PRIMARY OBJECTIVES:~I. To determine the safety and tolerability of peposertib (M3814) in combination with M1774. (DOSE ESCALATION AND EXPANSION COHORT) II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of peposertib (M3814) and M1774. (DOSE ESCALATION COHORT)~SECONDARY OBJECTIVES:~I. To observe and record anti-tumor activity. II. To determine the pharmacokinetic (PK) profiles of peposertib (M3814) and M1774 when administered in combination.~EXPLORATORY OBJECTIVES:~I. To explore correlations between pharmacodynamic (PD) and predictive biomarkers (gammaH2AX, phospho-KAP1 and phospho-RPA) with clinical outcomes.~II. To explore correlations between baseline genomic alterations of ataxia-telangiectasia mutated (ATM) or markers of replicative stress, ATM expression by immunohistochemistry (IHC), RAD5' foci formation with clinical outcomes.~III. To determine metrics of anticancer activity including the objective response rate (ORR) and progression-free survival (PFS).~OUTLINE: This a dose-escalation study of peposertib and tuvusertib, followed by a dose-expansion study.~Patients receive peposertib orally (PO) in combination with tuvusertib PO on study. Patients undergo tumor biopsy and blood sample collection during screening and on study. Patients also undergo positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) throughout the trial.
This phase I trial tests the safety, side effects and best dose of peposertib (M3814) in combination with tuvusertib (M1774) in treating patients with solid tumors that have spread to other places in the body (advanced). Peposertib and tuvusertib cells by blocking some of the enzymes needed for cell growth.