A First-in-human, Phase I, Open-label Study of the ATM Inhibitor M4076 in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 410)
Overview
- Phase
- Phase 1
- Intervention
- M4076
- Conditions
- Advanced Solid Tumors
- Sponsor
- EMD Serono Research & Development Institute, Inc.
- Enrollment
- 22
- Locations
- 3
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- last year
Overview
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.
Investigators
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:
- •Active infection (i.e., requiring systemic antibiotics or antifungals)
- •Uncontrolled arterial hypertension
- •Severe cardiac arrhythmia requiring medication
- •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
Arms & Interventions
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
Intervention: M4076
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.
Intervention: M4076
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.
Intervention: M4076
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.
Intervention: M4076
Outcomes
Primary Outcomes
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
Time Frame: Day 1 to Day 21 of Cycle 1 (21-day cycle)
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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs
Time Frame: From the first dose of study drug administration until 30 days after the last dose of study drug administration (up to 603 days)
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.
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Time Frame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
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.
Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0
Time Frame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
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.
Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values
Time Frame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
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.
Secondary Outcomes
- 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(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(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(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(Day 1 and Day 8)
- Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076(Day 1 and Day 8)
- Maximum Observed Plasma Concentration (Cmax) of M4076(Day 1 and Day 8)
- Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM(Baseline up to Day 23)
- Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2(Baseline up to Day 23)
- Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM(Baseline up to Day 23)
- Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2(Baseline up to Day 23)
- Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX(Baseline up to Day 23)