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Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer

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ClinicalTrials.gov Identifier: NCT03451331
Recruitment Status : Recruiting
First Posted : March 1, 2018
Last Update Posted : February 8, 2019
Sponsor:
Collaborators:
Bristol-Myers Squibb
Hoosier Cancer Research Network
Information provided by (Responsible Party):
Matthew Galsky, Hoosier Cancer Research Network

Tracking Information
First Submitted Date  ICMJE February 23, 2018
First Posted Date  ICMJE March 1, 2018
Last Update Posted Date February 8, 2019
Actual Study Start Date  ICMJE May 10, 2018
Estimated Primary Completion Date May 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 28, 2018)
Objective Response Rate (ORR) [ Time Frame: 1.5 years ]
(RECIST 1.1) to treatment with gemcitabine + carboplatin + nivolumab and gemcitabine + oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03451331 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2018)
  • Assess Safety [ Time Frame: 1.5 years ]
    Assess all adverse events according to the NCI Common Terminology Criteria for (NCI CTCAE) v4
  • Duration of Response [ Time Frame: 1.5 years ]
    Time from the first documentation of RECIST 1.1 response to the time of progression as per RECIST 1.1
  • Progression-Free Survival (PFS) [ Time Frame: 3 years ]
    Time from randomization to death or progression, depending on which occurs first
  • Overall Survival (OS) [ Time Frame: 3 years ]
    Time from randomization to death
Original Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2018)
  • Assess Safety [ Time Frame: 1.5 years ]
    Assess according to the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4
  • Duration of Response [ Time Frame: 1.5 years ]
    Time from the first documentation of RECIST 1.1 response to the time of progression as per RECIST 1.1
  • Progression-Free Survival (PFS) [ Time Frame: 3 years ]
    Time from randomization to death or progression, depending on which occurs first
  • Overall Survival (OS) [ Time Frame: 3 years ]
    Time from randomization to death
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer
Official Title  ICMJE Randomized Phase 2 Trial of Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer
Brief Summary This is a randomized phase 2 trial of gemcitabine + carboplatin + nivolumab or gemcitabine + oxaliplatin + nivolumab for the treatment of cisplatin-ineligible patients with metastatic urothelial cancer. Randomization will be stratified on the lymph node only (and/or unresectable primary) metastatic status.
Detailed Description Patients will be randomized to Arm A: gemcitabine plus carboplatin plus nivolumab versus Arm B: gemcitabine plus oxaliplatin plus nivolumab. Randomization will be stratified on the metastasis status (lymph node only vs. the rest). Patients on both treatment arms will receive up to 6 cycles of combination therapy in the absence of prohibitive adverse effects or disease progression. Patients with at least stable disease at the completion of 6 cycles of treatment may continue "maintenance" single agent nivolumab for up to 24 cycles. Patients who require discontinuation of chemotherapy (i.e., gemcitabine plus carboplatin or gemcitabine plus oxaliplatin) prior to Cycle 6, but who have at least stable disease, may be considered for ongoing treatment with single-agent nivolumab on the "maintenance" phase after discussion with the sponsor-investigator.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:
Open-label
Primary Purpose: Treatment
Condition  ICMJE Metastatic Urothelial Cancer
Intervention  ICMJE
  • Drug: Nivolumab
    Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting ~ 2-4 weeks after completing combination chemotherapy plus nivolumab)
    Other Name: OPDIVO®
  • Drug: Gemcitabine
    1000 mg/m^2
    Other Name: Gemzar
  • Drug: Carboplatin
    AUC 4.5 (based on the Calvert formula)
    Other Name: Paraplatin®
  • Drug: Oxaliplatin
    130 mg/m^2
    Other Name: Eloxatin
Study Arms  ICMJE
  • Experimental: Arm A
    Gemcitabine plus carboplatin plus nivolumab
    Interventions:
    • Drug: Nivolumab
    • Drug: Gemcitabine
    • Drug: Carboplatin
  • Experimental: Arm B
    Gemcitabine plus oxaliplatin plus nivolumab
    Interventions:
    • Drug: Nivolumab
    • Drug: Gemcitabine
    • Drug: Oxaliplatin
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: February 6, 2019)
48
Original Estimated Enrollment  ICMJE
 (submitted: February 28, 2018)
44
Estimated Study Completion Date  ICMJE December 1, 2020
Estimated Primary Completion Date May 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Subject must meet all the following applicable inclusion criteria to participate in this study:

  • Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  • Age ≥ 18 years at the time of consent.
  • Eastern Cooperative Oncology Group (ECOG) performance status of = 2
  • Able to comply with the study protocol, in the investigator's judgment.
  • Histologically documented, locally advanced (T4b, any N; or any T, N 2−3) or metastatic urothelial carcinoma (mUC) (M1, Stage IV) (also termed TCC or UCC of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra) Patients with mixed histologies are required to have a dominant transitional cell pattern. Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis (N2−N3).
  • Measurable disease, as defined by RECIST v1.1
  • Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (metastatic specimens preferable but if not available primary tumor specimens that are at least muscle-invasive are acceptable) in paraffin blocks (blocks preferred) or at least 15 unstained slides. Subjects without adequate archival tumor tissue or for whom a biopsy is not considered possible may be considered for enrollment on a case by case basis after discussion with the sponsor-investigator.
  • No prior chemotherapy for inoperable locally advanced or mUC. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval > 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naive in the metastatic setting.
  • Cisplatin-ineligible as defined by at least one of the following:

    • Calculated creatinine clearance ≥ 30 (Cockroft-Gault)
    • ECOG performance status of 2 or greater
    • CTCAE v4 Grade ≥ 2 audiometric hearing loss
  • Demonstrate adequate organ function. All screening labs to be obtained within 28 days prior to registration:

    • Hematological:

      • Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L
      • Hemoglobin (Hgb) ≥ 9 g/dL
      • Platelets ≥ 100 x 10^9/L
    • Renal:

      • Calculated creatinine clearance ≥ 30 mL/min (Cockroft-Gault)

    • Hepatic:

      • Bilirubin ≤ 1.5 × upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
      • Aspartate aminotransferase (AST) ≤ 3 × ULN
      • Alanine aminotransferase (ALT) ≤ 3 × ULN
  • Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception.
  • Women of childbearing potential must have a negative serum or urine pregnancy.
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

  • Active infection requiring systemic therapy.
  • Pregnant or breastfeeding
  • Any serious or uncontrolled medical disorder that, in the opinion of the site investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
  • Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured.
  • Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  • Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
  • Grade ≥ 2 neuropathy (NCI CTCAE version 4).
  • Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (RNA) or hepatitis C antibody (HCV antibody) indicating acute or chronic infection.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • Evidence of interstitial lung disease or active, non-infectious pneumonitis.
  • Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class III or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina.
  • Known left ventricular ejection fraction (LVEF) < 40% Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF 40%−50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
  • Solid organ or tissue transplant including stem cell transplant
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Matthew Galsky, M.D. 212-824-5452 matthew.galsky@mssm.edu
Contact: Ahran Lee 317.634.5842 ext 14 alee@hoosiercancer.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03451331
Other Study ID Numbers  ICMJE HCRN GU16-287
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Matthew Galsky, Hoosier Cancer Research Network
Study Sponsor  ICMJE Matthew Galsky
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Hoosier Cancer Research Network
Investigators  ICMJE
Principal Investigator: Matthew Galsky, M.D. Icahn School of Medicine at Mount Sinai; Tisch Cancer Institute
PRS Account Hoosier Cancer Research Network
Verification Date February 2019

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