An Open-label, Multicenter Phase Ib Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the ATR Inhibitor M1774 in Combination With DNA Damage Response Inhibitors or Immune Checkpoint Inhibitors in Patients With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 320)

MS201924_0020

This is an open-label, multicenter, clinical study conducted in multiple parts to establish the safety, tolerability, Pharmacokinetic/Pharmacodynamic (PK/PD) profile, maximum tolerated dose (MTD) combinations (if observed) and recommended dose for expansion (RDE) combination for M1774 in combination with M4076 (in Part A1), food effect on the PK of M4076 as monotherapy or in combination with M1774 (in Part A1.1), safety/tolerability and early signs of clinical activity of M1774 and M4076 in combination in patients with prostate cancer harboring loss of function (LoS) mutation in the gene ATM based on local data previously generated in circulating tumor (ct) DNA (liquid biopsies) or tumor biopsies (in Part A2), safety/tolerability and early signs of clinical activity of M1774 and M4076 in combination in patients with endometrial cancer harboring LoS mutation(s) in the gene ARID1A based on local data previously generated in ctDNA (liquid biopsies) or tumor biopsies (in Part A3), the relative bioavailability of a M1774 tablet formulation (TF1, test) compared to a capsule formulation (reference) will also be investigated (in Part A2/A3), and in combination with avelumab (in Part B1) in participants with metastatic or locally advanced unresectable solid tumors who are intolerant or have no standard therapy available.

2022-06-07

2026-03-31

2026-05-31

Recruiting

Early phase I

72

Inclusion Criteria: * Part A1, A1.1, A2, A3, and A2/3: Participants with metastatic or locally advanced unresectable solid tumors refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator, which may convey clinical benefit, or who cannot tolerate standard of care treatment * Part A1.1: Triple negative breast cancer, epithelial ovarian cancer, castrate resistant prostate cancer, urothelial cancer, endometrial cancer, and colorectal cancer independent of mutation status. * Part A2: Patients with advanced prostate cancer whose tumor carries a genetic loss of function (LoF) mutation(s) in the gene ataxia telangiectasia mutated (ATM). No more than 3 prior lines of therapy for castrate resistant disease. Prior therapy must have included a taxane and a novel antiandrogen (example \[e.g.\] enzalutamide). * Part A3: Patients with advanced endometrial cancer whose tumor carries a genetic LoF mutation(s) in the gene AT-rich interaction domain 1A (ARID1A). Prior therapy must have included a platinum agent. Prior therapy must also have included a checkpoint inhibitor if the patient has mismatch repair (MMR)-deficient endometrial cancer. - Note for Parts A2/A3: Patients with ATM LoF mutated prostate cancer and ARID1A LoF mutated endometrial cancer should be prioritized to the respective expansion arms instead of being enrolled in Part A1.1. The presence of ATM and ARID1A LoF mutations will be determined according to local data, generated by an assay with appropriate regulatory status, in either tumor or liquid biopsy. The Sponsor will confirm that mutations certified by local data fulfil this definition. * Participants with eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, with estimated life expectancy of at least 3 months * Adequate hematological, hepatic, and renal function as defined in the protocol * Other protocol defined inclusion criteria could apply Exclusion Criteria: * Participants with any condition, including any uncontrolled disease state other than with metastatic or locally advanced unresectable solid tumors, that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation * Participants with a known additional malignancy that is progressing and/or requires active treatment * Participants with carcinomatous meningitis are excluded regardless of clinical stability * Participants with serious gastrointestinal bleeding within 3 months, refractory nausea and vomiting, uncontrolled diarrhea, known malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes, other chronic gastrointestinal disease, and/or other situations that may preclude adequate absorption of oral medications * Participants with organ transplantation, including allogeneic stem cell transplant * Other protocol defined exclusion criteria could apply

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE1'], 'designInfo': {'allocation': 'NON_RANDOMIZED', 'interventionModel': 'PARALLEL', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 72, 'type': 'ESTIMATED'}}

2024-03-12