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

Metastatic or Locally Advanced Unresectable Solid Tumors Clinical Trial

Official title:

An Open-label, Multicenter Phase Ib Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the ATR Inhibitor Tuvusertib (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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05396833
• Other study ID #: MS201924_0020
• Secondary ID: 2022-500287-35-0
• Status: Recruiting
• Phase: Phase 1
• Start date: June 7, 2022
• Est. completion date: May 31, 2026

Study information

• Verified date: June 2024
• Source: EMD Serono
• Contact: US Medical Information
• Phone: 888-275-7376
• Email: eMediUSA[@]emdserono.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: May 31, 2026
• Est. primary completion date: March 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

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

Related Conditions & MeSH terms

• Metastatic or Locally Advanced Unresectable Solid Tumors
• Neoplasms

Intervention

Drug:
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Canada	Princess Margaret Cancer Centre	Toronto
Spain	Hospital QuironSalud Barcelona - Next Oncology	Barcelona
Spain	Hospital Universitario Quironsalud Madrid - NEXT Oncology	Madrid
United States	University of Texas M. D. Anderson Cancer Center - Partner	Houston	Texas
United States	NEXT Oncology	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.	Merck KGaA, Darmstadt, Germany

Countries where clinical trial is conducted

United States,  Canada,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A1: Number of Participants With Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period		Day 1 up to Day 28
Primary	Part A1: Number of Participants With Adverse Events (AEs) and Treatment-Related AEs		Baseline up to 18 months
Primary	Part B1: Number of Participants with Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period		Day 1 up to Day 28
Primary	Part B1: Number of Participants with AEs and Treatment-Related AEs		Baseline up to 18 months
Primary	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
Primary	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
Primary	Part A1.1: PK Plasma Concentration of Lartesertib Under Fed and Fasted Conditions		Day -1 up to Period 1 Day 1
Primary	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
Primary	Part A2/A3: Number of Participants With AEs and Treatment-Related AEs		Baseline up to 18 months
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Part A1: Pharmacokinetic (PK) Plasma Concentration of Tuvusertib and Lartesertib		Pre-dose up to approximately 6 months
Secondary	Parts A1.2 and B1: Pharmacokinetic (PK) Plasma Concentration of Tuvusertib		Pre-dose up to approximately 6 months
Secondary	Part B1: Pharmacokinetic (PK) Serum Concentration of Avelumab		Pre-dose up to approximately 18 months
Secondary	Part A1 and B1: Number of Participants with Clinically Significant Abnormalities in Digital Electrocardiogram (ECG) Measures		Baseline up to 18 months
Secondary	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
Secondary	Part B1: Number of Participants with Any Positive Anti-Drug Antibody (ADA) of Avelumab		Baseline up to 18 months
Secondary	Parts A1.1, A1.2 and A2/3: Number of Participants With AEs and Treatment-Related AEs		Baseline up to 18 months
Secondary	Part A1.1: PK Plasma and Urine Concentration of Lartesertib Under Fed and Fasted Conditions		Day -1 up to Period 1 Day 1
Secondary	Part A2/A3: Time to Reach Maximum Plasma Concentration (tmax) of Tuvusertib		Day -4 up to Period 1 Day 1
Secondary	Part A2/A3: Duration of Response according to RECIST v1.1		Up to 18 months after first dose administration
Secondary	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
Secondary	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

External Links

•   Trial Awareness and Transparency website