Study of M1774 in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320)

Study Overview
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Brief Summary
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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) 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.

Official Title
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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)

Conditions
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Metastatic or Locally Advanced Unresectable Solid Tumors

Intervention / Treatment
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* Drug: M1774
* Drug: M4076
* Drug: Avelumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A1: M1774 and M4076<br> | Drug: M1774<br>* M1774 will be administered orally once daily over a defined period of time in Part A1 and Part B1 until disease progression, death, discontinuation, or end of study.<br>Drug: M4076<br>* M4076 will be administered orally once daily over a defined period of time in Part A1 until disease progression, death, discontinuation, or end of study.<br>|
| Experimental: Part B1: M1774 and Avelumab<br> | Drug: M1774<br>* M1774 will be administered orally once daily over a defined period of time in Part A1 and Part B1 until disease progression, death, discontinuation, or end of study.<br>Drug: Avelumab<br>* Avelumab will be administered by intravenous infusion once a day over a defined period of time in Part B1 until disease progression, death, discontinuation, or end of study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A1: Number of Participants with Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period |  | Day 1 up to Day 28 | 
| Part A1: Number of Participants with Adverse Events (AEs) and Treatment-Related AEs |  | Baseline up to 18 months | 
| Part B1: Number of Participants with Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period |  | Day 1 up to Day 28 | 
| Part B1: Number of Participants with Adverse Events (AEs) and Treatment-Related AEs |  | Baseline up to 18 months | 
| Part A1: Change from Baseline in Pharmacodynamic (PD) Biomarker | The PD biomarker of histone variant will be measured by flow cytometry. | Pre-dose up to approximately 1 month | 
| Part B1: Change from Baseline in Pharmacodynamic (PD) Biomarker | The PD biomarker of histone variant will be measured by flow cytometry. | Pre-dose up to approximately 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A1: Pharmacokinetic (PK) Plasma Concentration of M1774 and M4076 |  | Pre-dose up to approximately 6 months | 
| Part B1: Pharmacokinetic (PK) Plasma Concentration of M1774 |  | Pre-dose up to approximately 6 months | 
| Part B1: Pharmacokinetic (PK) Serum Concentration of Avelumab |  | Pre-dose up to approximately 18 months | 
| Part A1 and B1: Number of Participants with Clinically Significant Abnormalities in Digital Electrocardiogram (ECG) Measures |  | Baseline up to 18 months | 
| Part A1 and B1: Objective Response (OR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 |  | Up to 18 months after first dose administration | 
| Part B1: Number of Participants with Any Positive Anti-Drug Antibody (ADA) of Avelumab |  | Baseline up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M1774, ATR inhibitor, ATM inhibitor, Immunotherapy, M4076, Avelumab, Metastatic or Locally Advanced Unresectable Solid Tumors, DNA Damage Response Inhibitor, Immune Checkpoint Inhibitor