First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410)

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) (if reached) and early signs of efficacy of M4076 monotherapy in participants with solid tumors in dose escalation (Part 1A). Once the recommended dose for expansion (RDE) is declared in Part 1A, a preliminary food effect cohort, Part 1B, will follow at the RDE determined from Part 1A.

Official Title
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A First-in-human, Phase I, Open-label Study of the ATM Inhibitor M4076 in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 410)

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: M4076


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with advanced solid tumors, for whom no standard of care therapy exists or for whom is not considered sufficiently effective, or who cannot tolerate standard of care Participants with Eastern Cooperative Oncology Group Performance status 0 or 1 Adequate hematological, hepatic, and renal function as defined in the protocol Participants in Part 1B (the preliminary food effect assessment) must agree to provide paired tumor biopsies if not contraindicated for medical reasons Other protocol defined inclusion criteria could apply Exclusion Criteria: Clinically significant (i.e., active) uncontrolled intercurrent illness including, but not limited to: Active infection (i.e., requiring systemic antibiotics or antifungals) Uncontrolled arterial hypertension Severe cardiac arrhythmia requiring medication Cerebral vascular accident/stroke Has known ataxia telangiectasia Participants with tumors harboring previously identified ATM mutations Participants with hypersensitivity to the active substance or to any of the excipients of M4076 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Dose Escalation Cohort (Part 1A): M4076 Monotherapy<br>Participants will receive M4076 film coated tablet at escalated doses orally, once daily under fasting condition until disease progression, death, Adverse events (AEs) leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurs first. | Drug: M4076<br>* M4076 will be administered orally, in Part 1A and Part 1B.<br>|
| Experimental: Experimental: Preliminary Food Effect Assessment Cohort (Part 1B): M4076<br>Participants in food effect assessment will receive M4076 at the dose and schedule determined as recommended dose for expansion (RDE) in Part 1A. A single dose of M4076 will be administered on Day -7 under a fed or fasted condition, followed by a 1-week washout period. | Drug: M4076<br>* M4076 will be administered orally, in Part 1A and Part 1B.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1A: Occurrence of Dose Limiting Toxicities (DLTs) During the DLT Observation Period |  | Day 1 up to Day 21 | 
| Part 1A: Occurrence of Adverse Events (AEs) and Treatment-Related AEs |  | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 1 years) | 
| Part 1A: Number of Participants With Clinical Significant Changes in Vital Signs, Laboratory Parameters, and 12-Lead Electrocardiogram (ECG) Findings |  | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 1 years) | 
| Part 1B: Occurrence of Adverse Events (AEs) and Treatment-Related AEs |  | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 1 years) | 
| Part 1B: Number of Participants With Clinical Significant Changes in Vital Signs, Laboratory Parameters, and 12-Lead Electrocardiogram (ECG) Findings |  | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 1 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1A and Part 1B: Objective Response According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Investigators |  | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 1 years) | 
| Part 1A and Part 1B: Duration of Response According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Investigators |  | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 1 years) | 
| Part 1A and Part 1B: Progression Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Investigators |  | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 1 years) | 
| Part 1A and 1B: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero (= Dosing Time) to the Last Sampling Time (tlast) of M4076 |  | Pre-dose up to 14 months post-dose | 
| Part 1A and Part 1B: Area Under Plasma Concentration (AUC) From Time Zero (Dosing Time) Extrapolated to Infinity (AUC0-inf) of M4076 |  | Pre-dose up to 14 months post-dose | 
| Part 1A and Part 1B: Maximum Observed Plasma Concentration (Cmax) of M4076 |  | Pre-dose up to 14 months post-dose | 
| Part 1A and Part 1B: Absolute and Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry | ATM pathway readouts including phosphorylated ataxia-telangiectasia mutated (p-ATM), gamma histone family member X (gamma-H2AX) and checkpoint kinase 2 protein (p-CHK2) will measure by flow cytometry and immunohistochemistry. | Pre-dose up to 14 months post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M4076, Maximum tolerated dose, Pharmacokinetics, Pharmacodynamics