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WO2025245463A1 - Polythérapies - Google Patents

Polythérapies

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Publication number
WO2025245463A1
WO2025245463A1 PCT/US2025/030801 US2025030801W WO2025245463A1 WO 2025245463 A1 WO2025245463 A1 WO 2025245463A1 US 2025030801 W US2025030801 W US 2025030801W WO 2025245463 A1 WO2025245463 A1 WO 2025245463A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
tuvusertib
niraparib
administered
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.)
Pending
Application number
PCT/US2025/030801
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English (en)
Other versions
WO2025245463A9 (fr
Inventor
Jatinder Kaur MUKKER
Ioannis GOUNARIS
Giuseppe Locatelli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of WO2025245463A1 publication Critical patent/WO2025245463A1/fr
Publication of WO2025245463A9 publication Critical patent/WO2025245463A9/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • PARP inhibitors show synergism with ATR inhibitors (ATRis) in vitro and in vivo.
  • ATR inhibitors ATR inhibitors
  • M1774 potent, selective, ATR inhibitor tuvusertib
  • tuvusertib and the PARPi niraparib may result in synthetic lethality, triggering replication fork collapse, mitotic catastrophe, and cancer cell death.
  • FIG.1 shows the overall study design.
  • FIG.2 shows homologous recombination repair (HRR) genetic alterations in patients in Part B1.
  • FIG.3 shows patient characteristics of patients in Part B1.
  • FIG.4 shows the types of tumors in patients in Part B1.
  • FIG.5 shows the dose finding strategy for Part B1.1/1: 1 week on/1 week off; 2/1: 2 weeks on/1 week off; 2/2: 2 weeks on/2 weeks off; C: cohort; DLT: dose-limiting toxicity; G: grade; N: niraparib; pts: patients; RDE: recommended dose for expansion; T: tuvusertib; QD: once daily.
  • FIG.6 shows dose combinations and dose-limiting toxicity in patients.1/1: 1 week on/1 week off; 2/1: 2 weeks on/1 week off; 2/2: 2 weeks on/2 weeks off; C: cohort; DLT: dose-limiting toxicity; G: grade; N: niraparib; pts: patients; RDE: recommended dose for expansion; T: tuvusertib; QD: once daily.
  • FIG.7 shows target modulation according to tuvusertib dose. a 4NQO-only valid data used for analysis; b Only one patient available in cohort 1 with a C1D16 h valid time point. C: cycle; D: day; h: hour.
  • FIG.8 shows relationship of tuvusertib steady-state AUC (AUCss) and dose.
  • c Symbols represent individual patient tuvusertib AUC ss data in combination with niraparib; the solid black line and the shaded grey area represent the model-predicted AUCtau and the 97.5% probability interval from tuvusertib monotherapy, respectively.1/1: 1 week on/1 week off; 2/2: 2 weeks on/2 weeks off; QD: once daily; T: tuvusertib; N: niraparib; w: week [0012]
  • FIG.9 shows a waterfall plot showing best change in the sum of diameters, according to best overall response.
  • EOC epithelial ovarian cancer
  • ER estrogen receptor
  • HER2 human epidermal growth factor receptor-2
  • NSCLC non-small cell lung cancer
  • PDAC pancreatic ductal adenocarcinoma
  • SCLC small-cell lung cancer
  • TNBC triple-negative breast cancer.
  • FIG.10 shows an MRI image of a patient with HER2-negative ER + BC and parenchymal CR.
  • ER estrogen receptor
  • HER2 human epidermal growth factor receptor-2
  • BC breast cancer
  • CR complete response.
  • FIG.11 shows a swimmer plot showing time on treatment per niraparib schedule.
  • FIG.12 shows BRCA1/2 status and change in methylated ctDNA.
  • BRCA 1 ⁇ 2 breast cancer gene 1 and 2;
  • ctDNA circulating tumor DNA;
  • PARPi PARP inhibitor.
  • FIG.13 shows a plot showing the duration of treatment and molecular response (MR). cOnly eight data point are shown for this category due to one patient’s duration of treatment not being defined.
  • MR molecular response
  • T tuvusertib
  • N niraparib
  • ctDNA circulating tumor DNA.
  • FIG.15A shows best change in ctDNA and correlation with clinical response.
  • FIG.15B shows correlation of clinical response with MR.
  • FIG.16 shows correlation of BRCA1 status with change in methylated ctDNA.
  • ctDNA circulating tumor DNA.
  • FIG.17 shows patient profiles and tumor marker status of breast cancer patients with prolonged benefit.
  • the present invention relates to methods of treating a proliferative disorder, comprising administering to a patient in need thereof a dose of tuvusertib, or a pharmaceutically acceptable salt thereof, in combination with a dose of niraparib, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to methods of treating solid tumors, comprising administering to a patient in need thereof a dose of tuvusertib, or a pharmaceutically acceptable salt thereof, in combination with a dose of niraparib, or a pharmaceutically acceptable salt thereof.
  • tuvusertib is in its freebase form.
  • niraparib is in its tosylate monohydrate salt form.
  • the proliferative disorder may be cancer, such as a solid tumor cancer.
  • the tumor is locally advanced or metastatic. In some embodiments, the tumor is locally advanced.
  • the tumor is metastatic.
  • the tumor is selected from breast cancer, epithelial ovarian cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic ductal adenocarcinoma, estrogen receptor-positive breast cancer, HER2-negative estrogen receptor-positive breast cancer, or triple-negative breast cancer.
  • the tumor is breast cancer.
  • the tumor is epithelial ovarian cancer.
  • the tumor is non-small cell lung cancer.
  • the tumor is small-cell lung cancer.
  • the tumor is pancreatic ductal adenocarcinoma.
  • the tumor is estrogen receptor-positive breast cancer.
  • the tumor is HER2-negative estrogen receptor-positive breast cancer. In some embodiments, the tumor is triple-negative breast cancer.
  • said cancer is a solid tumor cancer selected from the following cancers: Oral: buccal cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal:esophagus (s
  • the patient has platelets ⁇ 150,000/uL or weighs ⁇ 77 kg. In some embodiments, the patient has platelets less than about 150,000/uL. In some embodiments, the patient has platelets less than about 140,000/uL. In some embodiments, the patient has platelets less than about 130,000/uL. In some embodiments, the patient has platelets less than about 120,000/uL. In some embodiments, the patient has platelets less than about 110,000/uL. In some embodiments, the patient has platelets less than about 100,000/uL. In some embodiments, the patient has platelets less than about 90,000/uL. In some embodiments, the patient has platelets less than about 80,000/uL.
  • the patient has platelets less than about 70,000/uL. In some embodiments, the patient has platelets less than about 60,000/uL. In some embodiments, the patient has platelets less than about 50,000/uL. In some embodiments, the patient has platelets less than about 40,000/uL. [0028] In some embodiments, the patient weighs less than about 77 kg. In some embodiments, the patient weighs less than about 77 kg. In some embodiments, the patient weighs less than about 70 kg. In some embodiments, the patient weighs less than about 65 kg. 5 BUSINESS.32015741.1 394927-022WO (218385) In some embodiments, the patient weighs less than about 60 kg. In some embodiments, the patient weighs less than about 55 kg.
  • the patient weighs less than about 50 kg. In some embodiments, the patient weighs less than about 45 kg. In some embodiments, the patient weighs less than about 40 kg. In some embodiments, the patient weighs less than about 35 kg. [0029] In some embodiments, the patient has an alteration in a homologous recombination repair gene.
  • the gene is selected from BRCA1, BRCA2, RAD51B, ATM, RAD51D, and PALB2. In some embodiments, the gene is BRCA1. In some embodiments, the gene is BRCA2. In some embodiments, the gene is RAD51B. In some embodiments, the gene is ATM. In some embodiments, the gene is RAD51D. In some embodiments, the gene is PALB2.
  • the patient was previously treated with one or more poly-ADP ribose polymerase inhibitors.
  • the one or more poly-ADP ribose polymerase inhibitor is selected from Zejula (niraparib), Lynparza (olaparib), Talzenna (talazoparib), or Rubraca (rucaparib).
  • the one or more poly-ADP ribose polymerase inhibitor comprises Zejula (niraparib).
  • the one or more poly-ADP ribose polymerase inhibitor comprises Lynparza (olaparib).
  • the one or more poly-ADP ribose polymerase inhibitor comprises Talzenna (talazoparib). In some embodiments, the one or more poly-ADP ribose polymerase inhibitor comprises Rubraca (rucaparib). [0031] In some embodiments, the patient was previously treated with one or more platinum- based chemotherapeutics. In some embodiments, the one or more platinum-based chemotherapeutics is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • the one or more platinum-based chemotherapeutics comprises cisplatin. In some embodiments, the one or more platinum-based chemotherapeutics comprises carboplatin. In some embodiments, the one or more platinum-based chemotherapeutics comprises oxaliplatin. In some embodiments, the one or more platinum-based chemotherapeutics comprises nedaplatin. In some embodiments, the one or more platinum-based chemotherapeutics comprises triplatin tetranitrate. In some embodiments, the one or more platinum-based chemotherapeutics comprises phenanthriplatin. In some embodiments, the one or more platinum-based chemotherapeutics comprises picoplatin.
  • the one or more platinum- based chemotherapeutics comprises satraplatin. 6 BUSINESS.32015741.1 394927-022WO (218385) [0032]
  • the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 60 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 70 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 80 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 90 mg.
  • the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 100 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 120 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 140 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 160 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 180 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 200 mg.
  • the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 220 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 250 mg. [0033] In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 60 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 70 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 80 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 90 mg.
  • the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 100 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 120 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 140 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 160 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 180 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 200 mg.
  • the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 220 mg. In some embodiments, the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 250 mg. 7 BUSINESS.32015741.1 394927-022WO (218385) [0034] In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 90 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 100 mg.
  • the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 90 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 150 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 90 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 200 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 130 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 100 mg.
  • the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 130 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 150 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 130 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 200 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 180 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 100 mg.
  • the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 180 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 150 mg. In some embodiments, the tuvusertib, or pharmaceutically acceptable salt thereof is administered in a dose of about 180 mg, and wherein the niraparib, or pharmaceutically acceptable salt thereof is administered in a dose of about 200 mg. [0035]
  • the oral dose of niraparib is administered at a 7 days on, 7 days off regimen. In some embodiments, the 7 days on, 7 days off regimen comprises 3 or more cycles. In some embodiments, the 7 days on, 7 days off regimen comprises 4 cycles.
  • the oral dose of niraparib is administered in combination with tuvusertib. In some embodiments, the oral dose of niraparib is administered in combination with one or more additional active agents known to be useful in the treatment of cancer. In some embodiments, the oral dose of niraparib and tuvusertib are each administered at a 7 days on, 7 days off regimen. In some embodiments, the 7 days on, 7 days off regimen comprises 3 or more cycles. In some embodiments, the 7 days on, 7 days off regimen comprises 4 cycles.
  • the niraparib is administered at the first, third, fifth, and seventh week of 8 BUSINESS.32015741.1 394927-022WO (218385) the regimen, and tuvusertib is administered continuously or at the second, fourth, sixth, and eighth week of the regimen.
  • the oral dose of niraparib is administered at a 14 days on, 14 days off regimen.
  • the 14 days on, 14 days off regimen comprises 2 or more cycles.
  • the 14 days on, 14 days off regimen comprises 3 cycles.
  • the 14 days on, 14 days off regimen comprises 4 cycles.
  • the oral dose of niraparib is administered in combination with tuvusertib.
  • the oral dose of niraparib and tuvusertib are each administered at a 14 days on, 14 days off regimen.
  • the 14 days on, 14 days off regimen comprises 2 or more cycles.
  • the 14 days on, 14 days off regimen comprises 3 or more cycles.
  • the 14 days on, 14 days off regimen comprises 4 cycles.
  • the niraparib is administered during weeks 1-2, 5- 6, and 9-10 of the regimen, and tuvusertib is administered continuously or at weeks 3-4, 7-8, and 11-12 of the regimen.
  • the tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof are administered according to a treatment cycle lasting 7 days, followed by a non-treatment cycle during which the patient does not receive the tuvusertib, or a pharmaceutically acceptable salt thereof, or niraparib, or a pharmaceutically acceptable salt thereof for a duration of 7 days.
  • the tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof are administered according to a treatment cycle lasting 14 days, followed by a non-treatment cycle during which the patient does not receive the tuvusertib, or a pharmaceutically acceptable salt thereof, or niraparib, or a pharmaceutically acceptable salt thereof for a duration of 14 days.
  • the tuvusertib, or a pharmaceutically acceptable salt thereof is administered according to a treatment cycle lasting 7 days, followed by a non-treatment cycle during which the patient does not receive the tuvusertib, or a pharmaceutically acceptable salt thereof, for a duration of 7 days.
  • the tuvusertib, or a pharmaceutically acceptable salt thereof is administered according to a treatment cycle lasting 14 days, followed by a non-treatment cycle during which the patient does not receive the tuvusertib, thereof for a duration of 14 days.
  • the tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof are administered once daily.
  • the niraparib, or a pharmaceutically acceptable salt thereof is administered once daily.
  • the tuvusertib, or a pharmaceutically acceptable salt thereof is administered once daily during treatment cycles.
  • the niraparib, or a pharmaceutically acceptable salt thereof is administered once daily during treatment cycles.
  • the treatment cycle and non-treatment cycle are alternated until cessation of treatment.
  • administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof, to a patient in need thereof resulted in inhibition of ⁇ -H2AX expression in peripheral blood mononuclear cells.
  • ⁇ -H2AX expression is inhibited by at least 20-50% 3-6 hours after administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof.
  • ⁇ -H2AX expression is inhibited by at least 50-90% 3-6 hours after administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof.
  • at least 95% of patients exhibited a molecular response.
  • at least 90% of patients exhibited a molecular response.
  • at least 80% of patients exhibited a molecular response.
  • at least 70% of patients exhibited a molecular response.
  • at least 60% of patients exhibited a molecular response.
  • At least 40% of patients exhibited a molecular response. In some embodiments, at least 30% of patients exhibited a molecular response. In some embodiments, at least 20% of patients exhibited a molecular response. In some embodiments, at least 10% of patients exhibited a molecular response. [0045] In some embodiments, administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof resulted in a 10%- 100% reduction in circulating tumor DNA (ctDNA).
  • ctDNA circulating tumor DNA
  • administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof resulted in a 50%-100% reduction in circulating tumor DNA (ctDNA).
  • administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof resulted in at least about a 10% reduction in circulating tumor DNA (ctDNA).
  • administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a 10 BUSINESS.32015741.1 394927-022WO (218385) pharmaceutically acceptable salt thereof resulted in at least about a 30% reduction in circulating tumor DNA (ctDNA).
  • administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof resulted in at least about a 50% reduction in circulating tumor DNA (ctDNA).
  • administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof resulted in at least about a 70% reduction in circulating tumor DNA (ctDNA). In some embodiments, administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof resulted in at least about a 90% reduction in circulating tumor DNA (ctDNA). In some embodiments, administration of tuvusertib, or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof resulted in at least about a 95% reduction in circulating tumor DNA (ctDNA).
  • treatment cycle has its ordinary meaning in the art and may refer to a course of treatment that is repeated on a regular schedule, including periods of rest. For example, a treatment cycle of four weeks may include administration of agents during week one followed by three weeks of rest (e.g., no treatment).
  • treatment of a proliferative disorder using the methods described herein may result in a RECIST stable disease, a RECIST partial response, or a RECIST complete response. For instance, treatment may result in a RECIST partial or a RECIST complete response.
  • the term “RECIST partial response” has its ordinary meaning in the art and may refer to a 30% decrease in the sum of the longest diameter of target lesions as determined according to the RECIST (i.e., Response Evaluation Criteria in Solid Tumors) guidelines version 1.1 (see Eisenhauer et. al., Eur. J. Cancer.45 (2009) 228 – 247).
  • the term “RECIST complete response” has its ordinary meaning in the art and may refer to the disappearance of all target lesions as determined according to the RECIST guidelines version 1.1.
  • RECIST progressive disease has its ordinary meaning in the art and may refer to a 20% increase in the sum of the longest diameter of target lesions as determined according to the RECIST guidelines version 1.1.
  • RECIST stable disease has its ordinary meaning in the art and may refer to small changes that do not meet above criteria as determined according to the RECIST guidelines version 1.1.
  • the methods described herein may decrease the 11 BUSINESS.32015741.1 394927-022WO (218385) sum of the longest diameter of target lesions, decrease the sum of the longest diameter of non-target lesions, and/or decrease tumor burden by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60%. In certain embodiments, the methods described herein may decrease the sum of the longest diameter of target lesions, decrease the sum of the longest diameter of non-target lesions, and/or decrease tumor burden by between about 20% and about 60% or between about 40% and about 60%.
  • the term “refractory” has its ordinary meaning in the art and may refer to a proliferative disorder that progresses during treatment with an agent (e.g., DNA damaging agent) (first line treatment).
  • the term “resistant” has its ordinary meaning in the art and may refer to a proliferative disorder that recurs within a certain period of time after completing treatment with an agent.
  • the term “sensitive” has its ordinary meaning in the art and may refer to a proliferative disorder that recurs after a certain period of time from completing treatment with an agent (e.g., DNA damaging agent). In general, recurrence occurs after a longer period of time for a sensitive cancer than for a resistant cancer.
  • compositions described herein can exist in free form, or, where appropriate, as salts. Those salts that are pharmaceutically acceptable are of particular interest since they are useful in administering the compounds described below for medical purposes. Salts that are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compounds of the invention or intermediates thereof.
  • the term "pharmaceutically acceptable salt” refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • compositions described herein include those derived from suitable inorganic and organic 12 BUSINESS.32015741.1 394927-022WO (218385) acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.
  • Therapeutic Uses [0054] The present disclosure provides a method of treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation, including proliferative or hyperproliferative diseases, in a subject.
  • a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990).
  • homologous recombination refers to a process wherein nucleotide sequences between distinct stands of DNA are exchanged. Homologous recombination is involved in a number of different biological processes, for example, homologous recombination occurs as part of the DNA repair process (e.g., doubled-strand break repair pathway and synthesis-dependent strand annealing pathway) and during process of meiosis/gametogenesis of eukaryotic organisms.
  • DNA repair process e.g., doubled-strand break repair pathway and synthesis-dependent strand annealing pathway
  • homologous recombination deficiency refers to a reduction or impairment of the homologous recombination process. Such impairment may be via chromosomal aberrations or via mutations in one or more genes involved in DNA repair. Reduction or impairment of the homologous recombination process may also be measured by evaluating epigenetic alterations (i.e. hypermethylation) or mutations on the promoter of HRR genes, e.g. BRCA1 and RAD51C promoter methylation results in the repression of gene transcription and associated with PARP inhibitor sensitivity.
  • alteration in BRCA gene refers to a change or difference in the sequence of at least one copy of either or both of the BRCA1 or BRCA2 genes relative to an appropriate reference sequence (e.g., a wild type reference and/or a sequence that is present in non-cancerous cells in the subject).
  • a mutation in the BRCA1/2 gene may result in a BRCA1/2 deficiency, which may include, for example a loss or reduction in the expression or function of the BRCA gene and/or encoded protein.
  • Such mutations may also be referred to as “deleterious mutations” or may be suspected to be deleterious mutations.
  • a BRCA mutation can be a “germline BRCA mutation,” which indicates it was inherited from one or both parents. Germline mutations affect every cell in an organism and are passed on to offspring. A BRCA mutation can also be acquired during one’s lifetime, i.e. spontaneously arising in any cell in the body (“soma”) at 13 BUSINESS.32015741.1 394927-022WO (218385) any time during the patient's life, (i.e., non-inherited), which is referred to herein as a “sporadic BRCA mutation” or a “somatic BRCA mutation” interchangeably. Genetic tests are available, and known by those of skill in the art.
  • the term “genes involved in DNA repair” means any gene involved in repair of DNA in the cell.
  • the components of the homologous recombination dependent DNA DSB repair pathway include, but are not limited to, ATM (NM-000051), RAD51 (NM- 002875), RAD51LI (NM-002877), RAD51C (NM-002876), RAD51L3 (NM-002878), DMCl (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA1 (NM-007295), BRCA2 (NM- 000059), RAD5O (NM-005732), MRE11A (NM-005590), NBSl (NM-002485), ADPRT (PARP-1), ADPRTL2, (PARP2) CTPS, RPA, RPAI, RPA
  • the term “niraparib” means any of the free base compound ((3S)-3- [4- ⁇ 7-(aminocarbonyl)-2H-indazol-2-yl ⁇ phenyl]piperidine), a salt form, including pharmaceutically acceptable salts, of (3S)-3-[4- ⁇ 7-(aminocarbonyl)-2H-indazol-2- yl ⁇ phenyl]piperidine (e.g., (3S)-3-[4- ⁇ 7-(aminocarbonyl)-2H-indazol-2-yl ⁇ phenyl]piperidine tosylate), or a solvated or hydrated form thereof (e.g., (3S)-3-[4- ⁇ 7-(aminocarbonyl)-2H- indazol-2-yl ⁇ phenyl]piperidine tosylate), or a solvated or hydrated form thereof (e.g., (3S)-3-[4- ⁇ 7-(aminocarbonyl)
  • such forms may be individually referred to as “niraparib free base”, “niraparib tosylate” and “niraparib tosylate monohydrate”, respectively.
  • the term “niraparib” includes all forms of the compound (3S)-3-[4- ⁇ 7-(aminocarbonyl)-2H-indazol-2- yl ⁇ phenyl]piperidine.
  • Niraparib is an orally available, selective poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitor.
  • PARP selective poly(ADP-ribose) polymerase
  • niraparib tosylate monohydrate 2- ⁇ 4-[(3S)-piperidin-3- yl]phenyl ⁇ -2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1) and it has the following chemical structure: [0061] The and its molecular weight is 510.61 g/mol.
  • Niraparib tosylate monohydrate drug substance is a white to off- white, non-hygroscopic crystalline solid.
  • Niraparib solubility is pH independent below the pKa of 9.95, with an aqueous free base solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological pH range.
  • Certain solid forms of niraparib are described in WO 2018/183354, which is incorporated by reference in its entirety.
  • Methods for preparation of niraparib include those described in WO 2014/088983; WO 2014/088984; WO 2018/200517, US 8,071,623; US 8,436,185; US 62/489,415 filed April 24, 2017; and Jones et al., J. Med. Chem., 52:7170-7185, 2009, each of which is incorporated by reference in its entirety.
  • neoplasm and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
  • a neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
  • a “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. 15 BUSINESS.32015741.1 394927-022WO (218385) Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.”
  • An exemplary pre-malignant neoplasm is a teratoma.
  • a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue.
  • a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • metastasis refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
  • a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
  • cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues.
  • a subject in need of treatment is a subject identified as having a proliferative disorder i.e., the subject has been diagnosed by a physician (e.g., using methods well known in the art) as having a proliferative disorder (e.g., a cancer).
  • the subject in need of treatment is a subject suspected of having or developing a proliferative disorder, such as a subject presenting one or more symptoms indicative of a proliferative disorder.
  • the term “subject in need of treatment” further includes people who once had a proliferative disorder but whose symptoms have ameliorated.
  • the one or more symptoms or clinical features depend on the type and location of the tumor.
  • lung tumors may cause coughing, shortness of breath, or chest pain.
  • Tumors of the colon can cause weight loss, diarrhea, constipation, iron deficiency anemia, and blood in the stool.
  • the following symptoms occur with most tumors: chills, fatigue, fever, loss of appetite, malaise, night sweats, and weight loss.
  • the terms “administer,” “administering,” or “administration,” as used herein refers to implanting, absorbing, ingesting, injecting, or inhaling the one or more therapeutic agents.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of proliferative disorder.
  • treatment may be administered after one or more signs or symptoms have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the proliferative disorder.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • the terms “tumor burden” has its ordinary meaning in the art and may refer to the number of cancer cells, the size of a tumor, or the amount of cancer in the body.
  • the terms “about” has its ordinary meaning in the art. In some embodiments with respect to time, about may be within 50 minutes, within 40 minutes, within 30 minutes, within 20 minutes, within 10 minutes, within 5 minutes, or within 1 minute of the specified time. In some embodiments with respect to dosage, about may be within 20%, within 15%, within 10%, within 5%, or within 1% of the specified dosage.
  • An “effective amount” refers to an amount sufficient to elicit the desired biological response, i.e., treating the proliferative disorder.
  • the effective amount of the compounds described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount includes, but is not limited to, that amount necessary to slow, reduce, inhibit, ameliorate or reverse one or more symptoms associated with neoplasia.
  • an effective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration).
  • the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.
  • the compounds provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; 17 BUSINESS.32015741.1 394927-022WO (218385) by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments
  • Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply
  • direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds provided herein may be administered at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • administration of a compound provided herein occurs with food. In some embodiments, administration of a compound provided herein occurs without food.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical 18 BUSINESS.32015741.1 394927-022WO (218385) practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • Example 1 Open-label, Phase I, first-in-human (FIH) multicenter, clinical study conducted in multiple parts to establish the safety, tolerability and pharmacokinetic/pharmacodynamic (PK/PD) profile (with and without food) and early signs of efficacy of Tuvuseritib (M1774) as monotherapy and in combination with the poly (ADP- ribose) polymerase (PARP) inhibitor niraparib.
  • PK/PD pharmacokinetic/pharmacodynamic
  • M1774 pharmacokinetic/pharmacodynamic
  • M1774 early signs of efficacy of Tuvuseritib
  • PARP poly (ADP- ribose) polymerase
  • mmHg millimeter of mercury
  • Diastolic blood pressure >90mmHg Unstable angina
  • Part A1 of the study determined that 180 mg of tuvusertib daily was the maximum tolerated dose, with anemia as the main toxicity.
  • Patient Demographics [0090] Patients for Part B1 were recruited according to the eligibility criteria above.
  • FIG.2 Information regarding patient homologous recombination repair (HRR) genetic alterations (FIG.2), general patient characteristics (FIG.3), and tumor types (FIG.4) are shown in their corresponding figures.
  • HRR patient homologous recombination repair
  • FIG.3 general patient characteristics
  • FIG.4 tumor types
  • FIG.9 and Table 5 show the clinical response across dose levels, including patients with epithelial ovarian cancer.
  • FIG.10 shows an MRI image of a patient with HER2-negative ER + BC and parenchymal CR. Table 5. Clinical Outcomes in All cohorts and in patients with epithelial ovarian cancer.
  • FIG.11 shows time on treatment across dose levels, including patients with epithelial ovarian cancer.
  • Median duration of treatment DoT was longer in patients receiving tuvusertib + intermittent niraparib (14.1 weeks; range: 1.4–42.0) than patients receiving continuous niraparib (8.1 weeks; range: 3.1–42.0).
  • Median DoT in patients with epithelial ovarian cancer was 18.0 weeks (range: 1.4–42.0).
  • a novel dose-finding model enabled efficient exploration of multiple tuvusertib and niraparib doses and schedules.
  • Intermittent schedules of both drugs showed manageable safety profiles and two regimens were selected as RDEs: ⁇ Tuvusertib 90 mg daily + niraparib 200 mg daily 1 week on and 1 week off, ⁇ Tuvusertib 180 mg daily + niraparib 100 mg daily 1 week on and 1 week off
  • Myelosuppression mainly anemia, remains the most frequent toxicity; no new safety signals were observed.
  • Tuvusertib (M1774) is a potent, orally administered and selected ATR inhibitor (ATRi) with a manageable safety profile observed in patients with advanced solid tumors.
  • ATRi ATR inhibitor
  • Combining the ATR inhibitor tuvusertib and PARP inhibitor niraparib may synergistically enhance synthetic lethality, triggering replication fork collapse, mitotic catastrophe, and increase cancer cell death.
  • Part B1 of the DDRiver Solid Tumors 301 study (NCT04170153) is assessing this combination; acceptable tolerability and preliminary efficacy have been observed (Yap, et al. ASCO 2024).
  • tuvusertib pharmacokinetics, changes in levels of ⁇ -H2AX (a pharmacodynamic [PD] biomarker of ATR inhibition), and a retrospective analysis of molecular response (MR).
  • Methods Patients with metastatic or locally advanced unresectable solid tumors refractory to standard treatment were enrolled. No participants were selected according to tumor biomarkers. Intermittent tuvusertib (90–180 mg once-daily [QD]) and continuous or intermittent niraparib (100–200 mg QD) schedules were explored.
  • ctDNA single nucleotide variants
  • EOT end of treatment
  • MR methylation-based signatures in plasma samples.
  • SNVs single nucleotide variants
  • MR was defined as >50% reduction in ctDNA, according to changes from baseline in somatic single nucleotide variant (SNVs) allele frequencies or tumor-specific DNA- methylation levels. MRs reported here were the best ctDNA change from baseline to the most recent sampling timepoint.
  • MRs were observed in 44% (4/9) and 60% (6/10) of evaluable patients receiving tuvusertib at doses ⁇ 130 mg by mutation based (FIG.14A) and methylation based ctDNA assay (FIG.14B), respectively.
  • MRs were observed in 42.8% (3/7) and 25% (2/8) of evaluable patients receiving tuvusertib at doses ⁇ 130 mg by mutation based (FIG.14A) and methylation based ctDNA assay (FIG.14B), respectively.

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  • General Health & Medical Sciences (AREA)
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Abstract

Une étude clinique multicentrique ouverte, testée pour la première fois sur l'homme, de phase I, est réalisée en de multiples étapes pour établir la sécurité, la tolérabilité et le profil pharmacocinétique/pharmacodynamique (PK/PD) (avec et sans aliments) ainsi que des signes précoces d'efficacité du tuvuseritib (M1774) en tant que monothérapie et en combinaison avec l'inhibiteur de poly(ADP-ribose) polymérase (PARP) niraparib.
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