Clinical trial NCT05396833: Study of Tuvusertib (M1774) in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320)
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
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
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2022-05-31
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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
* 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

Primary outcomes:
measure: Part A1: Number of Participants With Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period
timeFrame: Day 1 up to Day 28
measure: Part A1: Number of Participants With Adverse Events (AEs) and Treatment-Related AEs
timeFrame: Baseline up to 18 months
measure: Part B1: Number of Participants with Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period
timeFrame: Day 1 up to Day 28
measure: Part B1: Number of Participants with AEs and Treatment-Related AEs
timeFrame: Baseline up to 18 months
measure: Part A1: Change From Baseline in Pharmacodynamic (PD) Biomarker
timeFrame: Pre-dose up to approximately 1 month
measure: Part B1: Change From Baseline in PD Biomarker
timeFrame: Pre-dose up to approximately 1 month
measure: Part A1.1: PK Plasma Concentration of Lartesertib Under Fed and Fasted Conditions
timeFrame: Day -1 up to Period 1 Day 1
measure: Part A2/A3: Objective Response according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by Investigator
timeFrame: Up to 18 months after first dose administration
measure: Part A2/A3: Number of Participants With AEs and Treatment-Related AEs
timeFrame: Baseline up to 18 months
measure: 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
timeFrame: Day -4 up to Period 1 Day 1
measure: 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
timeFrame: Day -4 up to Period 1 Day 1
measure: Part A1.2: Ratio Maximum Observed Plasma Concentration (Ratio[Cmax]) of Tuvusertib Test Treatment Compared to Tuvusertib Reference Treatment
timeFrame: Day -4 up to Period 1 Day 1
measure: 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
timeFrame: Day -4 up to Period 1 Day 1
measure: 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
timeFrame: Day -4 up to Period 1 Day 1
measure: Part A2/A3: Ratio Maximum Observed Plasma Concentration (Ratio[Cmax]) of Tuvusertib Test Treatment Compared to Tuvusertib Reference Treatment
timeFrame: Day -4 up to Period 1 Day 1
Secondary outcomes:
measure: Part A1: Pharmacokinetic (PK) Plasma Concentration of Tuvusertib and Lartesertib
timeFrame: Pre-dose up to approximately 6 months
measure: Parts A1.2 and B1: Pharmacokinetic (PK) Plasma Concentration of Tuvusertib
timeFrame: Pre-dose up to approximately 6 months
measure: Part B1: Pharmacokinetic (PK) Serum Concentration of Avelumab
timeFrame: Pre-dose up to approximately 18 months
measure: Part A1 and B1: Number of Participants with Clinically Significant Abnormalities in Digital Electrocardiogram (ECG) Measures
timeFrame: Baseline up to 18 months
measure: Part A1 and B1: Objective Response (OR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1
timeFrame: Up to 18 months after first dose administration
measure: Part B1: Number of Participants with Any Positive Anti-Drug Antibody (ADA) of Avelumab
timeFrame: Baseline up to 18 months
measure: Parts A1.1, A1.2 and A2/3: Number of Participants With AEs and Treatment-Related AEs
timeFrame: Baseline up to 18 months
measure: Part A1.1: PK Plasma and Urine Concentration of Lartesertib Under Fed and Fasted Conditions
timeFrame: Day -1 up to Period 1 Day 1
measure: Part A2/A3: Time to Reach Maximum Plasma Concentration (tmax) of Tuvusertib
timeFrame: Day -4 up to Period 1 Day 1
measure: Part A2/A3: Duration of Response according to RECIST v1.1
timeFrame: Up to 18 months after first dose administration
measure: Part A2/A3: Clinical benefit (either OR or stable disease for 6 months or more) according to RECIST v1.1.
timeFrame: Up to 18 months after first dose administration
measure: 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
timeFrame: Up to 18 months after first dose administration
Other outcomes:
Locations:
city: Santa Rosa
country: United States
facility: Providence Medical Foundation
state: California
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Augusta
country: United States
facility: Augusta University - formerly Georgia Regents University
state: Georgia
city: Kansas City
country: United States
facility: The University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Centers
state: Texas
city: Houston
country: United States
facility: University of Texas M. D. Anderson Cancer Center - Partner
state: Texas
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System - Division of Infectious Diseases
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Barcelona
country: Spain
facility: Hospital QuironSalud Barcelona - Next Oncology
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona - Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz - START Madrid FJD - Oncology Phase I
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal - Unidad de Fase I-Oncologica
city: Madrid
country: Spain
facility: Hospital Universitario Quironsalud Madrid - NEXT Oncology
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: