Clinical Trials /

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

NCT04882917

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

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

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
M4076Experimental: 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

NameTypeDescriptionInterventions
Experimental: Dose Escalation Cohort (Part 1A): M4076 MonotherapyExperimentalParticipants 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.
  • M4076
Experimental: Preliminary Food Effect Assessment Cohort (Part 1B): M4076ExperimentalParticipants 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.
  • M4076

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

June 7, 2021