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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03451331
Recruitment Status : Active, not recruiting
First Posted : March 1, 2018
Last Update Posted : April 11, 2023
Bristol-Myers Squibb
Hoosier Cancer Research Network
Information provided by (Responsible Party):
Matthew Galsky, Hoosier Cancer Research Network

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.

Condition or disease Intervention/treatment Phase
Metastatic Urothelial Cancer Drug: Nivolumab Drug: Gemcitabine Drug: Carboplatin Drug: Oxaliplatin Phase 2

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 12 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open-label
Primary Purpose: Treatment
Official Title: Randomized Phase 2 Trial of Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer
Actual Study Start Date : May 10, 2018
Estimated Primary Completion Date : July 1, 2023
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Arm A
Gemcitabine plus carboplatin plus nivolumab
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®

Experimental: Arm B
Gemcitabine plus oxaliplatin plus nivolumab
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: Oxaliplatin
130 mg/m^2
Other Name: Eloxatin

Primary Outcome Measures :
  1. 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

Secondary Outcome Measures :
  1. Assess Safety [ Time Frame: 1.5 years ]
    Assess all adverse events according to the NCI Common Terminology Criteria for (NCI CTCAE) v4

  2. 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

  3. Progression-Free Survival (PFS) [ Time Frame: 3 years ]
    Time from randomization to death or progression, depending on which occurs first

  4. Overall Survival (OS) [ Time Frame: 3 years ]
    Time from randomization to death

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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. If archival tissue is not available, subjects 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 must have a negative serum or urine pregnancy.
  • Women of childbearing potential (WOCBP) and male subjects must use appropriate method(s) of contraception as stated for the timeline below. Male subjects are not required to use contraception as outlined in protocol.

Exclusion Criteria:

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

  • Active infection requiring systemic therapy.
  • Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
  • 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).
  • Known positive result 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. Testing at screening is not required.
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03451331

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United States, Maryland
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States, 21287
United States, New Jersey
John Theuer Cancer Center
Hackensack, New Jersey, United States, 07601
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08903
United States, New York
Icahn School of Medicine: Tisch Cancer Institute at Mount Sinai Medical Center
New York, New York, United States, 10029
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Utah
Huntsman Cancer Institute University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
Matthew Galsky
Bristol-Myers Squibb
Hoosier Cancer Research Network
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Principal Investigator: Matthew Galsky, M.D. Icahn School of Medicine at Mount Sinai; Tisch Cancer Institute
Additional Information:
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Responsible Party: Matthew Galsky, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT03451331    
Other Study ID Numbers: HCRN GU16-287
First Posted: March 1, 2018    Key Record Dates
Last Update Posted: April 11, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Keywords provided by Matthew Galsky, Hoosier Cancer Research Network:
Additional relevant MeSH terms:
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Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors