M6620 And Irinotecan Hydrochloride In Treating Patients With Solid Tumors That Are Metastatic Or Cannot Be Removed By Surgery

Study Overview

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

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.

Metastatic Colorectal Carcinoma
Metastatic Lung Small Cell Carcinoma
Metastatic Malignant Solid Neoplasm
Metastatic Pancreatic Carcinoma
Refractory Colorectal Carcinoma
Refractory Lung Small Cell Carcinoma
Refractory Malignant Solid Neoplasm
Refractory Pancreatic Carcinoma
Stage III Colorectal Cancer AJCC v8
Stage III Lung Cancer AJCC v8
Stage III Pancreatic Cancer AJCC v8
Stage IV Colorectal Cancer AJCC v8
Stage IV Lung Cancer AJCC v8
Stage IV Pancreatic Cancer AJCC v8
Unresectable Colorectal Carcinoma
Unresectable Lung Small Cell Carcinoma
Unresectable Malignant Solid Neoplasm
Unresectable Pancreatic Carcinoma

DRUG: Berzosertib
PROCEDURE: Biopsy Specimen
PROCEDURE: Biospecimen Collection
PROCEDURE: Computed Tomography
DRUG: Irinotecan Hydrochloride

NCI-2015-01915
NCI-2015-01915 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
HCC 15-164
UPCI 15-164
HCC#15-164
9938 (OTHER Identifier) (OTHER: UPMC Hillman Cancer Center LAO)
9938 (OTHER Identifier) (OTHER: CTEP)
UM1CA186689 (U.S. NIH Grant/Contract)
UM1CA186690 (U.S. NIH Grant/Contract)
UM1CA186704 (U.S. NIH Grant/Contract)
UM1CA186717 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2015-11-03	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2024-12-13
First Submitted that Met QC Criteria 2015-11-03	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2024-12-16
First Posted (ESTIMATED) 2015-11-04	Results First Posted N/A	Last Verified 2024-12

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
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. Patients also undergo biopsy and coll	DRUG: Berzosertib Given IV PROCEDURE: Biopsy Specimen Undergo biopsy PROCEDURE: Biospecimen Collection Correlative studies PROCEDURE: Computed Tomography Undergo CT DRUG: Irinotecan Hydrochloride Given IV

Participant Group/Arm

Intervention/Treatment

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. Patients also undergo biopsy and coll

DRUG: Berzosertib

Given IV

PROCEDURE: Biopsy Specimen

Undergo biopsy

PROCEDURE: Biospecimen Collection

Correlative studies

PROCEDURE: Computed Tomography

Undergo CT

DRUG: Irinotecan Hydrochloride

Given IV

Primary Outcome Measures	Measure Description	Time Frame
Maximum tolerated dose (MTD)	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.	Up to 28 days
Recommended phase 2 dose (RP2D) of ATR kinase inhibitor M6620 (VX-970, berzosertib) and irinotecan hydrochloride	The RP2D will be determined based on MTD and the feasibility of the administration.	Up to 28 days

Secondary Outcome Measures	Measure Description	Time Frame
Incidence of adverse events of M6620 (VX-970, berzosertib) and irinotecan hydrochloride	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.	Up to 6 months after completion of study treatment
Overall response rate	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.	Up to 6 months after completion of study treatment
Incidence of stable disease	Tabulated by disease diagnosis and by dose level. Will also report the response rate and confidence limits at that dose level separately.	Up to 6 months after completion of study treatment
Progression-free survival	Estimated using the Kaplan-Meier method and the corresponding 95% confidence interval will be provided.	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
Pharmacokinetic parameters of M6620 (VX-970, berzosertib) in combination with irinotecan hydrochloride	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.	Days -14 through -11, 1, 2, and 15 through 18 of cycle 1 (each cycle = 28 days)
Pharmacodynamic parameters of M6620 (VX-970, berzosertib) in combination with irinotecan hydrochloride	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.	Up to day 15 of cycle 1 (each cycle = 28 days)

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Patients must have histologically confirmed metastatic or unresectable malignancy that is refractory to standard therapy or for which no standard therapy exists and where irinotecan is deemed a reasonable treatment option
FOR PATIENTS ENROLLED IN THE EXPANSION COHORT: Patients must have known deficiencies in the deoxyribonucleic acid (DNA)-Damage Response (DDR), e.g. mutations in ATM, PALB2, BRCA1/2 or other deficiencies after discussion with the Study Chair (prioritized), or patients can be enrolled with the following tumor types regardless of known DDR deficiency: pancreatic cancer, colorectal cancer, and small cell lung cancer
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam
No limit on prior lines of therapy for metastatic disease; prior adjuvant or neoadjuvant chemotherapy does not count as a prior line of therapy as long as completion of the adjuvant or neoadjuvant therapy was more than 1 year prior to patient enrollment
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of M6620 (VX-970, berzosertib) in combination with irinotecan in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)
Life expectancy of greater than 12 weeks
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Total bilirubin within normal institutional limits
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN); if liver involvement, =< 5 x ULN
Creatinine clearance >= 60 mL/min/1.73 m^2
Patients must have archived tumor tissue from prior tumor biopsy or surgical resections available for submission that is sufficient to complete molecular profiling
FOR PATIENTS ENROLLED IN THE EXPANSION COHORT: Willingness to undergo mandatory biopsies (day -13, approximately 18 to 22 hours post end of irinotecan infusion and day 2, approximately 18 to 22 hours post end of irinotecan infusion [= 17 to 21 hours post end of M6620 (VX-970, berzosertib)]); patients enrolled to this cohort should have tumors deemed easily accessible for biopsies with low likelihood of complication
The effects of M6620 (VX-970, berzosertib) on the developing human fetus are unknown; for this reason and because DNA-damage response (DDR) inhibitors may have teratogenic potential, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of M6620 (VX-970, berzosertib) administration

For this reason and because DNA-damage response (DDR) inhibitors may have teratogenic potential, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 6 months after study completion
Ability to understand and willingness to sign a written informed consent document

Patients who have had chemotherapy or other systemic therapy or radiotherapy or patients who have not recovered from adverse events due to prior administered agents as follows:

Chemotherapy < 4 weeks prior to entering the study
Radiotherapy < 4 weeks prior to entering the study
Nitrosoureas/mitomycin C < 6 weeks prior to entering the study
Targeted therapy < 2 weeks (or 5 half-lives, whichever is longer) prior to entering the study
Those who have not recovered from clinically significant adverse events due to prior agents administered to grade =< 1 or baseline, with exception of alopecia and peripheral neuropathy, unless approved by the protocol chair
Immunotherapy < 4 weeks prior to entering the study
Patients who are receiving any other investigational agents
Patients with unstable brain metastases should be excluded; however, patients with known brain metastases may participate in this clinical trial if they are clinically stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are on a stable or decreasing dose of steroids for at least 14 days prior to trial treatment
History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 (VX-970, berzosertib) or irinotecan
M6620 (VX-970, berzosertib) is primarily metabolized by CYP3A4; irinotecan and its active metabolite, SN-38, are metabolized by CYP3A4 and UGT1A1, respectively; therefore, concomitant administration with strong inhibitors or inducers of CYP3A4 should be avoided; valproic acid is known to inhibit the process of glucuronidation and may potentially enhance the toxicity of irinotecan; medications that enhance glucuronidation (i.e. phenytoin, phenobarbital, carbamazepine, rifampin, etc.) may also enhance clearance of SN-38, which may possibly decrease efficacy; therefore, concomitant administration of these drugs should be avoided; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
Uncontrolled intercurrent illness including, but not limited to, severe active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; patients with chronic viral hepatitis may participate in this clinical trial if they are clinically stable with acceptable liver function
Pregnant women are excluded from this study because M6620 (VX-970, berzosertib) as a DNA-damage response (DDR) inhibitor may have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M6620 (VX-970, berzosertib), breastfeeding should be discontinued if the mother is treated with M6620 (VX-970, berzosertib); these potential risks may also apply to other agents used in this study
Human immunodeficiency virus (HIV)-positive patients with well-controlled disease, as determined by CD4 count and viral load, who are on antiretroviral therapy that does not contain a strong inducer or inhibitor of CYP3A4 (e.g. regimens containing ritonavir, cobicistat, efavirenz or etravirine) are allowed on trial; HIV-positive patients on combination antiretroviral therapy with strong inducers or inhibitors of CYP3A4 are ineligible because of the potential for pharmacokinetic interactions with M6620 (VX-970, berzosertib); patients with poorly controlled HIV are not eligible due to the increased risk of lethal infections when treated with marrow-suppressive therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Liza C Villaruz, University of Pittsburgh Cancer Institute LAO

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

No publications available

Learn

Resources

Patients

Caregivers

Clinical Trial Record