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).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
120
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 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 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.
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
...and 12 more locations
Part A1: Number of Participants With Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period
Time frame: Day 1 up to Day 28
Part A1: Number of Participants With Adverse Events (AEs) and Treatment-Related AEs
Time frame: Baseline up to 18 months
Part B1: Number of Participants with Dose-Limiting Toxicities (DLTs) During the DLT Evaluation Period
Time frame: Day 1 up to Day 28
Part B1: Number of Participants with AEs and Treatment-Related AEs
Time frame: 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.
Time frame: 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.
Time frame: Pre-dose up to approximately 1 month
Part A1.1: PK Plasma Concentration of Lartesertib Under Fed and Fasted Conditions
Time frame: 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
Time frame: Up to 18 months after first dose administration
Part A2/A3: Number of Participants With AEs and Treatment-Related AEs
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Day -4 up to Period 1 Day 1
Part A1: Pharmacokinetic (PK) Plasma Concentration of Tuvusertib and Lartesertib
Time frame: Pre-dose up to approximately 6 months
Parts A1.2 and B1: Pharmacokinetic (PK) Plasma Concentration of Tuvusertib
Time frame: Pre-dose up to approximately 6 months
Part B1: Pharmacokinetic (PK) Serum Concentration of Avelumab
Time frame: Pre-dose up to approximately 18 months
Part A1 and B1: Number of Participants with Clinically Significant Abnormalities in Digital Electrocardiogram (ECG) Measures
Time frame: Baseline up to 18 months
Part A1 and B1: Objective Response (OR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1
Time frame: Up to 18 months after first dose administration
Part B1: Number of Participants with Any Positive Anti-Drug Antibody (ADA) of Avelumab
Time frame: Baseline up to 18 months
Parts A1.1, A1.2 and A2/3: Number of Participants With AEs and Treatment-Related AEs
Time frame: Baseline up to 18 months
Part A1.1: PK Plasma and Urine Concentration of Lartesertib Under Fed and Fasted Conditions
Time frame: Day -1 up to Period 1 Day 1
Part A2/A3: Time to Reach Maximum Plasma Concentration (tmax) of Tuvusertib
Time frame: Day -4 up to Period 1 Day 1
Part A2/A3: Duration of Response according to RECIST v1.1
Time frame: 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.
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Time frame: 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
Time frame: Up to 18 months after first dose administration