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

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ClinicalTrials.gov Identifier: NCT02567409
Recruitment Status : Recruiting
First Posted : October 5, 2015
Last Update Posted : March 21, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE October 2, 2015
First Posted Date  ICMJE October 5, 2015
Last Update Posted Date March 21, 2019
Actual Study Start Date  ICMJE August 19, 2016
Estimated Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History Complete list of historical versions of study NCT02567409 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2018)
  • 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 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.
  • Incidence of toxicity 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) [ 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.
  • 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  ICMJE
 (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  ICMJE Cisplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor M6620 in Treating Patients With Metastatic Urothelial Cancer
Official Title  ICMJE A Randomized Phase 2 Trial of Cisplatin/Gemcitabine With or Without M6620 (VX-970) in Metastatic Urothelial Carcinoma
Brief Summary 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.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine if the addition of ATR kinase inhibitor M6620 (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 ATR kinase inhibitor M6620 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter
  • Stage IV Bladder Urothelial Carcinoma AJCC v7
Intervention  ICMJE
  • Drug: ATR Kinase Inhibitor M6620
    Given IV
    Other Names:
    • M 6620
    • M6620
    • VX-970
  • 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
    • Gemzar
    • LY-188011
    • LY188011
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
Study Arms  ICMJE
  • Experimental: Arm A (M6620, 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 ATR kinase inhibitor M6620 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.
    Interventions:
    • Drug: ATR Kinase Inhibitor M6620
    • Drug: Cisplatin
    • Drug: Gemcitabine Hydrochloride
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
  • Experimental: Arm B (gemcitabine hydrochloride, cisplatin)
    Patients receive gemcitabine hydrochloride and cisplatin as in Arm A.
    Interventions:
    • Drug: Cisplatin
    • Drug: Gemcitabine Hydrochloride
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 2, 2015)
90
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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])
  • 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
  • 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 M6620 (VX970); these potential risks may also apply to other agents used in this study
  • Patients with >= grade 2 neuropathy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02567409
Other Study ID Numbers  ICMJE 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 No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sumanta K Pal City of Hope Comprehensive Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP