Study of Tuvusertib (M1774) in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320)
- Conditions
- Metastatic or Locally Advanced Unresectable Solid Tumors
- Interventions
- Registration Number
- NCT05396833
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 123
- Parta 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
- Other protocol defined inclusion criteria could apply
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part A1: Tuvusertib and Lartesertib Lartesertib - Part A2: Tuvusertib and Lartesertib Tuvusertib ATM in prostate cancer (Part A2) Part A2: Tuvusertib and Lartesertib Lartesertib ATM in prostate cancer (Part A2) Part A3: Tuvusertib and Lartesertib Tuvusertib ARID1A in endometrial cancer Part B1: Tuvusertib and Avelumab Tuvusertib - Part A1.2: Tuvusertib and Lartesertib Tuvusertib Relative Bioavailability Assessment of Tuvusertib Tablet (TF1) vs Capsule Followed by Treatment with Tuvusertib in Combination with Lartesertib Part A1.2: Tuvusertib and Lartesertib Lartesertib Relative Bioavailability Assessment of Tuvusertib Tablet (TF1) vs Capsule Followed by Treatment with Tuvusertib in Combination with Lartesertib Part A1.1: Tuvusertib and Lartesertib 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 Part A3: Tuvusertib and Lartesertib Lartesertib ARID1A in endometrial cancer Part A2/A3: Tuvusertib and Lartesertib Lartesertib Tablet formulation (TF1, test) compared to a capsule formulation (reference) Part A2/A3: Tuvusertib and Lartesertib Tuvusertib Tablet formulation (TF1, test) compared to a capsule formulation (reference) Part A1.1: Tuvusertib and Lartesertib Tuvusertib Assessment of the Effect of Food (Low-fat Meal) on the PK of M4076 Monotherapy Followed by Treatment with M1774 in Combination with M4076 Part A1: Tuvusertib and Lartesertib Tuvusertib - Part B1: Tuvusertib and Avelumab Avelumab -
- Primary Outcome Measures
Name Time Method Part B1: 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 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 A1: Number of Participants With Adverse Events (AEs) and Treatment-Related AEs Baseline up to 18 months Part A1.1: PK Plasma Concentration of Lartesertib Under Fed and Fasted Conditions Day -1 up to Period 1 Day 1 Part B1: Number of Participants with Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period Day 1 up to Day 28 Part A2/A3: Number of Participants With AEs and Treatment-Related AEs Baseline up to 18 months 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 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: 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 B1: Change From Baseline in PD Biomarker Pre-dose up to approximately 1 month The PD biomarker of histone variant will be measured by flow cytometry.
Part A1: Number of Participants With Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period Day 1 up to Day 28 Part A1: Change From Baseline in Pharmacodynamic (PD) Biomarker Pre-dose up to approximately 1 month The PD biomarker of histone variant will be measured by flow cytometry.
- Secondary Outcome Measures
Name Time Method 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 B1: Number of Participants with Any Positive Anti-Drug Antibody (ADA) of Avelumab Baseline up to 18 months Parts A1.1, A1.2 and A2/3: Number of Participants With AEs and Treatment-Related AEs Baseline up to 18 months Part A2/A3: Time to Reach Maximum Plasma Concentration (tmax) of Tuvusertib Day -4 up to Period 1 Day 1 Part A1 and B1: Number of Participants with Clinically Significant Abnormalities in Digital Electrocardiogram (ECG) Measures Baseline up to 18 months 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 A1.1: PK Plasma and Urine Concentration of Lartesertib Under Fed and Fasted Conditions Day -1 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
Trial Locations
- Locations (20)
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
Princess Margaret Cancer Centre
🇨🇦Toronto, Canada
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Korea, Republic of
Severance Hospital, Yonsei University Health System - Division of Infectious Diseases
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea, Seoul St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
Korea University Guro Hospital
🇰🇷Seoul, Korea, Republic of
Hospital QuironSalud Barcelona - Next Oncology
🇪🇸Barcelona, Spain
Hospital Clinic de Barcelona - Servicio de Oncologia
🇪🇸Barcelona, Spain
Hospital Universitario Fundacion Jimenez Diaz - START Madrid FJD - Oncology Phase I
🇪🇸Madrid, Spain
Centro Integral Oncologico Clara Campal - Unidad de Fase I-Oncologica
🇪🇸Madrid, Spain
Hospital Universitario Quironsalud Madrid - NEXT Oncology
🇪🇸Madrid, Spain