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

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.

• Berzosertib (Drug), also known as 2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970: Given IV
• Cisplatin (Drug), also known as 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: Given IV
• Gemcitabine Hydrochloride (Drug), also known as dFdCyd, Difluorodeoxycytidine Hydrochloride, Gemcitabine HCI, Gemzar, LY 188011, LY-188011, LY188011: Given IV

Primary outcomes

• Progression-free Survival (PFS) [Day of randomization, until progression, or death, assessed up to 12 months]: Estimated using the product-limit method of Kaplan and Meier. Event defined as progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary outcomes

• Overall Survival (OS) [Up to 36 months]: Estimated using the product-limit method of Kaplan and Meier. Event defined as death from any cause.
• Confirmed Objective Response Rate [Up to 36 months]: Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Confirmed Objective Response = CR + PR.
• Treatment Limiting Adverse Events [Assessed from the time of initial treatment until 30 days post discontinuation of treatment, up to 36 months.]: Adverse events that were fatal or led to treatment discontinuation.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Progression-free Survival (PFS) (Primary), Median, Months: Arm A (Berzosertib, Gemcitabine Hydrochloride, Cisplatin) 8.0 (6.0 to 14.4); Arm B (Gemcitabine Hydrochloride, Cisplatin) 8.0 (6.8 to NA)
• Overall Survival (OS) (Secondary), Median, Months: Arm A (Berzosertib, Gemcitabine Hydrochloride, Cisplatin) 14.4 (10.0 to NA); Arm B (Gemcitabine Hydrochloride, Cisplatin) 19.8 (14.8 to NA)
• Confirmed Objective Response Rate (Secondary), Number, percentage of participants: Arm A (Berzosertib, Gemcitabine Hydrochloride, Cisplatin) 54 (39 to 69); Arm B (Gemcitabine Hydrochloride, Cisplatin) 63 (47 to 78) (p 0.51)
• Treatment Limiting Adverse Events (Secondary), Count of participants, Participants: Arm A (Berzosertib, Gemcitabine Hydrochloride, Cisplatin) 0; Arm B (Gemcitabine Hydrochloride, Cisplatin) 1

Adverse events

Time frame: Adverse events were assessed from the time of initial treatment until 30 days post discontinuation of treatment, up to 36 months.

Serious adverse events by term

Other adverse events by term

218 more terms not shown.

• Results publication: 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. PMID 34436521

• Study Protocol and Statistical Analysis Plan (PDF, 2020-08-25)

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

NIH grants: N01CM00038, UM1CA186690, UM1CA186717