Cisplatin and Gemcitabine Hydrochloride With or Without Berzosertib in Treating Patients With Metastatic Urothelial Cancer

NCT ID: NCT02567409

Last Updated: 2025-03-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 87 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-31
• Study Completion Date: 2023-04-25

Brief Summary

This phase II trial studies how well cisplatin and gemcitabine hydrochloride with or without berzosertib works in treating patients with urothelial cancer that has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as cisplatin and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Berzosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if cisplatin and gemcitabine hydrochloride work better alone or with berzosertib in treating patients with urothelial cancer.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if the addition of berzosertib (M6620 [VX-970]) to cisplatin/gemcitabine hydrochloride (gemcitabine) improves progression-free survival (PFS) relative to cisplatin/gemcitabine alone.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.

II. To compare tumor response rate with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.

III. To compare safety with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.

IV. To assess the role of p53 status in predicting response to M6620 (VX-970)-based therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, and cisplatin IV over 60 minutes on day 1. Patients also receive berzosertib IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive gemcitabine hydrochloride and cisplatin as in Arm A.

After completion of study treatment, patients are followed up to 36 months.

Conditions

Metastatic Bladder Urothelial Carcinoma; Metastatic Renal Pelvis and Ureter Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; Stage IV Bladder Urothelial Carcinoma AJCC v7

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A (berzosertib, gemcitabine hydrochloride, cisplatin)

Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and cisplatin IV over 60 minutes on day 1. Patients also receive berzosertib IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Berzosertib

Intervention Type: DRUG

Given IV

Cisplatin

Intervention Type: DRUG

Given IV

Gemcitabine Hydrochloride

Intervention Type: DRUG

Given IV

Arm B (gemcitabine hydrochloride, cisplatin)

Patients receive gemcitabine hydrochloride and cisplatin as in Arm A.

Group Type: EXPERIMENTAL

Cisplatin

Intervention Type: DRUG

Given IV

Gemcitabine Hydrochloride

Intervention Type: DRUG

Given IV

Interventions

Berzosertib

Given IV

Intervention Type: DRUG

Cisplatin

Given IV

Intervention Type: DRUG

Gemcitabine Hydrochloride

Given IV

Intervention Type: DRUG

Other Intervention Names

2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-; M 6620; M6620; VX 970; VX-970; VX970; Abiplatin; Blastolem; Briplatin; CDDP; Cis-diammine-dichloroplatinum; Cis-diamminedichloridoplatinum; Cis-diamminedichloro Platinum (II); Cis-diamminedichloroplatinum; Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cismaplat; Cisplatina; Cisplatinum; Cisplatyl; Citoplatino; Citosin; Cysplatyna; DDP; Lederplatin; Metaplatin; Neoplatin; Peyrone's Chloride; Peyrone's Salt; Placis; Plastistil; Platamine; Platiblastin; Platiblastin-S; Platinex; Platinol; Platinol- AQ; Platinol-AQ; Platinol-AQ VHA Plus; Platinoxan; Platinum; Platinum Diamminodichloride; Platiran; Platistin; Platosin; dFdCyd; Difluorodeoxycytidine Hydrochloride; Gemcitabine HCI; Gemzar; LY 188011; LY-188011; LY188011

Eligibility Criteria

Inclusion Criteria

• Patients must have histologically or cytologically confirmed metastatic urothelial carcinoma; urothelial cancer derived from the bladder, ureter or upper tract is permitted
• 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 computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Patients must have access to archival tumor tissue for proposed correlative studies; these may be derived from transurethral resection of bladder tumors (TURBT), cystectomy, or biopsy; if archival tissue is not available for proposed correlatives, patients may be enrolled at the discretion of the study principal investigator (PI) (SKP)
• No prior cytotoxic chemotherapy for metastatic disease; prior immunotherapy is permitted
• At least 12 months have elapsed since platinum-based peri-operative treatment
• Karnofsky >= 70% (Eastern Cooperative Oncology Group [ECOG] performance status 0-1)
• Life expectancy of greater than 3 months
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin within institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Creatinine clearance >= 50 mL/min by either measured (using the Cockcroft-Gault, Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology [CKD-EPI] formula) or calculated clearance (i.e. glomerular filtration rate [GFR])
• The effects of M6620 (VX-970) on the developing human fetus are unknown; for this reason and because DNA-damage response (DDR) inhibitors as well as other therapeutic agents used in this trial 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) administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Radiotherapy within 4 weeks of protocol therapy
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 (VX970), cisplatin, or gemcitabine
• M6620 (VX-970) is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors or inducers of CYP3A4 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; Patient Drug Information Handout and Wallet Card should be provided to patients; 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, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because M6620 (VX-970) 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), breastfeeding should be discontinued if the mother is treated with M6620 (VX-970); these potential risks may also apply to other agents used in this study
• Patients with >= grade 2 neuropathy

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sumanta K Pal

Role: PRINCIPAL_INVESTIGATOR

City of Hope Comprehensive Cancer Center LAO

Locations

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, United States

Mayo Clinic in Arizona

Scottsdale, Arizona, United States

City of Hope Comprehensive Cancer Center

Duarte, California, United States

Los Angeles General Medical Center

Los Angeles, California, United States

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States

USC Norris Oncology/Hematology-Newport Beach

Newport Beach, California, United States

Stanford Cancer Institute Palo Alto

Palo Alto, California, United States

Keck Medical Center of USC Pasadena

Pasadena, California, United States

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States

UCHealth University of Colorado Hospital

Aurora, Colorado, United States

Mayo Clinic in Florida

Jacksonville, Florida, United States

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States

University of Kansas Clinical Research Center

Fairway, Kansas, United States

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas, United States

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, United States

Weisberg Cancer Treatment Center

Farmington Hills, Michigan, United States

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

Siteman Cancer Center-South County

St Louis, Missouri, United States

Siteman Cancer Center at Christian Hospital

St Louis, Missouri, United States

Nebraska Medicine-Bellevue

Bellevue, Nebraska, United States

Nebraska Medicine-Village Pointe

Omaha, Nebraska, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Case Western Reserve University

Cleveland, Ohio, United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, United States

Vanderbilt Breast Center at One Hundred Oaks

Nashville, Tennessee, United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

University of Virginia Cancer Center

Charlottesville, Virginia, United States

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin, United States

Countries

United States

References

Pal SK, Frankel PH, Mortazavi A, Milowsky M, Vaishampayan U, Parikh M, Lyou Y, Weng P, Parikh R, Teply B, Dreicer R, Emamekhoo H, Michaelson D, Hoimes C, Zhang T, Srinivas S, Kim WY, Cui Y, Newman E, Lara PN Jr. Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1536-1543. doi: 10.1001/jamaoncol.2021.3441.

Reference Type: DERIVED

PMID: 34436521 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2015-01642

Identifier Type: REGISTRY

Identifier Source: secondary_id

PHII-135

Identifier Type: -

Identifier Source: secondary_id

9947

Identifier Type: OTHER

Identifier Source: secondary_id

9947

Identifier Type: OTHER

Identifier Source: secondary_id

N01CM00038

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UM1CA186690

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UM1CA186717

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2015-01642

Identifier Type: -

Identifier Source: org_study_id