Description:
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.
Title
- Brief Title: First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410)
- Official Title: A First-in-human, Phase I, Open-label Study of the ATM Inhibitor M4076 in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 410)
Clinical Trial IDs
- ORG STUDY ID:
MS201512_0010
- NCT ID:
NCT04882917
Conditions
Interventions
Drug | Synonyms | Arms |
---|
M4076 | | Experimental: Dose Escalation Cohort (Part 1A): M4076 Monotherapy |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Experimental: Dose Escalation Cohort (Part 1A): M4076 Monotherapy | Experimental | 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. | |
Experimental: Preliminary Food Effect Assessment Cohort (Part 1B): M4076 | Experimental | 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. | |
Eligibility Criteria
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:
1. Active infection (i.e., requiring systemic antibiotics or antifungals)
2. Uncontrolled arterial hypertension
3. Severe cardiac arrhythmia requiring medication
4. 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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Part 1A: Occurrence of Dose Limiting Toxicities (DLTs) During the DLT Observation Period |
Time Frame: | Day 1 up to Day 21 |
Safety Issue: | |
Description: | |
Secondary Outcome Measures
Measure: | Part 1A and Part 1B: Objective Response According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Investigators |
Time Frame: | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) |
Safety Issue: | |
Description: | |
Measure: | Part 1A and Part 1B: Duration of Response According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Investigators |
Time Frame: | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) |
Safety Issue: | |
Description: | |
Measure: | 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 Frame: | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) |
Safety Issue: | |
Description: | |
Measure: | Part 1A and Part 1B: Overall Survival (OS) |
Time Frame: | Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) |
Safety Issue: | |
Description: | |
Measure: | Part 1A and 1B: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero (= Dosing Time) to the Last Sampling Time (tlast) of M4076 |
Time Frame: | Pre-dose up to 51 months post-dose |
Safety Issue: | |
Description: | |
Measure: | Part 1A and Part 1B: Area Under Plasma Concentration (AUC) From Time Zero (Dosing Time) Extrapolated to Infinity (AUC0-inf) of M4076 |
Time Frame: | Pre-dose up to 51 months post-dose |
Safety Issue: | |
Description: | |
Measure: | Part 1A and Part 1B: Maximum Observed Plasma Concentration (Cmax) of M4076 |
Time Frame: | Pre-dose up to 51 months post-dose |
Safety Issue: | |
Description: | |
Measure: | Part 1A and Part 1B: Absolute and Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry |
Time Frame: | Pre-dose up to 51 months post-dose |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | EMD Serono Research & Development Institute, Inc. |
Trial Keywords
- M4076
- Maximum tolerated dose
- Pharmacokinetics
- Pharmacodynamics
Last Updated
August 5, 2021