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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02567409
• Collaborator: (none)
• Enrollment: 90
• Locations: 39
• Arms: 2
• Anticipated Duration (Months): 84.4
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Bladder Urothelial Carcinoma; Metastatic Renal Pelvis and Ureter Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; Stage IV Bladder Urothelial Carcinoma AJCC v7	Drug: Berzosertib; Drug: Cisplatin; Drug: Gemcitabine Hydrochloride	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. 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:

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

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

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

4. 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 Design

• Study Type: Interventional
• Anticipated Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 2 Trial of Cisplatin/Gemcitabine With or Without M6620 (VX-970) in Metastatic Urothelial Carcinoma
• Actual Study Start Date: Aug 19, 2016
• Anticipated Primary Completion Date: Aug 31, 2023
• Anticipated Study Completion Date: Aug 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
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.	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
Experimental: Arm B (gemcitabine hydrochloride, cisplatin) Patients receive gemcitabine hydrochloride and cisplatin as in Arm A.	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

Outcome Measures

Primary Outcome Measures

1. Progression-free survival (PFS) [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.

Secondary Outcome Measures

1. Overall survival (OS) [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.

2. Overall response rate [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.

3. Incidence of toxicities [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.

4. Analysis of potential predictors of response (including p53, p21, and ERCC2 mutations) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Hospital in Arizona	Phoenix	Arizona	United States	85054
2	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
3	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
4	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
5	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
6	USC Norris Oncology/Hematology-Newport Beach	Newport Beach	California	United States	92663
7	Stanford Cancer Institute Palo Alto	Palo Alto	California	United States	94304
8	Keck Medical Center of USC Pasadena	Pasadena	California	United States	91105
9	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
10	University of Colorado Hospital	Aurora	Colorado	United States	80045
11	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
12	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
13	University of Kansas Clinical Research Center	Fairway	Kansas	United States	66205
14	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas	United States	66205
15	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
16	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
17	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
18	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
19	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
20	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
21	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
22	Weisberg Cancer Treatment Center	Farmington Hills	Michigan	United States	48334
23	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
24	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri	United States	63141
25	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
26	Siteman Cancer Center-South County	Saint Louis	Missouri	United States	63129
27	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri	United States	63136
28	Nebraska Medicine-Bellevue	Bellevue	Nebraska	United States	68123
29	Nebraska Medicine-Village Pointe	Omaha	Nebraska	United States	68118
30	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
31	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
32	Duke University Medical Center	Durham	North Carolina	United States	27710
33	Case Western Reserve University	Cleveland	Ohio	United States	44106
34	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
35	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania	United States	15232
36	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee	United States	37204
37	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
38	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
39	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02567409
• Other Study ID Numbers: NCI-2015-01642; NCI-2015-01642; PHII-135; 9947; 9947; N01CM00038; UM1CA186690; UM1CA186717
• First Posted: Oct 5, 2015
• Last Update Posted: Jul 14, 2022
• Last Verified: Jul 1, 2022

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Transitional Cell; Gemcitabine; Cisplatin

Study Results

No Results Posted as of Jul 14, 2022