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

• ClinicalTrials.gov Identifier: NCT02567409
• Recruitment Status: Active, not recruiting
• First Posted: October 5, 2015
• Last Update Posted: January 30, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: October 2, 2015
• First Posted Date: October 5, 2015
• Last Update Posted Date: January 30, 2023
• Actual Study Start Date: August 19, 2016
• Estimated Primary Completion Date: August 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 25, 2018)

Progression-free survival (PFS) [ Time Frame: Day of randomization, until progression, death, or the start of another treatment, assessed up to 12 months ]

PFS for each arm will be summarized with a Kaplan-Meier plot and 95% confidence intervals (at 3, 6, 9, and 12 months); the one-sided 0.10-level logrank test will be used to compare the two arms.

Original Primary Outcome Measures (submitted: October 2, 2015)

Progression-free survival [ Time Frame: Day of randomization, until progression, death, or the start of another treatment, assessed up to 12 months ]

PFS for each arm will be summarized with a Kaplan-Meier plot and 95% confidence intervals (at 3, 6, 9, and 12 months); the one-sided 0.10-level logrank test will be used to compare the two arms.

Current Secondary Outcome Measures (submitted: July 10, 2019)

• Overall survival (OS) [ Time Frame: Up to 36 months ]
  OS for each arm will be summarized with a Kaplan-Meier plot and 95% confidence intervals; the one-sided 0.10-level logrank test will be used to compare the two arms.
• Overall response rate [ Time Frame: Up to 36 months ]
  Will be assessed by the Response Evaluation Criteria in Solid Tumors version 1.1. The overall response rate will be calculated as the ratio of the number of eligible randomized patients who experienced a confirmed complete response or partial response divided by the total number of randomized eligible patients who began treatment; 95% confidence intervals will be constructed. Pearson chi-square test will be used to compare the two arms in terms of the overall response rate.
• Incidence of toxicities [ Time Frame: Up to 36 months ]
  Will be graded according the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (CTCAE version 5.0 will be utilized for adverse event reporting beginning April 1, 2018). All observed toxicities will be summarized in terms of type, severity, and time of onset. Tables will be created to summarize these toxicities and side effects, overall by arm and by course. Proportions and associated 95% confidence intervals will be calculated for each arm separately and if indicated, for the difference between the arms. The two treatment arms will be compared using Fisher's exact test when presence of toxicities are dichotomized and by the Cochran-Armitage test for trend if all grades are considered.
• Analysis of potential predictors of response (including p53, p21, and ERCC2 mutations) [ Time Frame: Up to 36 months ]
  Archival tumor tissue will be analyzed for the presence of p53, p21, and ERCC2 mutations. For each treatment arm separately and for each of the 3 indicators (one each for presence of p53, p21, and ERCC2 mutations), the hazard ratio will be used to quantify the overall association between that gene and PFS. The Cox proportional hazards model will be used to estimate the interactions between the genes and PFS as well as the interaction between the treatment arm and each of the genes.

Original Secondary Outcome Measures (submitted: October 2, 2015)

• Analysis of potential predictors of response (including p53, p21, and ERCC2 mutations) [ Time Frame: Up to 36 months ]
  Archival tumor tissue will be analyzed for the presence of p53, p21, and ERCC2 mutations. For each treatment arm separately and for each of the 3 indicators (one each for presence of p53, p21, and ERCC2 mutations), the hazard ratio will be used to quantify the overall association between that gene and PFS. The Cox proportional hazards model will be used to estimate the interactions between the genes and PFS as well as the interaction between the treatment arm and each of the genes.
• Incidence of toxicity graded according the Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 36 months ]
  All observed toxicities will be summarized in terms of type, severity, and time of onset. Tables will be created to summarize these toxicities and side effects, overall by arm and by course. Proportions and associated 95% confidence intervals will be calculated for each arm separately and if indicated, for the difference between the arms. The two treatment arms will be compared using Fisher's exact test when presence of toxicities are dichotomized and by the Cochran-Armitage test for trend if all grades are considered.
• Overall response rate assessed by the Response Evaluation Criteria in Solid Tumors version 1.1 [ Time Frame: Up to 36 months ]
  The overall response rate will be calculated as the ratio of the number of eligible randomized patients who experienced a confirmed complete response or partial response divided by the total number of randomized eligible patients who began treatment; 95% confidence intervals will be constructed. Pearson chi-square test will be used to compare the two arms in terms of the overall response rate.
• Overall survival [ Time Frame: Up to 36 months ]
  OS for each arm will be summarized with a Kaplan-Meier plot and 95% confidence intervals; the one-sided 0.10-level logrank test will be used to compare the two arms.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cisplatin and Gemcitabine Hydrochloride With or Without Berzosertib in Treating Patients With Metastatic Urothelial Cancer
• Official Title: A Randomized Phase 2 Trial of Cisplatin/Gemcitabine With or Without M6620 (VX-970) in Metastatic Urothelial Carcinoma
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Berzosertib
  Given IV
  Other 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
• Drug: Cisplatin
  Given IV
  Other Names:

  • 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
• Drug: Gemcitabine Hydrochloride
  Given IV
  Other Names:

  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011

Study Arms

• Experimental: 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.
  Interventions:

  • Drug: Berzosertib
  • Drug: Cisplatin
  • Drug: Gemcitabine Hydrochloride
• Experimental: Arm B (gemcitabine hydrochloride, cisplatin)
  Patients receive gemcitabine hydrochloride and cisplatin as in Arm A.
  Interventions:

  • Drug: Cisplatin
  • Drug: Gemcitabine Hydrochloride

• Publications *: 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: October 2, 2015): 90
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 31, 2023
• Estimated Primary Completion Date: August 31, 2023 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02567409
• Other Study ID Numbers: NCI-2015-01642; NCI-2015-01642 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); PHII-135; 9947 ( Other Identifier: City of Hope Comprehensive Cancer Center LAO ); 9947 ( Other Identifier: CTEP ); N01CM00038 ( U.S. NIH Grant/Contract ); UM1CA186690 ( U.S. NIH Grant/Contract ); UM1CA186717 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sumanta K Pal; City of Hope Comprehensive Cancer Center LAO

• PRS Account: National Cancer Institute (NCI)
• Verification Date: January 2023