Study of M1774 in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320)

An Open-label, Multicenter Phase Ib Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the ATR Inhibitor M1774 in Combination With DNA Damage Response Inhibitors or Immune Checkpoint Inhibitors in Patients With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 320)

This is an open-label, multicenter, clinical study conducted in multiple parts to establish the safety, tolerability, Pharmacokinetic/Pharmacodynamic (PK/PD) profile, maximum tolerated dose (MTD) combinations (if observed) and recommended dose for expansion (RDE) combination for M1774 in combination with M4076 (in Part A1), food effect on the PK of M4076 as monotherapy or in combination with M1774 (in Part A1.1), safety/tolerability and early signs of clinical activity of M1774 and M4076 in combination in patients with prostate cancer harboring loss of function (LoS) mutation in the gene ATM based on local data previously generated in circulating tumor (ct) DNA (liquid biopsies) or tumor biopsies (in Part A2), safety/tolerability and early signs of clinical activity of M1774 and M4076 in combination in patients with endometrial cancer harboring LoS mutation(s) in the gene ARID1A based on local data previously generated in ctDNA (liquid biopsies) or tumor biopsies (in Part A3), the relative bioavailability of a M1774 tablet formulation (TF1, test) compared to a capsule formulation (reference) will also be investigated (in Part A2/A3), and in combination with avelumab (in Part B1) in participants with metastatic or locally advanced unresectable solid tumors who are intolerant or have no standard therapy available.

Study Overview

• Status: Recruiting
• Conditions: Metastatic or Locally Advanced Unresectable Solid Tumors
• Intervention / Treatment: Drug: Avelumab; Drug: M1774; Drug: M4076

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: US Medical Information; Phone Number: 888-275-7376; Email: eMediUSA@emdserono.com
• Study Contact Backup: Name: Communication Center; Phone Number: +49 6151 72 5200; Email: service@emdgroup.com

Study Locations

• Canada
  • Toronto, Canada, M5G 2C1
    • Recruiting
    • Princess Margaret Cancer Centre
• Spain
  • Barcelona, Spain, 08023
    • Recruiting
    • Hospital QuironSalud Barcelona - Next Oncology
  • Madrid, Spain, 28223
    • Recruiting
    • Hospital Universitario Quironsalud Madrid - NEXT Oncology
• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas M. D. Anderson Cancer Center - Partner
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • NEXT Oncology

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Part A1, A1.1, A2, A3, and A2/3: Participants with metastatic or locally advanced unresectable solid tumors refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator, which may convey clinical benefit, or who cannot tolerate standard of care treatment
• Part A1.1: Triple negative breast cancer, epithelial ovarian cancer, castrate resistant prostate cancer, urothelial cancer, endometrial cancer, and colorectal cancer independent of mutation status.
• Part A2: Patients with advanced prostate cancer whose tumor carries a genetic loss of function (LoF) mutation(s) in the gene ataxia telangiectasia mutated (ATM).

No more than 3 prior lines of therapy for castrate resistant disease. Prior therapy must have included a taxane and a novel antiandrogen (example [e.g.] enzalutamide).

• Part A3: Patients with advanced endometrial cancer whose tumor carries a genetic LoF mutation(s) in the gene AT-rich interaction domain 1A (ARID1A).

Prior therapy must have included a platinum agent. Prior therapy must also have included a checkpoint inhibitor if the patient has mismatch repair (MMR)-deficient endometrial cancer. - Note for Parts A2/A3: Patients with ATM LoF mutated prostate cancer and ARID1A LoF mutated endometrial cancer should be prioritized to the respective expansion arms instead of being enrolled in Part A1.1. The presence of ATM and ARID1A LoF mutations will be determined according to local data, generated by an assay with appropriate regulatory status, in either tumor or liquid biopsy. The Sponsor will confirm that mutations certified by local data fulfil this definition.

• Participants with eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, with estimated life expectancy of at least 3 months
• Adequate hematological, hepatic, and renal function as defined in the protocol
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Participants with any condition, including any uncontrolled disease state other than with metastatic or locally advanced unresectable solid tumors, that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation
• Participants with a known additional malignancy that is progressing and/or requires active treatment
• Participants with carcinomatous meningitis are excluded regardless of clinical stability
• Participants with serious gastrointestinal bleeding within 3 months, refractory nausea and vomiting, uncontrolled diarrhea, known malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes, other chronic gastrointestinal disease, and/or other situations that may preclude adequate absorption of oral medications
• Participants with organ transplantation, including allogeneic stem cell transplant
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A1: M1774 and M4076	Drug: M1774; M1774 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.; Drug: M4076; M4076 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.
Experimental: Part B1: M1774 and Avelumab	Drug: Avelumab; Avelumab will be administered by intravenous infusion once a day over a defined period of time in Part B1 until disease progression, death, discontinuation, or end of study.; Drug: M1774; M1774 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.
Experimental: Part A1.1: M1774 and M4076; Assessment of the Effect of Food (Low-fat Meal) on the PK of M4076 Monotherapy Followed by Treatment with M1774 in Combination with M4076	Drug: M1774; M1774 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.; Drug: M4076; M4076 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.
Experimental: Part A2: M1774 and M4076; ATM in prostate cancer (Part A2)	Drug: M1774; M1774 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.; Drug: M4076; M4076 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.
Experimental: Part A3: M1774 and M4076; ARID1A in endometrial cancer (Part A3	Drug: M1774; M1774 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.; Drug: M4076; M4076 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.
Experimental: Part A2/A3: M1774 and M4076; Tablet formulation (TF1, test) compared to a capsule formulation (reference)	Drug: M1774; M1774 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.; Drug: M4076; M4076 will be administered orally once daily over a defined period of time in Part A1, A1.1, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part B1: Number of Participants with Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period		Day 1 up to Day 28
Part A1: Number of Participants With Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period		Day 1 up to Day 28
Part A1: Number of Participants With Adverse Events (AEs) and Treatment-Related AEs		Baseline up to 18 months
Part B1: Number of Participants with AEs and Treatment-Related AEs		Baseline up to 18 months
Part A1: Change From Baseline in Pharmacodynamic (PD) Biomarker	The PD biomarker of histone variant will be measured by flow cytometry.	Pre-dose up to approximately 1 month
Part B1: Change From Baseline in PD Biomarker	The PD biomarker of histone variant will be measured by flow cytometry.	Pre-dose up to approximately 1 month
Part A1.1: PK Plasma Concentration of M4076 Under Fed and Fasted Conditions		Day -1 up to Period 1 Day 1
Part A2/A3: Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero Extrapolated to Infinity [Frel(AUC0-inf)] of M1774 Test Treatment Compared to M1774 Reference Treatment		Day -4 up to Period 1 Day 1
Part A2/A3: Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero to Last Quantifiable Concentration [Frel(AUC0-t)] of M1774 Test Treatment Compared to M1774 Reference Treatment		Day -4 up to Period 1 Day 1
Part A2/A3: Ratio Maximum Observed Plasma Concentration (Ratio[Cmax]) of M1774 Test Treatment Compared to M1774 Reference Treatment		Day -4 up to Period 1 Day 1
Part A2/A3: Objective Response according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by Investigator		Up to 18 months after first dose administration
Part A2/A3: Number of Participants With AEs and Treatment-Related AEs		Baseline up to 18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Part B1: Pharmacokinetic (PK) Plasma Concentration of M1774	Pre-dose up to approximately 6 months
Part A1 and B1: Number of Participants with Clinically Significant Abnormalities in Digital Electrocardiogram (ECG) Measures	Baseline up to 18 months
Part A1 and B1: Objective Response (OR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1	Up to 18 months after first dose administration
Part A1: Pharmacokinetic (PK) Plasma Concentration of M1774 and M4076	Pre-dose up to approximately 6 months
Part B1: Pharmacokinetic (PK) Serum Concentration of Avelumab	Pre-dose up to approximately 18 months
Part B1: Number of Participants with Any Positive Anti-Drug Antibody (ADA) of Avelumab	Baseline up to 18 months
Part A1.1: Number of Participants With AEs and Treatment-Related AEs	Baseline up to 18 months
Part A1.1: PK Plasma and Urine Concentration of M4076 Under Fed and Fasted Conditions	Day -1 up to Period 1 Day 1
Part A2/A3: Time to Reach Maximum Plasma Concentration (tmax) of M1774	Day -4 up to Period 1 Day 1
Part A2/A3: Duration of Response according to RECIST v1.1	Up to 18 months after first dose administration
Part A2/A3: Clinical benefit (either OR or stable disease for 6 months or more) according to RECIST v1.1.	Up to 18 months after first dose administration
Part A2/A3: Progression Free Survival according to RECIST v1.1 modified according to the Prostate Cancer Working Group 3 (PCWG-3), assessed by Investigator	Up to 18 months after first dose administration
Part A2/A3: Overall Survival	Up to 18 months after first dose administration

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): June 7, 2022
• Primary Completion (Estimated): March 31, 2026
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: May 24, 2022
• First Submitted That Met QC Criteria: May 27, 2022
• First Posted (Actual): May 31, 2022

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Avelumab; Immune Checkpoint Inhibitor; M4076; M1774; ATR inhibitor; Metastatic or Locally Advanced Unresectable Solid Tumors; ATM inhibitor; DNA Damage Response Inhibitor
• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Avelumab
• Other Study ID Numbers: MS201924_0020; 2022-500287-35-00 (Other Identifier: EU Trial Number)

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 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