-p-D- glucopyranoside] is commercially available as an injectable solution or capsules as
  • VePESID® and is commonly known as VP-16.
  • Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
  • Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-p-D- glucopyranoside] is commercially available as an injectable solution as VUMON® and is commonly known as VM-26.
  • Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.
  • Teniposide can induce both leucopenia and thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
  • 5-fluorouracil 5-fluoro-2,4- (1 H,3H) pyrimidinedione
  • fluorouracil is commercially available as fluorouracil.
  • Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas.
  • fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
  • Cytarabine 4-amino-1-p-D-arabinofuranosyl-2 (I H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
  • Mercaptopurine 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®.
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • a useful mercaptopurine analog is
  • Thioguanine 2-amino-1 ,7-dihydro-6H-purine-6-thione
  • TABLOID® Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
  • Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate.
  • Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4- methylpiperazino-methylene)-10, 1 1-ethylenedioxy-20-camptothecin described below.
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
  • Topotecan HCI (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®.
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule.
  • Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
  • the dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia.
  • Rituximab is a chimeric monoclonal antibody which is sold as RITUXAN® and MABTHERA®.
  • Rituximab binds to CD20 on B cells and causes cell apoptosis.
  • Rituximab is administered intravenously and is approved for treatment of rheumatoid arthritis and B-cell non-Hodgkin's lymphoma.
  • Ofatumumab is a fully human monoclonal antibody which is sold as ARZERRA®.
  • Ofatumumab binds to CD20 on B cells and is used to treat chronic lymphocytic leukemia (CLL; a type of cancer of the white blood cells) in adults who are refractory to treatment with fludarabine (Fludara) and alemtuzumab (Campath).
  • CLL chronic lymphocytic leukemia
  • Fludara fludarabine
  • alemtuzumab Campath
  • mTOR inhibitors include but are not limited to rapamycin and rapalogs, RAD001 or everolimus (Afinitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687 and Pp121.
  • Bexarotene is sold as Targretin® and is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs).
  • RXRs retinoid X receptors
  • RARs retinoic acid receptors
  • the chemical name is 4-[1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid.
  • Bexarotene is used to treat cutaneous T-cell lymphoma (CTCL, a type of skin cancer) in people whose disease could not be treated successfully with at least one other medication.
  • CTCL cutaneous T-cell lymphoma
  • Sorafenib marketed as Nexavar® is in a class of medications called multikinase inhibitors. Its chemical name is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-/V-methyl-pyridine-2-carboxamide. Sorafenib is used to treat advanced renal cell carcinoma (a type of cancer that begins in the kidneys). Sorafenib is also used to treat unresectable hepatocellular carcinoma (a type of liver cancer that cannot be treated with surgery).
  • wild type refers to a polypeptide
  • a "mutant" includes a polypeptide or polynucleotide sequence having at least one modification to an amino acid or nucleic acid compared to the
  • mutant Single Nucleotide Polymorphism (SNP) where a single base pair distinction exists in the sequence of a nucleic acid strand compared to the most prevalently found (wild type) nucleic acid strand.
  • SNP Single Nucleotide Polymorphism
  • genotyping a cell including a tumor cell from a subject (or DNA or other biological sample) for a mutation or a polymorphic allele of a gene(s) means detecting which allelic or polymorphic form(s) and/or wild type or somatically mutated form(s) of the gene(s) or gene expression products (e.g., hnRNA, mRNA or protein) are present or absent in a subject (or a sample).
  • gene expression products e.g., hnRNA, mRNA or protein
  • Related RNA or protein expressed from such gene may also be used to detect polymorphic variation.
  • “genotyping” includes the determination of somatic as well as genotypic mutations from a sample.
  • an allele may be 'detected' when other possible allelic variants have been ruled out; e.g., where a specified nucleic acid position is found to be neither adenine (A), thymine (T) or cytosine (C), it can be concluded that guanine (G) is present at that position (i.e., G is 'detected' or 'diagnosed' in a subject).
  • Sequence variations may be detected directly (by, e.g. sequencing, for example, EST sequencing or partial or full genome sequencing) or indirectly (e.g., by restriction fragment length polymorphism analysis, or detection of the hybridization of a probe of known sequence, or reference strand conformation
  • sequence of any nucleic acid including a gene or PCR product or a fragment or portion thereof may be sequenced by any method known in the art (e.g., chemical sequencing or enzymatic sequencing).
  • “Chemical sequencing” of DNA may denote methods such as that of Maxam and Gilbert (1977) (Proc. Natl. Acad. Sci. USA 74:560), in which DNA is randomly cleaved using individual base-specific reactions.
  • “Enzymatic sequencing” of DNA may denote methods such as that of Sanger (Sanger, et al., (1977) Proc. Natl. Acad. Sci. USA 74:5463).
  • PNA affinity assay is a derivative of traditional hybridization assays (Nielsen et al., Science 254: 1497-1500 (1991); Egholm et al., J. Am. Chem. Soc. 1 14:1895-1897 (1992); James et al., Protein Science 3: 1347-1350 (1994)).
  • PNAs are structural DNA mimics that follow Watson-Crick base pairing rules, and are used in standard DNA hybridization assays. PNAs display greater specificity in hybridization assays because a PNA/DNA mismatch is more destabilizing than a DNA/DNA mismatch and complementary PNA/DNA strands form stronger bonds than complementary DNA/DNA strands.
  • DNA microarrays have been developed to detect genetic variations and
  • DNA microarrays are fabricated by high-speed robotics, on glass or nylon substrates, and contain DNA fragments with known identities ("the probe”). The microarrays are used for matching known and unknown DNA fragments ("the target”) based on traditional base-pairing rules.
  • a TRAIL protein may be produced by a cell in a truncated form and the sequence of the truncated form may be wild type over the sequence of the truncate.
  • a deletion may mean the absence of all or part of a gene or protein encoded by a gene.
  • a protein expressed in or encoded by a cell may be mutated while other copies of the same protein produced in the same cell may be wild type.
  • a mutation in a TRAIL protein would include a TRAIL protein having one or more amino acid differences in its amino acid sequence compared with wild type of the same TRAIL protein.
  • polypeptide As used herein "genetic abnormality” is meant a deletion, substitution, addition, translocation, amplification and the like relative to the normal native nucleic acid content of a cell of a subject.
  • polypeptide and “protein” are used interchangeably and are used herein as a generic term to refer to native protein, fragments, peptides, or analogs of a polypeptide sequence. Hence, native protein, fragments, and analogs are species of the polypeptide genus.
  • TRAIL protein means the TNF-related apoptosis-inducing ligand, a protein involved in apoptosis or cell death.
  • TRAIL is often referred to as a cytokine.
  • TRAIL can also be called CD253 or tumor necrosis factor superfamily member 10
  • TRAIL binds death receptors DR4 (TRAIL-RI) and DR5 (TRAIL-RII), as well as DcR1 and DcR2.
  • DR4 TRAIL-RI
  • TRAIL-RII death receptors DR4
  • DR5 TRAIL-RII
  • TRAIL protein means any part of a gene or polynucleotide encoding any TRAIL protein. Included within the meaning of this term are exons encoding TRAIL.
  • amplification and grammatical variations thereof refers to the presence of one or more extra gene copies in a chromosome complement.
  • Amplification of the HER2 gene has been correlated with certain types of cancer. Amplification of the HER2 gene has been found in human salivary gland and gastric tumor-derived cell lines, gastric and colon adenocarcinomas, and mammary gland adenocarcinomas. Semba et al., Proc. Natl. Acad. Sci.
  • expression of a protein or polypeptide and grammatical variations thereof means that a given cell makes an mRNA or protein product from the corresponding gene. Expression may be detected in a number of ways known by one of skill in the art, including detecting portions of an mRNA or protein product either directly or indirectly.
  • overexpressed and overexpression of a protein or polypeptide and grammatical variations thereof means that a given cell produces an increased number of a certain protein relative to a normal cell.
  • a protein may be overexpressed by a tumor cell relative to a non-tumor cell.
  • a mutant protein may be
  • expression levels of a polypeptide in a cell can be normalized to a housekeeping gene such as actin.
  • a certain polypeptide may be underexpressed in a tumor cell compared with a non-tumor cell.
  • nucleic acid necessary for expression of at least one gene product refers to a nucleic acid sequence that encodes any portion of a gene and/or is operably linked to a nucleic acid encoding a gene product but does not necessarily comprise encoding sequence.
  • a nucleic acid sequence necessary for the expression of at least one gene product includes, but is not limited to, enhancers, promoters, regulatory sequences, start codons, stop codons, polyadenylation sequences, and/or encoding sequences. Expression levels of a polypeptide in a particular cell can be effected by, but not limited to, mutations, deletions and/or substitutions of various regulatory elements and/or non-encoding sequence in the cell genome.
  • mutant B-raf protein refers to a B-raf polypeptide comprising at least one mutation.
  • Certain exemplary mutant B-raf polypeptides include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, and/or insertion variants, fusion polypeptides, orthologs, and interspecies homologs.
  • a mutant B-raf polypeptide includes additional residues at the C- or N- terminus, such as, but not limited to, leader sequence residues, targeting residues, amino terminal methionine residues, lysine residues, tag residues and/or fusion protein residues.
  • B-raf mutants include but are not limited to BRAF having an amino acid substitution selected from the group consisting of R462I, I463S, G464V, G464E, G466A, G466E, G466V, G469A, G469E, D594V, F595L, G596R, L597V, L597R, T599I, V600E, V600D, V600K, V600R, T1 19S, and K601 E. See, for example, FIG. 2 of Halilovic and Solvit (2008) Current Opinion in Pharmacology 8:419-26.
  • BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation via kinase pathway activation.
  • polynucleotide as referred to herein means a polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • the term includes single and double stranded forms of DNA.
  • oligonucleotide includes naturally occurring and modified nucleotides linked together by naturally occurring, and non-naturally occurring oligonucleotide linkages.
  • Oligonucleotides are a polynucleotide subset generally comprising a length of 200 bases or fewer. Preferably oligonucleotides are 10 to 60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 bases in length.
  • Oligonucleotides are usually single stranded, e.g. for probes, although oligonucleotides may be double stranded, e.g. for use in the construction of a gene mutant. Oligonucleotides can be either sense or antisense oligonucleotides.
  • An oligonucleotide probe, or probe is a nucleic acid molecule which typically ranges in size from about 8 nucleotides to several hundred nucleotides in length. Such a molecule is typically used to identify a target nucleic acid sequence in a sample by hybridizing to such target nucleic acid sequence under stringent hybridization conditions. Hybridization conditions have been described in detail above.
  • PCR primers are also nucleic acid sequences, although PCR primers are typically oligonucleotides of fairly short length which are used in polymerase chain reactions. PCR primers and hybridization probes can readily be developed and produced by those of skill in the art, using sequence information from the target sequence. (See, for example, Sambrook et al., supra or Glick et al., supra).
  • primers are known for use in PCR for detecting expression of genes such as TRAIL, as well as Braf mutations.
  • primers for detecting mutations in Braf are presented in several research articles and US patents including, but not limited to, Brose, et al. Cancer Research 62:6997-7000 (2002), Xu, et al. Cancer research 63:4561-4567 (2003), as well as US Patent No. 7,745,128, and several commercially available kits (see Dxs Diagnostic Innovations, Applied Biosystems, and Quest diagnostics).
  • TRAIL expression and/or elevated levels of TRAIL can be identified using what is known in the art as Cytokine and Angiogenesis Analysis (CAF Analysis) which is known in the art.
  • CAF Analysis Cytokine and Angiogenesis Analysis
  • Circulating cytokines and angiogenic factors (CAF) profiles have shown potential for identification of prognostic and predictive markers in subjects with cancer.
  • Biomarkers that provide information about the outcome of cancer subjects are classified by whether they are prognostic or predictive.
  • Prognostic markers are those which provide information about outcome regardless of treatment.
  • Predictive markers identify sub-populations of subjects that are most likely to benefit from a particular therapy. Certain biomarkers can provide both prognostic and predictive information.
  • the level of TRAIL in a patient is determined using CAF Analysis.
  • the CAF Analysis is performed by quantitative PCR or microarray analysis or any of a number of other molecular techniques known to one of skill in the art.
  • a mammal or human can be determined to have elevated level of TRAIL by any of a number of means known in the art.
  • the elevated level of trail can be determined by performing Cytokine and Angiogenesis Factor (CAF) analysis where TRAIL is an included as one of the cytokine and angiogenesis factors.
  • CAF Cytokine and Angiogenesis Factor
  • the determining can involve measuring levels of TRAIL protein expression, for example in a blood or plasma sample. Determining that TRAIL is elevated can involve measuring the level of TRAIL protein expression relative to a control sample, such as a reference sample or blood sample of a mammal, e.g. human not in need of treatment for cancer.
  • circulating TRAIL levels are elevated 1 %, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • TRAIL is elevated, e.g., relative to a control sample or a sample from a human not in need of treatment for cancer by a fold difference or elevated 2 fold, 3 fold, 4 fold, 5 fold, or 10 fold.
  • TRAIL circulating blood levels
  • a tyrosine kinase inhibitor is provided for use in a mammal, wherein said mammal is classified as a responder, and wherein a responder is characterized by an elevated level of TRAIL, e.g. an elevated level of circulating blood levels of TRAIL.
  • a mammal by the presence of an elevated level of TRAIL and administering a MEK inhibitor or a pharmaceutical composition comprising a MEK inhibitor to the identified mammal, e.g. human.
  • methods of treating cancer in a mammal e.g. in a human, e.g., in a human patient in need of treatment for cancer, comprising identifying the mammal, e.g. human, as a responder based on an elevated level of TRAIL, and administering a MEK inhibitor or a pharmaceutical composition comprising a MEK inhibitor to the identified responder.
  • a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof as described herein is provided for use in a mammal, e.g. in a human, e.g., in a human patient in need of treatment for cancer, wherein said mammal is determined to have an elevated level of TRAIL, e.g. an elevated level of circulating blood levels of TRAIL.
  • a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof as described herein, or a pharmaceutical composition comprising a MEK inhibitor as described herein is provided for use in a mammal, wherein said mammal is classified as a responder, and wherein a responder is characterized by an elevated level of TRAIL, e.g. an elevated level of circulating blood levels of TRAIL.
  • the MEK inhibitor is suitably trametinib.
  • the MEK inhibitor is Compound A or a solvate or salt thereof, or Compound A 2 .
  • the MEK inhibitor comprises a compound of Structure (I):
  • the MEK inhibitor e.g. having Structure (I)
  • the MEK inhibitor is in the sodium salt form.
  • the MEK inhibitor having Structure (I) is alternatively in the form of a dimethyl sulfoxide solvate.
  • the MEK inhibitor, or pharmaceutically acceptable salt or solvate e.g. the dimethyl sulfoxide solvate
  • the methods comprising administering at least one Braf inhibitor or a pharmaceutically acceptable salt thereof to said mammal in addition to the MEK i is suitably a compound of Structure (II):
  • the methods comprise, in addition to administering a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, and/or a BRAF inhibitor or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical compositions comprising the same as describe herein, further comprises administering at least one additional anti-neoplastic agent.
  • the at least one additional antineoplastic agent is gemcetabine.
  • the at least one additional antineoplastic agent in any of those known in the art to be of the same class as gemcetabine, or any anti-neoplastic agent known in the art such as those described herein.
  • methods of treating cancer in a mammal comprising treating with an antineoplastic agent that elevates circulating TRAIL and then administering at least one tyrosine kinase inhibitor or a pharmaceutical composition comprising at least one tyrosine kinase inhibitor.
  • methods of treating cancer in a mammal e.g., in a human, e.g., in a human patient in need of treatment for cancer, comprising treating with an antineoplastic agent that elevates circulating TRAIL and then administering at least one tyrosine kinase inhibitor or a pharmaceutical composition comprising at least one tyrosine kinase inhibitor.
  • antineoplastic agent that elevates circulating TRAIL and then administering at least one tyrosine kinase inhibitor or a pharmaceutical composition comprising at least one MEK inhibitor, or at least one MEK inhibitor and at least one BRAF inhibitor, e.g. having Structure I or Structure II herein, or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical compositions comprising the same as described herein.
  • antineoplastic agent that elevates circulating TRAIL and at least one tyrosine kinase inhibitor or one or pharmaceutical compositions comprising the same for use in treating a mammal, e.g.
  • antineoplastic agent that elevates circulating TRAIL and at least one MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof (as described herein) or one or pharmaceutical compositions (as described herein) comprising the same for use in treating a mammal, e.g. a human, e.g. a human patient in need of treatment for cancer.
  • Example 1 TRAIL induces apoptosis in a wide variety of transformed cell lines
  • the Study design was an open-label, multicenter phase 2 study in patients with KRAS- and non-KRAS mutant NSCLC, randomized 2: 1 to treatment with trametinib or docetaxel.
  • a schematic is shown in Figure 1.
  • the primary objective was progression-free survival (PFS) and secondary objectives included the following:
  • CAF's cytokines and angiogenic factors
  • TRAIL was identified as a potential high value biomarker for NSCLC patients response to trametinib. Patients with higher circulating levels of TRAIL had longer OS in NSCLC studies (and pancreatic cancer studies, as shown below). Thus, though not wishing to be bound by theory, it is believed that apoptosis machinery may be key for the efficacy of trametinib treatment.
  • GSK1120212+Gemcitabine > median 32 20 12 37.5 9.9 (7.9, 12.1)
  • Figure 7 demonstrates that gemcitabine dampens the apoptotic dependency of trametinib and suggests that treating first or co-treating with gemcitabine may prime patients for successful treatment with trametinib.

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Abstract

L'invention concerne des méthodes de traitement du cancer chez un mammifère, tel qu'un être humain, atteint d'un cancer, lesdites méthodes de traitement consistant à déterminer si le mammifère présente un niveau élevé de TRAIL et, si tel est le cas, à administrer une composition pharmaceutique comprenant au moins un inhibiteur de MEK comprenant un composé de structure (I), ou un sel ou un solvate pharmaceutiquement acceptable de celui-ci.
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