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

NCT05396833 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: MS201924_00202022-500287-35-00
• Study Type: interventional
• Target: 120
• Locations: 5 countries
• Sites: 22

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

Keywords

ATR inhibitor; ATM inhibitor; Immunotherapy; Tuvusertib (M1774); Lartesertib (M4076); Avelumab; Metastatic or Locally Advanced Unresectable Solid Tumors; DNA Damage Response Inhibitor; Immune Checkpoint Inhibitor

Outcome Measures

Primary Outcomes (15)

• 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 Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period

  Day 1 up to Day 28

• 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 Lartesertib Under Fed and Fasted Conditions

  Day -1 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

• Part A1.2: Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero Extrapolated to Infinity [Frel(AUC0-inf)] of Tuvusertib Test Treatment Compared to Tuvusertib Reference Treatment

  Day -4 up to Period 1 Day 1

• Part A1.2: Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero to Last Quantifiable Concentration [Frel(AUC0-t)] of Tuvusertib Test Treatment Compared to Tuvusertib Reference Treatment

  Day -4 up to Period 1 Day 1

• Part A1.2: Ratio Maximum Observed Plasma Concentration (Ratio[Cmax]) of Tuvusertib Test Treatment Compared to Tuvusertib 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 Extrapolated to Infinity [Frel(AUC0-inf)] of Tuvusertib Test Treatment Compared to Tuvusertib 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 Tuvusertib Test Treatment Compared to Tuvusertib Reference Treatment

  Day -4 up to Period 1 Day 1

• Part A2/A3: Ratio Maximum Observed Plasma Concentration (Ratio[Cmax]) of Tuvusertib Test Treatment Compared to Tuvusertib Reference Treatment

  Day -4 up to Period 1 Day 1

Secondary Outcomes (12)

• Part A1: Pharmacokinetic (PK) Plasma Concentration of Tuvusertib and Lartesertib

  Pre-dose up to approximately 6 months

• Parts A1.2 and B1: Pharmacokinetic (PK) Plasma Concentration of Tuvusertib

  Pre-dose up to approximately 6 months

• Part B1: Pharmacokinetic (PK) Serum Concentration of Avelumab

  Pre-dose up to approximately 18 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

Study Arms (7)

Part A1: Tuvusertib and Lartesertib

EXPERIMENTAL

Drug: Tuvusertib; Drug: Lartesertib

Part A1.1: Tuvusertib and Lartesertib

EXPERIMENTAL

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: Tuvusertib; Drug: Lartesertib

Part A1.2: Tuvusertib and Lartesertib

EXPERIMENTAL

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

Drug: Tuvusertib; Drug: Lartesertib

Part A2: Tuvusertib and Lartesertib

EXPERIMENTAL

ATM in prostate cancer (Part A2)

Drug: Tuvusertib; Drug: Lartesertib

Part A3: Tuvusertib and Lartesertib

EXPERIMENTAL

ARID1A in endometrial cancer

Drug: Tuvusertib; Drug: Lartesertib

Part A2/A3: Tuvusertib and Lartesertib

EXPERIMENTAL

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

Drug: Tuvusertib; Drug: Lartesertib

Part B1: Tuvusertib and Avelumab

EXPERIMENTAL

Drug: Tuvusertib; Drug: Avelumab

Interventions

Tuvusertib 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.

Also known as: M1774

Part A1.1: Tuvusertib and Lartesertib; Part A1.2: Tuvusertib and Lartesertib; Part A1: Tuvusertib and Lartesertib; Part A2/A3: Tuvusertib and Lartesertib; Part A2: Tuvusertib and Lartesertib; Part A3: Tuvusertib and Lartesertib; Part B1: Tuvusertib and Avelumab

Lartesertib 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.

Also known as: M4076

Part A1.1: Tuvusertib and Lartesertib; Part A1.2: Tuvusertib and Lartesertib; Part A1: Tuvusertib and Lartesertib; Part A2/A3: Tuvusertib and Lartesertib; Part A2: Tuvusertib and Lartesertib; Part A3: Tuvusertib and Lartesertib

Avelumab 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.

Part B1: Tuvusertib and Avelumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: collaborator
• EMD Serono Research & Development Institute, Inc.: lead

Study Sites (22)

Providence Medical Foundation

Santa Rosa, California, 95403, United States

Location

University of Miami School of Medicine

Miami, Florida, 33136, United States

Location

Augusta University - formerly Georgia Regents University

Augusta, Georgia, 30912, United States

Location

The University of Kansas Medical Center Research Institute, Inc.

Kansas City, Kansas, 66205, United States

Location

Carolina Urologic Research Center

Myrtle Beach, South Carolina, 29572, United States

Location

Mary Crowley Cancer Research Centers

Dallas, Texas, 75230, United States

Location

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

Houston, Texas, 77030, United States

Location

NEXT Oncology

San Antonio, Texas, 78229, United States

Location

Royal North Shore Hospital

St Leonards, Australia

Location

Calvary Mater Newcastle - PARENT

Waratah, Australia

Location

Princess Margaret Cancer Centre

Toronto, M5G 2C1, Canada

Location

Seoul National University Bundang Hospital

Seongnam-si, 13620, South Korea

Location

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

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

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

Seoul, 06591, South Korea

Location

Korea University Guro Hospital

Seoul, 08308, South Korea

Location

Hospital QuironSalud Barcelona - Next Oncology

Barcelona, 08023, Spain

Location

Hospital Clinic de Barcelona - Servicio de Oncologia

Barcelona, Spain

Location

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

Madrid, 28050, Spain

Location

Hospital Universitario Quironsalud Madrid - NEXT Oncology

Madrid, 28223, Spain

Location

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

Madrid, Spain

Location

Related Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

avelumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Medical Responsible

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

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2022
• First Posted: May 31, 2022
• Study Start: June 7, 2022
• Primary Completion: April 10, 2026
• Study Completion: April 10, 2026
• Last Updated: February 19, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2); US (8); KR (6); ES (5); CA (1)