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

NCT ID: NCT05396833

Last Updated: 2025-09-26

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-07
• Study Completion Date: 2026-04-03

Brief Summary

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 tuvusertib in combination with lartesertib (in Part A1), food effect on the PK of lartesertib as monotherapy followed by treatment with tuvusertib in combination with lartesertib in participants with specific tumor types (in Part A1.1), relative bioavailability of a tuvusertib tablet formulation vs capsule formulation followed by treatment with tuvusertib (capsule) in combination with lartesertib in participants with specific tumor types (in Part A1.2), safety/tolerability and early signs of clinical activity of tuvusertib (capsule)and lartesertib in combination in participants with prostate cancer harboring loss of function (LoS) mutation in the gene ATM based on historic data collected prior to prescreening in circulating tumor (ct) DNA (liquid biopsies) or tumor biopsies (in Part A2), safety/tolerability and early signs of clinical activity of tuvusertib and lartesertib in combination in participants with endometrial cancer harboring LoS mutation(s) in the gene ARID1A based on historic data collected prior to prescreening in ctDNA (liquid biopsies) or tumor biopsies (in Part A3), the relative bioavailability of a tuvusertib tablet formulation (TF1, test) compared to a capsule formulation (reference) will also be investigated (in Part A2/A3), and identify a potential set of MTD combinations, and establish the RDE for the combination of tuvusertib and avelumab in participants with metastatic or locally advanced unresectable solid tumors (in Part B1).

Conditions

Metastatic or Locally Advanced Unresectable Solid Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part A1: Tuvusertib and Lartesertib

Group Type: EXPERIMENTAL

Tuvusertib

Intervention Type: DRUG

Tuvusertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.

Lartesertib

Intervention Type: DRUG

Lartesertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.

Part A1.1: Tuvusertib and Lartesertib

Assessment of the Effect of Food (Low-fat Meal) on the PK of M4076 Monotherapy Followed by Treatment with M1774 in Combination with M4076

Group Type: EXPERIMENTAL

Tuvusertib

Intervention Type: DRUG

Tuvusertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.

Lartesertib

Intervention Type: DRUG

Lartesertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.

Part A1.2: Tuvusertib and Lartesertib

Relative Bioavailability Assessment of Tuvusertib Tablet (TF1) vs Capsule Followed by Treatment with Tuvusertib in Combination with Lartesertib

Group Type: EXPERIMENTAL

Tuvusertib

Intervention Type: DRUG

Tuvusertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.

Lartesertib

Intervention Type: DRUG

Lartesertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.

Part A2: Tuvusertib and Lartesertib

ATM in prostate cancer (Part A2)

Group Type: EXPERIMENTAL

Tuvusertib

Intervention Type: DRUG

Tuvusertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.

Lartesertib

Intervention Type: DRUG

Lartesertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.

Part A3: Tuvusertib and Lartesertib

ARID1A in endometrial cancer

Group Type: EXPERIMENTAL

Tuvusertib

Intervention Type: DRUG

Tuvusertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.

Lartesertib

Intervention Type: DRUG

Lartesertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.

Part A2/A3: Tuvusertib and Lartesertib

Tablet formulation (TF1, test) compared to a capsule formulation (reference)

Group Type: EXPERIMENTAL

Tuvusertib

Intervention Type: DRUG

Tuvusertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.

Lartesertib

Intervention Type: DRUG

Lartesertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.

Part B1: Tuvusertib and Avelumab

Group Type: EXPERIMENTAL

Tuvusertib

Intervention Type: DRUG

Tuvusertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.

Avelumab

Intervention Type: DRUG

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.

Interventions

Tuvusertib

Tuvusertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, and Part B1 until disease progression, death, discontinuation, or end of study.

Intervention Type: DRUG

Lartesertib

Lartesertib will be administered orally once daily over a defined period of time in Part A1, A1.1, A1.2, A2, A3, A2/A3, until disease progression, death, discontinuation, or end of study.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

M1774; M4076

Eligibility Criteria

Inclusion Criteria

• Parts A1, A1.1, A1.2, 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
• Parts A1.1 and A1.2: Triple negative breast cancer, epithelial ovarian cancer, castrate resistant prostate cancer, urothelial cancer, endometrial cancer, and colorectal cancer independent of mutation status.
• Part A2: Participants 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: Participants 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 participant has mismatch repair (MMR)-deficient endometrial cancer. Note for Parts A2/A3: Participants 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 historic data collected prior to prescreening, generated by an assay with appropriate regulatory status, in either tumor or liquid biopsy. The Sponsor will confirm that mutations certified by historic 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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: collaborator

EMD Serono Research & Development Institute, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Responsible

Role: STUDY_DIRECTOR

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Locations

Providence Medical Foundation

Santa Rosa, California, United States

University of Miami School of Medicine

Miami, Florida, United States

Augusta University - formerly Georgia Regents University

Augusta, Georgia, United States

The University of Kansas Medical Center Research Institute, Inc.

Kansas City, Kansas, United States

Carolina Urologic Research Center

Myrtle Beach, South Carolina, United States

Mary Crowley Cancer Research Centers

Dallas, Texas, United States

University of Texas M. D. Anderson Cancer Center - Partner

Houston, Texas, United States

NEXT Oncology

San Antonio, Texas, United States

Royal North Shore Hospital

St Leonards, , Australia

Calvary Mater Newcastle - PARENT

Waratah, , Australia

Princess Margaret Cancer Centre

Toronto, , Canada

Seoul National University Bundang Hospital

Seongnam-si, , South Korea

Severance Hospital, Yonsei University Health System - Division of Infectious Diseases

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, , South Korea

Korea University Guro Hospital

Seoul, , South Korea

Hospital QuironSalud Barcelona - Next Oncology

Barcelona, , Spain

Hospital Clinic de Barcelona - Servicio de Oncologia

Barcelona, , Spain

Centro Integral Oncologico Clara Campal - Unidad de Fase I-Oncologica

Madrid, , Spain

Hospital Universitario Quironsalud Madrid - NEXT Oncology

Madrid, , Spain

Hospital Universitario Fundacion Jimenez Diaz - START Madrid FJD - Oncology Phase I

Madrid, , Spain

Countries

United States; Australia; Canada; South Korea; Spain

Related Links

https://clinicaltrials.emdgroup.com/en/trial-details/?id=MS201924_0020

Trial Awareness and Transparency website

https://medical.emdserono.com/en_US/home.html

US Medical Information website, Medical Resources

Other Identifiers

2022-500287-35-00

Identifier Type: OTHER

Identifier Source: secondary_id

MS201924_0020

Identifier Type: -

Identifier Source: org_study_id