M6620 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02595931|
Recruitment Status : Recruiting
First Posted : November 4, 2015
Last Update Posted : August 3, 2020
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Malignant Neoplasm Refractory Malignant Neoplasm Unresectable Malignant Neoplasm||Drug: Berzosertib Drug: Irinotecan Hydrochloride||Phase 1|
I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of berzosertib (M6620) in combination with irinotecan hydrochloride (irinotecan) in patients with advanced solid tumors.
I. To estimate the safety and tolerability of M6620 in combination with irinotecan.
II. To document anti-tumor activity. III. To determine the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of M6620 and irinotecan.
I. To identify molecular subpopulations of patients with increased sensitivity to the irinotecan and M6620 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.
After completion of study treatment, patients are followed up for 30 days, then at 3 and 6 months.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||51 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Clinical Trial of M6620 in Combination With the Topoisomerase I Inhibitor Irinotecan in Patients With Advanced Solid Tumors|
|Actual Study Start Date :||June 8, 2016|
|Estimated Primary Completion Date :||April 30, 2021|
Experimental: Treatment (irinotecan, M6620)
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.
Drug: Irinotecan Hydrochloride
- Maximum tolerated dose (MTD) [ Time Frame: Up to 28 days ]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.
- Recommended phase 2 dose (RP2D) of ATR kinase inhibitor M6620 (VX-970) and irinotecan hydrochloride [ Time Frame: Up to 28 days ]The RP2D will be determined based on MTD and the feasibility of the administration.
- Incidence of adverse events of VX-970 and irinotecan hydrochloride [ Time Frame: Up to 6 months after completion of study treatment ]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.
- Overall response rate [ Time Frame: Up to 6 months after completion of study treatment ]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.
- Incidence of stable disease [ Time Frame: Up to 6 months after completion of study treatment ]Tabulated by disease diagnosis and by dose level. Will also report the response rate and confidence limits at that dose level separately.
- Progression-free survival [ Time Frame: Duration of time from start of treatment to time of progression or death, whichever occurs first, assessed up 6 months after completion of study treatment ]Estimated using the Kaplan-Meier method and the corresponding 95% confidence interval will be provided.
- Pharmacokinetic parameters of VX-970 in combination with irinotecan hydrochloride [ Time Frame: Days -14 through -11, 1, and 15 through 18 of cycle 1 (each cycle = 28 days) ]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.
- Pharmacodynamic parameters of VX-970 in combination with irinotecan hydrochloride [ Time Frame: Up to day 15 of cycle 1 (each cycle = 28 days) ]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.
- Change in biomarker levels [ Time Frame: Baseline to up 6 months after completion of study treatment ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02595931
|Principal Investigator:||Liza C Villaruz||University of Pittsburgh Cancer Institute LAO|