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All Drugs and Chemicals

Irinotecan

Camptothecin

Topoisomerase I Inhibitors

Enzyme Inhibitors

Patients receive irinotecan hydrochloride IV over 90 minutes and M6620 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy and collection of blood samples throughout the study and undergo CT at screening, throughout the study, and during follow up.

Berzosertib

Biopsy Specimen

Biospecimen Collection

Computed Tomography

Irinotecan Hydrochloride

Liza C Villaruz

This phase I trial studies the side effects and best dose of M6620 and irinotecan hydrochloride in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). M6620 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of M6620 (VX-970, berzosertib) in combination with irinotecan hydrochloride (irinotecan) in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

I. To estimate the safety and tolerability of M6620 (VX-970, berzosertib) in combination with irinotecan.

II. To document anti-tumor activity. III. To determine the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of M6620 (VX-970, berzosertib) and irinotecan.

EXPLORATORY OBJECTIVE:

I. To identify molecular subpopulations of patients with increased sensitivity to the irinotecan and M6620 (VX-970, berzosertib) combination.

OUTLINE: This is a dose-escalation study.

Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes and M6620 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy and collection of blood samples throughout the study and undergo CT at screening, throughout the study, and during follow up.

After completion of study treatment, patients are followed up for 30 days, then at 3 and 6 months.

M6620 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

Phase I Clinical Trial of M6620 (VX-970, Berzosertib) in Combination With the Topoisomerase I Inhibitor Irinotecan in Patients With Advanced Solid Tumors

Paired t tests will be used to compare biomarker levels before and after treatment. The Benjamini and Hochberg's procedure will be used to control the false discovery rate at 30%. A descriptive analysis of patient tumor genotype and response to therapy will be performed.

Will be defined as the highest dose level at which =\< 20% patients experience dose limiting toxicity. A logistic regression model will be used to determine the MTD using all patients.

The RP2D will be determined based on MTD and the feasibility of the administration.

Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. A toxicity will be considered to be an adverse event that is possibly, probably or definitely related to treatment. The maximum grade of toxicity for each category of interest will be recorded for each patient, and the summary results will be tabulated by category, grade, and dose level. Serious (\>= grade 3) toxicities will be described on a patient-by-patient basis and will include any relevant baseline data.

Will be evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1. Tabulated by disease diagnosis and by dose level. Will also report the 95% confidence limits on the response rates. Will also report the response rate and confidence limits at that dose level separately.

Tabulated by disease diagnosis and by dose level. Will also report the response rate and confidence limits at that dose level separately.

Estimated using the Kaplan-Meier method and the corresponding 95% confidence interval will be provided.

Within-subject comparison of day 15 and day -14 irinotecan hydrochloride and SN38 area under the curve (AUC) and half-life (t1/2) will be performed. Maximum concentration (Cmax), AUC, t1/2, clearance (CL), and volume in steady state (Vss) of VX-970 with single-agent historical data at comparable doses will be compared. Induction of gamma H2AX as a marker of ATR-dependent replication stress in peripheral blood mononuclear cells (PBMCs) and tumor will be characterized.

Within-subject comparison of day 15 and day -14 irinotecan hydrochloride and SN38 AUC and t1/2 will be performed. Cmax, AUC, t1/2, CL, and Vss of VX-970 with single-agent historical data at comparable doses will be compared. Induction of gamma H2AX as a marker of ATR-dependent replication stress in PBMCs and tumor will be characterized.

Spots Global Cancer Trial Database for refractory lung small cell carcinoma