Clinical Trials /

Cisplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor M6620 in Treating Patients With Metastatic Urothelial Cancer

NCT02567409

Description:

This randomized phase II trial studies how well cisplatin and gemcitabine hydrochloride with or without ATR kinase inhibitor M6620 works in treating patients with urothelial cancer that has spread to other places in the body. 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. ATR kinase inhibitor M6620 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 ATR kinase inhibitor M6620 in treating patients with urothelial cancer.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cisplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor VX-970 in Treating Patients With Metastatic Urothelial Cancer
  • Official Title: A Randomized Phase 2 Trial of Cisplatin/Gemcitabine With or Without VX-970 in Metastatic Urothelial Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01642
  • SECONDARY ID: NCI-2015-01642
  • SECONDARY ID: PHII-135
  • SECONDARY ID: 9947
  • SECONDARY ID: 9947
  • SECONDARY ID: N01CM00038
  • SECONDARY ID: P30CA033572
  • SECONDARY ID: UM1CA186690
  • SECONDARY ID: UM1CA186717
  • NCT ID: NCT02567409

Conditions

  • Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter
  • Stage IV Bladder Urothelial Carcinoma

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor VX-970VX-970Arm A (VX-970, gemcitabine hydrochloride, cisplatin)
CisplatinAbiplatin, 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, PlatosinArm A (VX-970, gemcitabine hydrochloride, cisplatin)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011, LY188011Arm A (VX-970, gemcitabine hydrochloride, cisplatin)

Purpose

This randomized phase II trial studies how well cisplatin and gemcitabine hydrochloride with or without ATR kinase inhibitor VX-970 works in treating patients with urothelial cancer that has spread to other places in the body. 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. ATR kinase inhibitor VX-970 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 ATR kinase inhibitor VX-970 in treating patients with urothelial cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if the addition of ATR kinase inhibitor VX-970 (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 VX-970 to cisplatin/gemcitabine
      relative to cisplatin/gemcitabine alone.

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

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

      IV. To assess the role of p53 status in predicting response to 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 ATR kinase
      inhibitor VX-970 IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for 6
      courses 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (VX-970, gemcitabine hydrochloride, cisplatin)ExperimentalPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and cisplatin IV over 60 minutes on day 1. Patients also receive ATR kinase inhibitor VX-970 IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor VX-970
  • Cisplatin
  • Gemcitabine Hydrochloride
Arm B (gemcitabine hydrochloride, cisplatin)ExperimentalPatients receive gemcitabine hydrochloride and cisplatin as in Arm A.
  • Cisplatin
  • Gemcitabine Hydrochloride

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

          -  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 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

          -  Creatinine clearance >= 50 mL/min by either measured or calculated clearance

          -  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 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 VX-970, cisplatin, or gemcitabine

          -  Concomitant administration with strong inhibitors or inducers of CYP3A4 should be
             avoided; it is important to regularly consult a frequently-updated medical reference
             for a list of drugs to avoid or minimize use of

          -  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; breastfeeding should be discontinued if
             the mother is treated with VX-970; these potential risks may also apply to other
             agents used in this study

          -  Patients with >= grade 2 neuropathy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Measure:Analysis of potential predictors of response (including p53, p21, and ERCC2 mutations)
Time Frame:Up to 36 months
Safety Issue:
Description: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.
Measure:Incidence of toxicity graded according the Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 36 months
Safety Issue:
Description: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.
Measure:Overall response rate assessed by the Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up to 36 months
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:Up to 36 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 13, 2017