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WO2025078667A1 - Dégradeur mrt-2359 de colle moléculaire gspt1 destiné à être utilisé dans le traitement d'un cancer entraîné par myc - Google Patents

Dégradeur mrt-2359 de colle moléculaire gspt1 destiné à être utilisé dans le traitement d'un cancer entraîné par myc Download PDF

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Publication number
WO2025078667A1
WO2025078667A1 PCT/EP2024/078801 EP2024078801W WO2025078667A1 WO 2025078667 A1 WO2025078667 A1 WO 2025078667A1 EP 2024078801 W EP2024078801 W EP 2024078801W WO 2025078667 A1 WO2025078667 A1 WO 2025078667A1
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compound
subject
administered
days
day
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Inventor
Filip JANKU
Chris King
Owen Wallace
Markus Warmuth
Anne-Laure LAINÉ
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Monte Rosa Therapeutics AG
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Monte Rosa Therapeutics AG
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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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • MRT-2359 is a potent and selective molecular glue degrader (MGD) that induces the interaction between the E3 ubiquitin ligase component cereblon (CRBN) and the translation termination factor G1 to S phase transition protein 1 (GSPT1), leading to the degradation of GSPT1 protein.
  • MYC myelocytomatosis
  • c-MYC, L MYC, and N MYC myelocytomatosis
  • the present invention relates to treatment of diseases comprising administering to a subject in need thereof “Compound A”, as shown below:
  • the invention provides a method of treating a disease in a subject in need of such treatment, comprising administering Compound A to the subject, wherein Compound A is administered according to a dosing regimen comprising administering Compound A to the subject daily for more than 5 consecutive days.
  • the dosing regimen may comprise administering 45 mg or less of Compound A in a 28-day period.
  • the method of the invention may comprise administering no more than 5 mg of Compound A to the subject on any day on which the compound is administered.
  • the method of the invention may comprise not administering Compound A to the subject for at least one day.
  • Figure 3 provides exemplary tumour growth inhibition data for two different PDX models of nonsmall cell lung cancer (NSCLC).
  • NSCLC nonsmall cell lung cancer
  • Figure 4 provides exemplary tumour growth inhibition data for a PDX model of small cell lung cancer (SCLC).
  • Figure 6 provides ionized calcium changes on Day 5 of a repeat-dose toxicity study in cynomolgus monkeys, as reported in Example 4. Data represent ionized calcium in serum relative to predose levels.
  • Figure 12 shows the % change in tumour size for 6 patients treated with MRT-2359. Each bar shows the % change in tumour size and dose associated with one patient. The biomarker status of each patient for various biomarkers (N-Myc, L-Myc and NE) is shown underneath the bar, with a ‘+’ denoting positive for that biomarker and denoting negative for that biomarker.
  • Figures 15A and 15B show the effect on expression of c-MYC ( Figure 15A) and CCND1 ( Figure 15B) of MRT-2359 administered alone continuously, fulvestrant administered alone and the combination of continuous MRT-2359 and fulvestrant, as % relative to the vehicle.
  • the dosing regimen may comprise administering to the subject 30 mg to 35 mg of Compound A in a 28-day period, for example 35 mg, 34 mg, 33 mg, 32 mg, 31 mg or 30 mg.
  • the dosing regimen may comprise administering 30 mg to 32 mg of Compound A to the subject in a 28-day period.
  • the dosing regimen may comprise administering 30mg or 32 mg of Compound A to the subject in a 28-day period.
  • the dosing regimen may comprise administering 15 mg to 21 mg of Compound A to the subject in a 28-day period.
  • the dosing regimen may comprise administering 15 mg, 16 mg or 21 mg of Compound A to the subject in a 28-day period.
  • the dosing regimen may comprise administering to the subject 11 mg of Compound A in a 28-day period.
  • the amount of Compound A which is administered does not have to be the same for each day of the treatment period in which the dosing regimen is given to the subject. Typically, but not always, the same daily amounts will be used throughout the treatment. Thus, in preferred embodiments, the same amount of Compound A is administered on each day of the regimen when Compound A is administered. For instance, the same amount of Compound A may be administered on multiple days within a 28-day period. In subsequent 28-day periods, the same or different amounts of Compound A may be administered.
  • the amount of Compound A administered to the subject per day may be 1 mg or less, or 1 .0 mg or less.
  • the amount of Compound A administered to the subject per day may be less than 1 mg, 0.9 mg or less, 0.8 mg or less, 0.75 mg or less, 0.7 mg or less, 0.6 mg or less, 0.5 mg or less, 0.4 mg or less, 0.3 mg or less, 0.2 mg or less, or 0.1 mg or less.
  • the daily amount of Compound A administered to the subject may be in the range of 0.5 mg or more and 3.5 mg or less on days where the compound is administered.
  • the amount may be in the range of 0.75 mg or more and 3.5 mg or less, 1 .0 mg or more and 3.5 mg or less, 1 .5 mg or more and 3.5 mg or less, 2.0 mg or more and 3.5 mg or less, 2.5 mg or more and 3.5 mg or less, or 3.0 mg or more and 3.5 mg or less.
  • the daily amount of Compound A administered to the subject may be in the range of from 0.1 mg to 5 mg on days where the compound is administered.
  • the amount of Compound A administered to the subject per day may be from 0.15 mg to 4 mg, from 0.25 mg to 3 mg, from 0.5 mg to 2 mg, from 0.5 mg to 1 .5 mg, or from 0.5 mg to 1 mg.
  • the daily amount of Compound A administered to the subject may be in the range of from 0.25 mg to 5 mg on days where the compound is administered.
  • the amount may be in the range of from 0.25 mg to 4 mg, from 0.25 mg to 3 mg, from 0.25 mg to 2 mg, from 0.25 mg to 1 .5 mg, from 0.25 mg to 1 mg, 0.25 mg to 0.75 mg, or from 0.25 mg to 0.5 mg.
  • the daily amount of Compound A administered to the subject may be 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 .0 mg, 1 .5 mg, or 2.0 mg on days where the compound is administered.
  • the amount may be in the range of 0.5 mg to 1 mg.
  • These daily amounts of Compound A can be used in conjunction with any of the aspects described above.
  • the methods of treatment according to the invention may be defined in terms of the amount of Compound A which is administered to a subject in a 28-day period and the amount of Compound A which is administered to a subject on any given day of the dosing regimen.
  • any such daily and monthly amount described herein can be combined with each other, and the embodiments described below are merely specific examples of such combinations.
  • the amount of Compound A administered to the subject in a 28-day period may be 5 mg to 45 mg, 5 mg to 42 mg, 5 mg to 40 mg, 5 mg to 35 mg, 5 mg to 32 mg, 5 mg to 30 mg, 5 mg to 25 mg, 5 mg to 21 mg, 5 mg to 20 mg, 5 mg to 16 mg, 5 mg to 11 mg, 5 mg to 10 mg, 5 mg to 8 mg, 10 mg to 45 mg, 10 mg to 42 mg, 10 mg to 40 mg, 10 mg to 35 mg, 10 mg to 32 mg, 10 mg to 30 mg, 10 mg to 25 mg, 10 mg to 21 mg, 10 mg to 20 mg, 10 mg to 16 mg, 10 mg to 1 1 mg, 15 mg to 45 mg, 15 mg to 42 mg, 15 mg to 40 mg, 15 mg to 35 mg, 15 mg to 32 mg, 15 mg to 30 mg, 15 mg to 25 mg, 15 mg to 21 mg, 15 mg to 20 mg, 15 mg to 16 mg; and the daily amount of the compound administered to the subject may be 0.1 to 5 mg, 0.1 to 4 mg, 0.1
  • the amount of Compound A administered to the subject in a 28-day period may be 10 mg or less and the daily amount of the compound administered to the subject may be between 0.1 to 1 mg on days where the compound is administered. For example, wherein the amount of Compound A administered to the subject per day is from 0.1 to 0.5 mg.
  • the dosing regimen may comprise administering to the subject 30 mg to 35 mg of Compound A in a 28-day period, for example 35 mg, 34 mg, 33 mg, 32 mg, 31 mg or 30 mg, and the daily amount of the compound administered to the subject may be between 0.5 to 3.5 mg on days where the compound is administered.
  • the dosing regimen may comprise administering 32 mg, wherein the daily amount administered to the subject may be 1 .5 mg on days where the compound is administered, or 30mg, wherein the daily amount administered to the subject may be 3 mg on days where the compound is administered, of Compound A to the subject in a 28-day period.
  • the dosing regimen comprises not administering Compound A to the subject for up to and including 9 consecutive days following the administration of the compound to the subject.
  • the compound may not be administered for 9 consecutive days or fewer, 8 consecutive days or fewer, 7 consecutive days or fewer, 6 consecutive days or fewer, 5 consecutive days or fewer, 4 consecutive days or fewer, 3 consecutive days or fewer, or 2 consecutive days or fewer.
  • these periods of administration and non-administration are repeated one or more times.
  • the dosing regimen may comprise not administering Compound A for 7 consecutive days following the administration of the compound to the subject.
  • the dosing regimen may comprise administering Compound A to the subject daily on 5 consecutive days or less, wherein the amount of Compound A administered to the subject per day is 4 mg or less and/or the amount of Compound A administered to the subject in a 28-day period may be 40 mg or less.
  • the dosing regimen may comprise administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 4 mg or less and/or the amount of Compound A administered to the subject in a 28-day period may be 40 mg or less.
  • the dosing regimen may comprise administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is less than 2 mg and/or the amount of Compound A administered to the subject in a 28-day period may be less than 20 mg.
  • the dosing regimen may comprise administering Compound A for 21 consecutive days and not administering Compound A for 7 consecutive days following the administration of the compound to the subject, wherein the amount of Compound A administered to the subject per day is 1 .5 mg or less and/or the amount of Compound A administered to the subject in a 28-day period may be 32 mg or less.
  • the dosing regimen may comprise administering Compound A for 21 consecutive days and not administering Compound A for 7 consecutive days following the administration of the compound to the subject, wherein the amount of Compound A administered to the subject per day is 0.5 mg or less and/or the amount of Compound A administered to the subject in a 28-day period may be 1 1 mg or less.
  • the invention provides methods of treatment wherein the AUCo-24h of the subject on day 1 of the method of treatment may be 1200 nghr/mL or less.
  • the AUCo-24h of the subject following on day 1 of the method of treatment may be between 300 nghr/mL and 1200 nghr/mL.
  • the invention provides methods of treatment wherein the dosing regimen comprises administering Compound A to the subject on at least 5 consecutive days, wherein the Cmax of the subject following the administration of Compound A on the 5th day may be 120 ng/mL or less.
  • the dosing regimen may comprise administering Compound A to the subject on at least 5 consecutive days, wherein the Cmax of the subject following the administration of Compound A on the 5th day may be between 40 ng/mL and 120 ng/mL.
  • the invention provides methods of treatment wherein the dosing regimen leads to two or more of the parameters i)-iv) in the subject, for example wherein the dosing regimen leads to three or more of the parameters i)-iv) in the subject, or wherein the dosing regimen leads to all of the parameters i)-iv) in the subject. Dosina reductions
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.75 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered orally daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels.
  • the one or more agent(s) may comprise calcium and/or an agent to enhance calcium absorption.
  • the amount of calcium administered may be from 500 mg to 3000 mg, for example, from 1000 mg to 2500 mg, from 1500 mg to 2000 mg.
  • the amount of calcium administered may be 1800 mg.
  • An agent to enhance calcium absorption can be any agent that increases the absorption of calcium from a supplement given to a subject.
  • the agent can be a Vitamin D supplement or an analogue of vitamin D.
  • the amount of calcium administered may be 1800 mg, and the amount of calcitriol administered may be 0.5 pg.
  • the one or more agent(s) may be administered if the subject has a blood calcium level below normal after the administration of at least one dose of Compound A.
  • the methods of invention may comprise measuring the calcium levels of a subject and administering one or more agents to the subject to supplement their calcium levels if their blood calcium level is low.
  • the method of treatment may comprise administering Compound A as a pharmaceutically acceptable composition.
  • the composition may be suitable for oral administration.
  • the dosage regimen of the invention may comprise the oral administration of a composition comprising Compound A.
  • the tablet may comprise a flow aid, such as colloidal silica dioxide (CSD) or magnesium stearate.
  • the flow aid may comprise colloidal silica dioxide.
  • the tablet may comprise between 0.5 and 2.5 wt% of the flow aid, for example about 1 .5 wt%.
  • the tablet may comprise about 1 .5 wt% of CSD.
  • the extragranular portion may contain a disintegrant such as CCS, a flow aid such as colloidal silica dioxide, and a lubricant such as SSF.
  • the extragranular portion may comprise about 2.33 wt% of CCS, about 0.5 wt % of CSD, and about 0.5 wt% of SSF.
  • the tablet weight may be between 50 mg and 300 mg. In preferred embodiments, the tablet weight is 100 mg or 150 mg. In embodiments where the tablet weight is 10Omg, the tablet may contain 5 mg of a 10:90 solid dispersion of Compound A and HPMCAS-M, 43 mg of microcrystalline cellulose, 43 mg of mannitol, 6 mg of CCS, 1 .5 mg of CSD and 1.5 mg of SSF. In these embodiments, 2.33 mg of CCS, 0.5 mg of CSD and 0.5 mg of SSF are in the extragranular portion, and the remaining tablet components are in the intragranular portion.
  • the tablet contains 7.5 mg of a 10:90 solid dispersion of Compound A and HPMCAS-M, 64.5 mg of microcrystalline cellulose, 64.5 mg of mannitol, 9 mg of CCS, 2.25 mg of CSD and 2.25 mg of SSF.
  • 7.5 mg of CCS, 0.75 mg of CSD and 0.75 mg of SSF are in the extragranular portion, and the remaining tablet components are in the intragranular portion.
  • the invention provides a pharmaceutically acceptable composition as described herein, comprising Compound A.
  • the methods of treatment provided by the invention may also be expressed in terms of the use of Compound A in these methods.
  • the invention provides Compound A for use in any method of treating a disease in a subject in need of such treatment defined herein.
  • the invention also provides the use of Compound A in the manufacture of a medicament for treating a disease in a subject in need of such treatment according to any method herein.
  • treat refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition or one or more symptoms of such disorder or condition. This includes but is not limited to the use of the methods described herein for prophylaxis, or the prevention of disease.
  • the cancer may be prostate cancer. In some embodiments, the cancer may be castration resistant prostate cancer. In some embodiments, the prostate cancer is an ARV7-driven prostate cancer. In some embodiments, the prostate cancer is not an ARV7-driven prostate cancer.
  • the cancer may be breast cancer. In some embodiments, the cancer may be ER-positive breast cancer.
  • the cancer is a myc-driven cancer.
  • the cancer is a solid tumor cancer, such as breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu-NETs), liver cancer, stomach cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, skin cancer, brain cancer, cervical cancer, ovarian cancer, melanoma and head and neck cancer.
  • a solid tumor cancer such as breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu-NETs)
  • liver cancer stomach cancer
  • pancreatic cancer gastric cancer
  • the cancer may be a solid tumour with Myc amplification, e.g. L-Myc or N-Myc amplification.
  • L- Myc or N-Myc amplification can be measured from a sample taken from a subject, e.g. a tumour sample, according to any suitable commercially available assay.
  • Subjects with Myc amplification, e.g. L-Myc or N- Myc, amplification may be particularly suited to the methods of treatment described herein.
  • Assays for determining Myc amplification include the FoundationOne CDx (F1CDx) assay or the Tempus xT assay, to detect the copy number alterations and therefore the alterations.
  • Copy number variations are a deviation from the normal number of copies of a gene, which is typically 2. They are reported either as a Copy Number Gain (amplification) or a Copy Number Loss (deletion).
  • RT-qPCR may be carried out on a biological sample taken from a subject.
  • RNA isolation may be carried out using formalin-fixed paraffin-embedded (FFPE) slides as starting material.
  • FFPE formalin-fixed paraffin-embedded
  • RNA may be extracted using an isolation kit, or any other such method known in the art, such as, for example, using the High Pure FFPET RNA isolation kit (Roche, cat. no. 06650775001).
  • RNA may be eluted using a 30 pl elution buffer.
  • Such a buffer may be any such buffer known in the art.
  • Synthesis of cDNA is performed using random primers, using any such method to do so; for example, the iScriptTM Advanced cDNA Synthesis Kit for RT-qPCR (Bio-Rad, cat. no. 1725038).
  • 15 pL RNA sample may be mixed with 4 pL of 5x iScript Advanced reaction mix and 1 pL iScript Advanced Reverse transcriptase. The mixture may be incubated for 20 min at 46 °C, 1 min at 95 °C.
  • qPCR analysis may be performed in order to quantify the transcript abundance of each gene of interest in the FFPE tissue samples.
  • the patient is biomarker positive for neuroendocrine (NE). This can mean that patient has a neuroendocrine cancer. This can be determined by any suitable method, e.g. through a pathology report.
  • NE neuroendocrine
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is a solid tumour with L-MYC or N-MYC amplification.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.75 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is a solid tumour with L-MYC or N-MYC amplification.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is a solid tumour with L-MYC or N-MYC amplification.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is a high-grade NE tumour.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is a high-grade NE tumour.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is non-small cell lung cancer.
  • the non-small cell lung cancer may exhibit high L-Myc or N-Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is lung cancer.
  • the lung cancer may exhibit high L-Myc or N-Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is non-small cell lung cancer.
  • the non-small cell lung cancer may exhibit high L-Myc or N-Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is small cell lung cancer.
  • the small cell lung cancer may exhibit high L-Myc or N-Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is non-small cell lung cancer.
  • the non-small cell lung cancer may exhibit high L-Myc or N- Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is small cell lung cancer.
  • the small cell lung cancer may exhibit high L-Myc or N-Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.75 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is non-small cell lung cancer.
  • the non-small cell lung cancer may exhibit high L- Myc or N-Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.75 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is small cell lung cancer.
  • the small cell lung cancer may exhibit high L-Myc or N- Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is small cell lung cancer.
  • the small cell lung cancer may exhibit high L-Myc or N-Myc expression.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is prostate cancer.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.75 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is castration resistant prostate cancer.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.75 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is prostate cancer.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is prostate cancer.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is castration resistant prostate cancer.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is breast cancer.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 0.5 mg of Compound A is administered once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is ER-positive breast cancer.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 21 and Compound A is not administered on days 22 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is ER-positive breast cancer.
  • the methods of the invention include administering Compound A to the subject according to a dosing regimen wherein 1 mg of Compound A is administered orally once daily on days 1 to 5 and days 15 to 19 and is not administered on days 6 to 14 and 20 to 28 of a 28-day cycle, and wherein one or more agent(s) is administered to the subject to supplement their calcium levels, wherein the disease to be treated is ER-positive breast cancer.
  • the method of the invention may comprise degrading GSPT1 in a subject suffering from cancer, comprising administering the subject a therapeutically effective amount of a compound or a composition as described herein.
  • the method of the invention may comprise reducing the level of GSPT1 in a subject suffering from cancer, comprising administering the subject a therapeutically effective amount of a compound or a composition as described herein.
  • the dosing regimens described are not necessarily limited to the administration of only Compound A.
  • Compound A may be administered in combination with any other suitable therapeutic agent, for example another anti-cancer agent.
  • At least one other suitable therapeutic agent is administered during the time period of the specified dosing regimen.
  • the at least one other suitable therapeutic agent is a known treatment for the disease to be treated. In some embodiments, the at least one other suitable therapeutic agent is the standard of care treatment for the disease to be treated.
  • V (L x W x W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L).
  • mRNA expression levels of L-MYC and N-MYC were determined and integrated into a “MYC status” indicating whether L-MYC or N-MYC levels or both exceeded a certain threshold.
  • lung PDX models were categorized as neuroendocrine (NE) or not, based on an mRNA-derived signature. The relationship between efficacy and MYC status or NE signature positivity analyzed separately for NE- negative NSCLC, NE-positive NSCLC and SCLC.
  • Rh] AUCo-24hr Day 7/AUCo-24hr Day 1 .
  • NOAEL for this study was considered to be 300 mg/kg/day or greater.
  • the dose of 300 mg/kg/day was associated with mean Cmax and AUC values for males of 11000 ng/mL and 175000 hr «ng/mL, and for females of 22500 ng/mL and 397000 hr «ng/mL after 28 days of treatment.
  • Altered calcium and phosphorus excretion in the kidney may have contributed to these changes, as supported by mild increases in the fractional excretion of calcium in the urine of both sexes at 0.5 mg/kg/day (indicating increased urine calcium excretion), and mild decreases in the fractional excretion of phosphorus in the urine of females at 0.5 mg/kg/day (indicating decreased urine phosphorus excretion).
  • changes attributed to altered calcium and phosphorus regulation were limited to minimal decreases in total serum calcium and minimal increases in serum phosphorus concentration at the end of the dosing period. Changes in ionized calcium were not observed.
  • Tmax time of maximum plasma concentration. Data are from a single male or female animal.
  • MRT-2359-related clinical observations were seen in the surviving male and female at 0.4 mg/kg/day.
  • the male exhibited decreased appetite, slight trembling (at rest) and decreased activity and muscle fasciculations on Day 20 before necropsy.
  • Calcium gluconate (2.3%) was administered subcutaneously on Day 20 due to decreased blood calcium levels to prevent further decline before necropsy.
  • the female had decreased calcium levels on Day 4 but was otherwise stable and, therefore, was not administered calcium gluconate but later exhibited hunched posture only on Day 7. There were no other test article-related clinical observations in surviving animals.
  • MRT-2359 at 0.4 mg/kg/day was associated with minimal increases in mean urea nitrogen concentration and mean AST, ALT, and total bilirubin.
  • the increase in AST and ALT in females were mostly attributable to increases in 1 individual. No microscopic correlates were observed, and increases resolved after the 2-week recovery period.
  • MRT-2359-related organ weight changes were observed in the thymus (decreased trend) in males and females dosed at > 0.1 mg/kg/day, correlating microscopically to decreased lymphoid cellularity observed in males and females at 0.4 mg/kg/day, and in the spleen (decreased trend) in males and females at 0.4 mg/kg/day with no microscopic correlate.
  • the HNSTD (highest non-severely toxic dose) was considered to be 0.2 mg/kg/day and associated with mean Cmax and AUC values for males of 44.5 ng/mL and 625 hr «ng/mL, and for females of 61.2 ng/mL and 714 hr «ng/mL, respectively, after the 19- day treatment schedule.
  • This HNSTD in monkeys corresponds to a human dose of 3.84 mg, suggesting a daily dose of less than 4 mg in dosing regimens having 5 days of continuous dosing or less.
  • Increased liver vacuolation at > 0.2 mg/kg/day corresponded with changes in liver markers on clinical chemistry evaluation (total bilirubin concentration, AST activity, and/or ALT activity).
  • Clinical pathology changes that did not have correlative microscopic findings included coagulation; males at > 0.2 mg/kg/day and females at 0.3 mg/kg/day had minimal prolongations in PT and aPTT, and males at 0.2 mg/kg/day had a concurrent minimal decrease in FIB concentration.
  • MRT-2359 was associated with slight, reversible, non-dose-dependent decreases in mean heart rate following administration of doses > 0.1 mg/kg/day (mean decreases up to 17%, 24 beats/minute) on Day 27.
  • Administration of MRT-2359 at 0.2 mg/kg/day was also associated with increases in uncorrected QT interval and QTc in a single animal on Day 27.
  • the high- dose group (0.3 mg/kg/day) was terminated prior to the scheduled postdose telemetry monitoring and was, therefore, not conducted.
  • Example 7 Effects of repeat dosing of MRT-2359 on GSPT1 protein levels in Cynomolgus monkeys PBMCs
  • a Phase 1/2, open-label, multicenter, dose escalation and expansion study is underway and is designed to assess the safety, tolerability, PK, pharmacodynamics, and preliminary clinical activity of MRT-2359.
  • the subjects have previously treated selected solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), high-grade neuroendocrine cancer of any primary site, diffuse large B-cell lymphoma (DLBCL), and solid tumors with L-MYC or N-MYC amplification.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • LLBCL diffuse large B-cell lymphoma
  • solid tumors with L-MYC or N-MYC amplification solid tumors with L-MYC or N-MYC amplification.
  • Phase 1 Dose Escalation evaluates the effect of a high-fat meal on the relative bioavailability of MRT-2359 by standard primary PK parameters including, but not limited to, AUC and Cmax [ Time Frame: 7 days ]
  • Dose level -1 may be used if appropriate (e.g., if the starting dose level is not well tolerated or a dose reduction is necessary). Dosing schedule may be decreased to D1 to D3 and D15 to D17 in the 5/9/579 schedule and to D1 to D14 in the 21/7 schedule.
  • MRT-2359 is spray dried with hypromellose acetate succinate (HPMCAS-M) as a polymer (10:90 MRT-2359:HPMCAS-M), then SDD formulated in tablet form in strengths of 0.5 mg (100 mg round-shaped tablet) and 2 mg (100 mg oval-shaped tablet) for PO administration.
  • HPMCAS-M hypromellose acetate succinate
  • SDD formulated in tablet form in strengths of 0.5 mg (100 mg round-shaped tablet) and 2 mg (100 mg oval-shaped tablet) for PO administration.
  • Table 7 MRT-2359 Excipients
  • MRT-2359 is supplied as tablets in strengths of 0.5 mg (100 mg round-shaped tablet) and 2 mg (100 mg oval-shaped tablet).
  • Dose escalation, cohort expansion, and dose de-escalation may occur in accordance with the recommendations of the BOIN algorithm. Advancement to higher dose levels will not proceed beyond the recommended next dose level of the BOIN algorithm.
  • Example 9 Outcomes from Clinical Trial of Example 8
  • FFPE Formalin-Fixed Paraffin-Embedded
  • Tumours from 6 patients were identified as biomarker positive for at least one of N-Myc, L-Myc and NE. Of these 6 biomarker positive patients, 2 have experienced a PR (1 confirmed, 1 unconfirmed) and 1 patient has SD. % change refers to % change in tumour volume.
  • mice were inoculated subcutaneously in the right flank region with 1 x10 7 cells in 0.1 mL of PBS solution + Matrigel (1 :1). Mice were castrated as described above when the mean tumor size reached approximately 200 mm 3 . Treatment was initiated when the tumor volume recovered to ⁇ 204.78 mm 3 after castration. 48 mice were enrolled in the study (Table 11). All animals were randomly allocated to 6 study groups. Randomization was performed based on “Matched distribution” method (StudyDirectorTM software, version 3.1 .399.19). The date of randomization was denoted as day 0.
  • MRT-2359 Anti-tumor activity of MRT-2359 as single agent or in combination with enzalutamide, was measured.
  • MRT-2359 was administered orally (PO) to tumor-bearing mice in different regimens, which included both daily (QD) or intermittent (5 days on / 9 days off) dosing.
  • Enzalutamide was administered at a dose of 30 mg/kg QD, PO. Treatment duration was ⁇ 4 weeks. Results are shown in Figures 13A and 13B.
  • solid dispersions consisting of Compound A and a polymer were chemically and physically stable for at least a year. This was unexpected in view of the typically short shelf life (e.g. 6 months) of early-stage unoptimized amorphous solid dispersions consisting of API and polymer, and lacking additional excipients like stabilizers, antioxidants, or plasticizers that might otherwise enhance stability.
  • the long shelf-life of the solid dispersion allowed the inventors to reuse solid dispersions that had been stored for more than a year, avoiding wastage of material.
  • the 0.5 mg tablet formulation was prepared with two fillers, including a granulation binder/ductile filler (Avicel PH-113) and a compressible filler/brittle filler (Mannitol, Parteck M100).
  • the powder formulations were designed for a direct compression process, a 0.5 mg dose strength, and a 100 mg final tablet weight.
  • the SDD blend was automatically sieved through 1 mm mesh at 1000 rpms.
  • colloidal silica and Acdisol SD-711 were bag blended with 11 grams of granules for 20 seconds. Then, the pre-blend was manually sieved through 0.630 mm mesh and added to the blend. The components were blended for 20 mins and 20 rpms.
  • Tableting was carried out with 6.35 mm round punches (IDI-181), with a press speed of 5000 tabs per hour.
  • the process parameters are shown in Table 19.
  • the SDD blend was automatically sieved through 1 mm mesh at 1000 rpms.
  • the initial blend was compacted using an Alexanderwerk WP 120 pharma roller compactor (with mini-production kit) to give granules.
  • Colloidal silica and Acdisol SD-711 were bag blended with 66 grams of granules for 20 seconds. Then, the pre-blend was manually sieved through 0.630 mm mesh and added to the blend. The components were blended for 20 mins and 20 rpms. 9. Sodium stearil fumarate (Pruv) was manually sieved through 0.630 mm mesh and added to the blend. Then, it was blended 5 minutes at 20 rpms to give the final blend.
  • Tableting was carried with 7.00 mm round punches (IDI-156), with a press speed of 10,000 tabs per hour.
  • the process parameters are shown in Table 21 .
  • Table 22 Physical characterization of the tablets (0.5 mg and 0.75 mg strength) at various time- points.
  • a method of treating a disease in a subject in need of such treatment comprises administering Compound A to the subject according to a dosing regimen wherein the amount of Compound A administered to the subject is 45 mg or less in a 28-day period, and wherein Compound A has the following structure:
  • dosing regimen comprises administering Compound A to the subject daily on at least 4 consecutive days.
  • the dosing regimen comprises not administering Compound A to the subject for 1 day or more following the administration of the compound to the subject.
  • the method of any of embodiments 14 to 16 wherein the dosing regimen comprises not administering Compound A for less than 9 consecutive days following the administration of the compound to the subject.
  • the method of any of embodiments 14 to 17 wherein the dosing regimen comprises not administering Compound A for 8 consecutive days or less following the administration of the compound to the subject.
  • the method of any of embodiments 14 to 18 wherein the dosing regimen comprises not administering Compound A for 7 consecutive days following the administration of the compound to the subject.
  • the dosing regimen comprises administering Compound A daily for 21 consecutive days and not administering Compound A for 7 consecutive days following the administration of the compound to the subject.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 42 mg or less of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 40 mg or less of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 30 mg or less of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 25 mg or less of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering
  • the dosing regimen comprises administering 11 mg or less of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 10 mg or less of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 5 mg or less of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 10 mg or more of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 5 mg or more of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 5 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 4 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 3 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 2 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 1 .5 mg or less.
  • the daily amount of the compound administered to the subject is from 0.1 mg to 1 .5 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.1 mg to 1 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.1 mg to 0.5 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.15 mg to 4 mg on days where the compound is administered.
  • the daily amount of the compound administered to the subject is from 0.25 mg to 3 mg on days where the compound is administered.
  • the daily amount of the compound administered to the subject is from 0.5 mg to 2 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.5 mg to 1 .5 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.5 mg to 1 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is selected from 0.1 mg, 0.25 mg, 0.5 mg, 1 .0 mg, 1 .5 mg, or 2.0mg on days where the compound is administered.
  • any of embodiments 1 to 25 wherein the amount of Compound A administered to the subject is 11 mg or less in a 28-day period and wherein the daily amount of the compound administered to the subject is from 0.1 mg to 1 mg on days where the compound is administered.
  • the method of any of embodiments 1 to 25 wherein the amount of Compound A administered to the subject is 10 mg or less in a 28-day period and wherein the daily amount of the compound administered to the subject is from 0.1 mg to 1 mg on days where the compound is administered.
  • the method of any of embodiments 1 to 25 wherein the amount of Compound A administered to the subject is 5 mg or less in a 28-day period and wherein the daily amount of the compound administered to the subject is from 0.1 mg to 0.5 mg on days where the compound is administered.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 4 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 40 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 3.5 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 35 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 3 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 30 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 2.5 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 25 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 2 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 20 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is less than 2 mg and/or the amount of Compound A administered to the subject in a 28-day period is less than 20 mg.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 1 .5 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 15 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 1 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 10 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 0.5 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 5 mg or less.
  • the method of embodiment 1 or embodiment 15 wherein the dosage regimen comprises administering Compound A to the subject daily on more than 5 consecutive days, wherein the amount of Compound A administered to the subject per day is 2 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 45 mg or less.
  • the method of embodiment 1 or embodiment 15 wherein the dosage regimen comprises administering Compound A for 21 consecutive days and not administering Compound A for 7 consecutive days following the administration of the compound to the subject, wherein the amount of Compound A administered to the subject per day is 2 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 42 mg or less.
  • the method of embodiment 1 or embodiment 15 wherein the dosage regimen comprises administering Compound A for 21 consecutive days and not administering Compound A for 7 consecutive days following the administration of the compound to the subject, wherein the amount of Compound A administered to the subject per day is 1 .5 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 32 mg or less.
  • the method of any preceding embodiment wherein the AUCo-24h of the subject on day 1 of the method of treatment is 1200 nghr/mL or less.
  • the method of any preceding embodiment wherein the AUCo-24h of the subject on day 1 of the method of treatment is between 300 nghr/mL and 1200 nghr/mL.
  • the method of any preceding embodiment wherein the AUCo-24h Of the subject on the 5th day of the method of treatment is 2500 nghr/mL or less.
  • the method of any preceding embodiment wherein the AUCo-24h of the subject following the administration of Compound A on the 5th day is between 700 ng/mL and 2500 nghr/mL.
  • the method of any preceding embodiment wherein the Cmax of the subject following the first administration of Compound A is between 20 ng/mL and 60 ng/mL.
  • the method of any preceding embodiment wherein the Cmax of the subject on the 5th day of the method of treatment is 120 ng/mL or less.
  • the method of any preceding embodiment wherein the Cmax on the 5th day is between 40 ng/mL and 120 ng/mL.
  • the dosing regimen comprises administering Compound A to the subject on at least 5 consecutive days, wherein the Cmax of the subject following the administration of Compound A on the 5th day is 120 ng/mL or less.
  • the dosing regimen comprises administering Compound A to the subject on at least 5 consecutive days, wherein the Cmax of the subject following the administration of Compound A on the 5th day is between 40 ng/mL and 120 ng/mL.
  • the dosing regimen leads to one or more of the following parameters in the subject:
  • the AUCo-24h of the subject on day 1 of the method of treatment may be 1200 nghr/mL or less; for example, the AUCo-24h of the subject following on day 1 of the method of treatment may be between 300 nghr/mL and 1200 nghr/mL;
  • the Cmax of the subject on the 5th day of the method of treatment is 120 ng/mL or less; for example, the Cmax on the 5th day may be between 40 ng/mL and 120 ng/mL.
  • the method of embodiment 99 wherein the dosing regimen leads to two or more of the parameters i)-iv) in the subject.
  • the method of embodiment 99 wherein the dosing regimen leads to three or more of the parameters i)-iv) in the subject.
  • the method of embodiment 99 wherein the dosing regimen leads to all of the parameters i)-iv) in the subject.
  • the method of any preceding embodiment wherein Compound A is administered once daily.
  • the method comprises administering one or more agent(s) to the subject to supplement their calcium levels.
  • the method of embodiment 105 wherein the one or more agent(s) comprise calcium and/or an agent to enhance calcium absorption.
  • the method of embodiment 105 or embodiment 106 wherein the one or more agent(s) comprise calcium and the amount of calcium administered is from 500 mg to 3000 mg.
  • the method of embodiment 107 wherein the amount of calcium administered is from 1000 mg to 2500 mg.
  • the method of embodiment 108 wherein the amount of calcium administered is from 1500 mg to 2000 mg.
  • the method of embodiment 109 wherein the amount of calcium administered is 1800 mg.
  • the method of any of embodiments 105 to 110 wherein the agent to enhance calcium absorption is a Vitamin D supplement or an analogue of vitamin D.
  • the method of embodiment 115 wherein the amount of calcitriol administered is from 0.4 pg to 1.0 pg.
  • the method of embodiment 116 wherein the amount of calcitriol administered is 0.5 pg.
  • the method of any of embodiments 105 to 117 wherein the one or more agent(s) comprise calcium and calcitriol, the amount of calcium administered is 1800 mg, and the amount of calcitriol administered is 0.5 pg.
  • the method of any of embodiments 105 to 118 wherein the one or more agent(s) are administered once daily for the period of time that Compound A is administered.
  • the method of any of embodiments 105 to 119 wherein the one or more agent(s) are administered once daily for a time period before Compound A is administered.
  • the method of any of embodiments 119 to 122 wherein the time period is between 1 to 7 days.
  • the method of embodiment 123 wherein the time period is between 2 to 4 days.
  • the method of embodiment 124 wherein the time period is 3 days.
  • the method of any preceding embodiment wherein the method comprises measuring the calcium levels of a subject and administering one or more agents to the subject to supplement their calcium levels if their calcium level is low.
  • the method of any of embodiments 105 to 127 wherein the calcium level of the subject is between 6 mg/dL and 8 mg/dL.
  • the method of embodiment 128 wherein the calcium level of the subject is between 6 mg/dL and 7 mg/dL.
  • Compound A is administered to the subject as a tablet.
  • the method of embodiment 130 wherein the tablet comprises Compound A as a solid dispersion.
  • the method of embodiment 131 wherein the solid dispersion comprises a polymer suitable for forming such a solid dispersion so that the drug is stabilised by the polymer.
  • the method of embodiment 132 wherein the polymer is hypromellose acetate succinate.
  • the method of embodiment 133 wherein the solid dispersion comprises 10:90 Compound
  • A:Hypromellose acetate succinate The method of any of embodiments 130 to 134 wherein the tablet comprises a ductile filler, a brittle filler, a disintegrant, a flow aid, and/or a lubricant.
  • MMC microcrystalline cellulose
  • CCS croscarmellose sodium
  • Compound A is in the form of an amorphous free base.
  • the method of any preceding embodiment where the disease to be treated is a disease associated with or caused by GSPT1 .
  • the method of any preceding embodiment wherein the disease to be treated is cancer associated with GSPT1 .
  • the disease is cancer.
  • the method of embodiment 144 or 145 wherein the cancer is a solid cancer including but not limited to cancers of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx and salivary glands), neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, uterus, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, re
  • the method of embodiment 145 wherein the cancer is breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu-NETs), liver cancer, stomach cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, skin cancer, brain cancer, cervical cancer, ovarian cancer, melanoma and head and neck cancer.
  • the disease is lung cancer.
  • the method of embodiment 1 or embodiment 15 wherein the dosing regimen comprises administering 0.5 mg of Compound A orally once daily on days 1 to 5 and days 15 to 19 and not administering Compound A on days 6 to 14 and 20 to 28 of a 28-day cycle, wherein one or more agent(s) is administered to the subject to supplement their calcium levels and wherein the disease to be treated is lung cancer.
  • the method of embodiment 158 wherein the lung cancer is NSCLC.
  • the method of embodiment 158 wherein the lung cancer is SCLC.
  • the method of any one of embodiments 158 to 160 wherein the lung cancer is a cancer with high L-MYC or N-MYC expression.
  • the method of embodiment 1 or embodiment 15 wherein the dosing regimen comprises administering 1 mg of Compound A orally once daily on days 1 to 21 and not administering Compound A on days 22 to 28 of a 28-day cycle, wherein one or more agent(s) is administered to the subject to supplement their calcium levels and wherein the disease to be treated is lung cancer.
  • the method of embodiment 162 wherein the lung cancer is NSCLC.
  • the method of embodiment 162 wherein the lung cancer is SCLC.
  • the method of any one of embodiments 162 to 164 wherein the lung cancer is a cancer with high L-MYC or N-MYC expression.
  • the method comprises treating a Myc-driven cancer in a subject, comprising administering the subject a therapeutically effective amount of the compound or a composition as described herein.
  • the method of any preceding embodiment wherein the method comprises degrading GSPT 1 in a subject suffering from cancer, comprising administering the subject a therapeutically effective amount of a compound or a composition as described herein.
  • the method of any preceding embodiment wherein the method comprises reducing the level of GSPT1 in a subject suffering from cancer, comprising administering the subject a therapeutically effective amount of a compound or a composition as described herein.
  • a method of treating a disease in a subject in need of such treatment comprises administering Compound A to the subject according to a dosing regimen wherein the amount of Compound A administered to the subject is 45 mg or less in a 28-day period, and wherein Compound A has the following structure:
  • dosing regimen comprises administering Compound A to the subject daily on at least 2 consecutive days.
  • dosing regimen comprises administering Compound A to the subject daily on at least 5 consecutive days.
  • dosing regimen comprises administering Compound A to the subject daily on 5 consecutive days.
  • the dosing regimen comprises not administering Compound A to the subject for up to and including 9 consecutive days following the administration of the compound to the subject.
  • the method of any preceding embodiment wherein the dosing regimen comprises not administering Compound A to the subject for 9 consecutive days following the administration of the compound to the subject.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering Compound A to the subject daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering Compound A to the subject daily for days 1 to 5 of a time period, and not administering Compound A for days 6 to 14 of a time period.
  • the dosing regimen comprises administering Compound A to the subject daily for days 1 to 5 of a time period, not administering Compound A for days 6 to 14 of a time period, administering Compound A to a subject daily for days 15 to 19 of a time period, and not administering Compound A for days 20 to 28 of a time period.
  • the method of any of embodiments 1 to 5 wherein the dosing regimen comprises administering Compound A to the subject daily for more than 5 consecutive days.
  • the dosing regimen comprises administering Compound A to the subject daily for more than 10 consecutive days.
  • the method of any of embodiments 14 to 20 wherein the dosing regimen comprises administering Compound A to the subject daily for more than 15 consecutive days.
  • the method of any of embodiments 14 to 21 wherein the dosing regimen comprises administering Compound A to the subject daily for more than 20 consecutive days.
  • the method of any of embodiments 14 to 22 wherein the dosing regimen comprises administering Compound A to the subject daily for 21 consecutive days.
  • the method of any of embodiments 14 to 23 wherein the dosing regimen comprises administering Compound A to the subject daily for 21 consecutive days and not administering Compound A for less than 9 consecutive days following the administration of the compound to the subject.
  • the dosing regimen comprises administering Compound A daily for 21 consecutive days and not administering Compound A for 7 consecutive days following the administration of the compound to the subject.
  • the dosing regimen comprises administering mg or less of Compound A to the subject in a 28-day period.
  • the dosing regimen comprises administering mg or less of Compound A to the subject in a 28-day period.
  • the dosing regimen comprises administering mg or less of Compound A to the subject in a 28-day period.
  • the dosing regimen comprises administering mg or less of Compound A to the subject in a 28-day period.
  • the dosing regimen comprises administering mg or less of Compound A to the subject in a 28-day period.
  • the dosing regimen comprises administering mg or less of Compound A to the subject in a 28-day period.
  • the dosing regimen comprises administering mg or more of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the dosing regimen comprises administering 5 mg or more of Compound A to the subject in a 28-day period.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 5 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 4 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 3 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 2 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 1 .5 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 1 mg or less.
  • the method of any preceding embodiment wherein the amount of Compound A administered to the subject per day is 0.75 mg or less.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is 0.1 mg or more, on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.1 mg to 5 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.1 mg to 2 mg on days where the compound is administered.
  • the daily amount of the compound administered to the subject is from 0.1 mg to 1 .5 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.1 mg to 1 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.1 mg to 0.5 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is from 0.15 mg to 4 mg on days where the compound is administered.
  • the daily amount of the compound administered to the subject is from 0.25 mg to 3 mg on days where the compound is administered.
  • the daily amount of the compound administered to the subject is selected from 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg or 1 .0 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is 0.5 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is 0.75 mg on days where the compound is administered.
  • the method of any preceding embodiment wherein the daily amount of the compound administered to the subject is 1 mg on days where the compound is administered.
  • the daily amount of the compound administered to the subject is 1 .5 mg on days where the compound is administered.
  • any of embodiments 1 to 25 wherein the amount of Compound A administered to the subject is 5 mg or less in a 28-day period and wherein the daily amount of the compound administered to the subject is from 0.1 mg to 0.5 mg on days where the compound is administered.
  • the dosage regimen comprises administering Compound A to the subject daily on 5 consecutive days or more, wherein the amount of Compound A administered to the subject per day is 5 mg or less, and/or the amount of Compound A administered to the subject in a 28-day period is 45 mg or less.
  • the dosage regimen comprises administering Compound A to the subject daily on 5 consecutive days or less, wherein the amount of Compound A administered to the subject per day is 4 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 40 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 4 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 40 mg or less.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is less than 2 mg and/or the amount of Compound A administered to the subject in a 28-day period is less than 20 mg.
  • the method of embodiment 1 wherein the dosage regimen comprises administering Compound A daily for 5 consecutive days and not administering Compound A for the following 9 consecutive days, wherein the amount of Compound A administered to the subject per day is 1 .5 mg or less and/or the amount of Compound A administered to the subject in a 28-day period is 15 mg or less.
  • the method of any preceding embodiment wherein the method comprises measuring the calcium levels of a subject and administering one or more agents to the subject to supplement their calcium levels if their calcium level is low.
  • the method of any of embodiments 123 to 145 wherein the calcium level of the subject is between 6 mg/dL and 8 mg/dL.
  • the method of embodiment 146 wherein the calcium level of the subject is between 6 mg/dL and 7 mg/dL.
  • Compound A is administered to the subject as a tablet.
  • the method of embodiment 172 wherein the cancer is breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu-NETs), liver cancer, stomach cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, skin cancer, brain cancer, cervical cancer, ovarian cancer, melanoma and head and neck cancer.
  • the disease is lung cancer.
  • B-Cell lymphoma The method of any of embodiments 171 to 181 , wherein the cancer is a Myc-driven cancer.
  • the method of any of embodiments 171 to 182 wherein the disease to be treated is a solid tumour with L-Myc or N-Myc amplification.
  • the method of any of embodiments 171 to 183 wherein the disease to be treated is a cancer with high L-Myc or N-Myc expression.
  • the method of embodiment 1 or embodiment 15 wherein the dosing regimen comprises administering 0.5 mg of Compound A orally once daily on days 1 to 21 and not administering Compound A on days 22 to 28 of a 28-day cycle, wherein one or more agent(s) is administered to the subject to supplement their calcium levels and wherein the disease to be treated is lung cancer.
  • the method of embodiment 185 wherein the lung cancer is NSCLC.
  • the method of embodiment 185 wherein the lung cancer is SCLC.
  • the method of any one of embodiments 185 to 187 wherein the lung cancer is a cancer with high L-MYC or N-MYC expression.
  • the method of embodiment 195 wherein the breast cancer is ER-positive breast cancer.
  • the method of embodiment 1 or embodiment 15 wherein the dosing regimen comprises administering 1 mg of Compound A orally once daily on days 1 to 21 and not administering Compound A on days 22 to 28 of a 28-day cycle, wherein one or more agent(s) is administered to the subject to supplement their calcium levels and wherein the disease to be treated is lung cancer.
  • the method of embodiment 197 wherein the lung cancer is NSCLC.
  • the method of embodiment 197 wherein the lung cancer is SCLC.
  • the method of any one of embodiments 197 to 199 wherein the lung cancer is a cancer with high L-MYC or N-MYC expression.
  • the method of embodiment 1 or embodiment 15 wherein the dosing regimen comprises administering 1 mg of Compound A orally once daily on days 1 to 5 and days 15 to 19 and not administering Compound A on days 6 to 14 and 20 to 28 of a 28-day cycle, wherein one or more agent(s) is administered to the subject to supplement their calcium levels and wherein the disease to be treated is lung cancer.
  • the method of embodiment 201 wherein the lung cancer is NSCLC.
  • the method of embodiment 201 wherein the lung cancer is SCLC.
  • the method of any one of embodiments 201 to 203 wherein the lung cancer is a cancer with high L-MYC or N-MYC expression.
  • Compound A is administered in combination with at least one further therapeutic agent.
  • the method of embodiment 205 wherein the disease to be treated is prostate cancer and the further therapeutic agent is an anti-androgen agent, such as an AR antagonist, for example, enzalutamide.
  • the method of embodiment 206 wherein the dosing regimen comprises administering 0.5 mg of Compound A orally once daily on days 1 to 21 and not administering Compound A on days 22 to 28 of a 28-day cycle, wherein one or more agent(s) is administered to the subject to supplement their calcium levels.
  • the method of embodiment 206 or embodiment 207 wherein the prostate cancer is castration resistant prostate cancer.
  • the method of any of embodiments 206 to 208 wherein enzalutamide is administered at a dose of 160 mg daily.
  • the method of embodiment 205 wherein the disease to be treated is breast cancer and the further therapeutic agent is a selective estrogen receptor degrader (SERD), for example, fulvestrant.
  • SESD selective estrogen receptor degrader
  • the method of embodiment 210 wherein the dosing regimen comprises administering 0.5 mg of Compound A orally once daily on days 1 to 21 and not administering Compound A on days 22 to 28 of a 28-day cycle, wherein one or more agent(s) is administered to the subject to supplement their calcium levels.
  • the method of embodiment 210 or embodiment 211 wherein the breast cancer is ER-positive breast cancer.
  • the method of any of embodiments 210 to 212 wherein fulvestrant is administered at a dose of 500 mg monthly.
  • the method comprises treating a Myc-driven cancer in a subject, comprising administering the subject a therapeutically effective amount of the compound or a composition as described herein.
  • the method of any preceding embodiment wherein the method comprises degrading GSPT 1 in a subject suffering from cancer, comprising administering the subject a therapeutically effective amount of a compound or a composition as described herein.
  • the method of any preceding embodiment wherein the method comprises reducing the level of GSPT1 in a subject suffering from cancer, comprising administering the subject a therapeutically effective amount of a compound or a composition as described herein.
  • a tablet as defined in any one of embodiments 148 to 169.

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Abstract

La présente divulgation concerne des méthodes de traitement d'une maladie chez un sujet ayant besoin d'un tel traitement avec un composé d'isoindolinone. En particulier, le composé A d'isoindolinone peut être administré au sujet selon une ou plusieurs méthodes définies dans la description. L'invention concerne également le composé d'isoindolinone destiné à être utilisé dans lesdites méthodes.
PCT/EP2024/078801 2023-10-13 2024-10-11 Dégradeur mrt-2359 de colle moléculaire gspt1 destiné à être utilisé dans le traitement d'un cancer entraîné par myc Pending WO2025078667A1 (fr)

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