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

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: M4076

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Princess Margaret Cancer Centre
• United States
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Center
    • San Antonio, Texas, United States, 78229
      • Next Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1A Dose Escalation: M4076 100 mg; Participants received M4076 film coated tablets at a dose of 100 milligrams (mg), orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study	Drug: M4076; M4076 was administered orally.
Experimental: Part 1A Dose Escalation: M4076 200 mg; Participants received M4076 film coated tablets at a dose of 200 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study.	Drug: M4076; M4076 was administered orally.
Experimental: Part 1A Dose Escalation: M4076 300 mg; Participants received M4076 film coated tablets at a dose of 300 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study.	Drug: M4076; M4076 was administered orally.
Experimental: Part 1A Dose Escalation: M4076 400 mg; Participants received M4076 film coated tablets at a dose of 400 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study.	Drug: M4076; M4076 was administered orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	A DLT was defined as the occurrence of any of following events that were judged by the study investigator, received at least 80% of the planned cumulative dose during the DLT period of each study intervention and completed the DLT period or additionally, participants who did not receive 80% of the planned total dose of study intervention, but at least 80% dosing of a different dose cohort and finished the DLT period are eligible for the DLT analysis set to be analyzed in the highest dose cohort for which they received 80% of dosing.	Day 1 to Day 21 of Cycle 1 (21-day cycle)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs.	From the first dose of study drug administration until 30 days after the last dose of study drug administration (up to 603 days)
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight, respiratory rate and temperature. Clinical significance was assessed by the investigator. Number of participants who with clinically significant changes from baseline in vital signs were reported.	Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0	The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with change from baseline to grade 3 or higher values for the hematology and biochemistry were reported.	Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values	ECG parameters included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, QT intervals, and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant change from baseline in 12-lead ECG were reported.	Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Confirmed objective response was defined as the number of participants with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR).	Time from first study treatment up to 603 days
Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator	DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.	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
Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators	PFS is defined as the time (in months) from date of first administration of study intervention to the date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was to be estimated using Kaplan-Meier (KM) plots.	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)
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076	Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-tlast was to be calculated according to the mixed log-linear trapezoidal rule.	Day 1 and Day 8
Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076	The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-tlast +Clast pred/ lambda z (single dose only)	Day 1 and Day 8
Maximum Observed Plasma Concentration (Cmax) of M4076	Cmax was obtained directly from the concentration versus time curve.	Day 1 and Day 8
Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM	Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported.	Baseline up to Day 23
Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2	p-CHK2 is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported.	Baseline up to Day 23
Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM	Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported.	Baseline up to Day 23
Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2	p-CHK2 is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported.	Baseline up to Day 23
Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX	gamma-H2AX is measured by flow cytometry and immunohistochemistry. Absolute values were reported for each participant as descriptive data for this outcome measure was not calculated. P= Part, D=Day, H=Hour in the below mentioned categories. Mean Fluorescent Intensity (MFI) is a number generated by the flow cytometer; an instrument that measures the fluorescent signal emitted by a sample. The stronger the fluorescent signal, the higher the MFI value detected by the instrument's acquisition software. The values displayed in the system represent each MFI measurement at different time points, with the MFI value for the blank sample subtracted.	Baseline up to Day 23

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2021
• Primary Completion (Actual): March 31, 2023
• Study Completion (Actual): March 31, 2023

Study Registration Dates

• First Submitted: May 7, 2021
• First Submitted That Met QC Criteria: May 7, 2021
• First Posted (Actual): May 12, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 4, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Maximum tolerated dose; Pharmacodynamics; M4076
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: MS201512_0010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website http://bit.ly/IPD21

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No