Clinical trial NCT04882917: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Keywords: M4076
Maximum tolerated dose
Pharmacokinetics
Pharmacodynamics
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2021-05-12
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was 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) was declared in Part 1A, a preliminary food effect cohort, Part 1B, will follow at the RDE determined from Part 1A.


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

Primary outcomes:
measure: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0
timeFrame: Day 1 to Day 21 of Cycle 1 (21-day cycle)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs
timeFrame: From the first dose of study drug administration until 30 days after the last dose of study drug administration (up to 603 days)
measure: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
timeFrame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
measure: Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0
timeFrame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
measure: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values
timeFrame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
Secondary outcomes:
measure: Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
timeFrame: Time from first study treatment up to 603 days
measure: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
timeFrame: Time from first documentation of objective response to the date of first documentation of PD or death due to any cause, assessed up to 603 days
measure: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators
timeFrame: Time from the first dose of study intervention until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 603 days)
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076
timeFrame: Day 1 and Day 8
measure: Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076
timeFrame: Day 1 and Day 8
measure: Maximum Observed Plasma Concentration (Cmax) of M4076
timeFrame: Day 1 and Day 8
measure: Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM
timeFrame: Baseline up to Day 23
measure: Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2
timeFrame: Baseline up to Day 23
measure: Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM
timeFrame: Baseline up to Day 23
measure: Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2
timeFrame: Baseline up to Day 23
measure: Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX
timeFrame: Baseline up to Day 23
Other outcomes:
Locations:
city: Houston
country: United States
facility: MD Anderson Center
state: Texas
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: