First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410)
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Experimental: Dose Escalation Cohort (Part 1A): M4076 Monotherapy 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
M4076 will be administered orally, in Part 1A and Part 1B.
|
| Experimental: Experimental: Preliminary Food Effect Assessment Cohort (Part 1B): M4076 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
M4076 will be administered orally, in Part 1A and Part 1B.
|
Outcome Measures
Primary Outcome Measures
- 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
- 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 [Pre-dose up to 14 months post-dose]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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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
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Participants with Eastern Cooperative Oncology Group Performance status 0 or 1
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Adequate hematological, hepatic, and renal function as defined in the protocol
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Participants in Part 1B (the preliminary food effect assessment) must agree to provide paired tumor biopsies if not contraindicated for medical reasons
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Other protocol defined inclusion criteria could apply
Exclusion Criteria:
- Clinically significant (i.e., active) uncontrolled intercurrent illness including, but not limited to:
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Active infection (i.e., requiring systemic antibiotics or antifungals)
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Uncontrolled arterial hypertension
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Severe cardiac arrhythmia requiring medication
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Cerebral vascular accident/stroke
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Has known ataxia telangiectasia
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Participants with tumors harboring previously identified ATM mutations
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Participants with hypersensitivity to the active substance or to any of the excipients of M4076
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Other protocol defined exclusion criteria could apply
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | MD Anderson Center | Houston | Texas | United States | 77030 |
| 2 | NEXT Oncology | San Antonio | Texas | United States | 78229 |
| 3 | Princess Margaret Cancer Centre | Toronto | Ontario | Canada | M5G 1Z5 |
Sponsors and Collaborators
- EMD Serono Research & Development Institute, Inc.
- Merck KGaA, Darmstadt, Germany
Investigators
- Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Trial Awareness and Transparency website
- US Medical Information website, Medical Resources
- DDRiver website
Publications
None provided.- MS201512_0010