Advanced Malignant Solid Neoplasm Clinical Trial
Official title:
A Molecularly Driven Phase 1b Dose Escalation and Dose Expansion Study of the DNA-PK Inhibitor Peposertib (M3814) in Combination With the ATR Inhibitor M1774
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 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
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 once (QD) or twice (BID) daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy before cycle(C) 1 day (D)1, C1D10 and at progression and blood sample collection during prestudy and weeks 1, 2, 3, 4, 5, 6, and at progression. Patients additionally undergo positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) at baseline and are repeated every 8 weeks for 24 weeks then every 12 weeks unless clinically indicated. ;
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