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

Randomized Phase 2 Trial of Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Urothelial Cancer
• Intervention / Treatment: Drug: Nivolumab; Drug: Gemcitabine; Drug: Carboplatin; Drug: Oxaliplatin

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.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theuer Cancer Center
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine: Tisch Cancer Institute at Mount Sinai Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: OPDIVO®; Drug: Gemcitabine; 1000 mg/m^2; Other Names: Gemzar; Drug: Carboplatin; AUC 4.5 (based on the Calvert formula); Other Names: 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 Names: OPDIVO®; Drug: Gemcitabine; 1000 mg/m^2; Other Names: Gemzar; Drug: Oxaliplatin; 130 mg/m^2; Other Names: Eloxatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	(RECIST 1.1) to treatment with gemcitabine + carboplatin + nivolumab and gemcitabine + oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer	1.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess Safety	Assess all adverse events according to the NCI Common Terminology Criteria for (NCI CTCAE) v4	1.5 years
Duration of Response	Time from the first documentation of RECIST 1.1 response to the time of progression as per RECIST 1.1	1.5 years
Progression-Free Survival (PFS)	Time from randomization to death or progression, depending on which occurs first	3 years
Overall Survival (OS)	Time from randomization to death	3 years

Collaborators and Investigators

• Sponsor: Matthew Galsky
• Collaborators: Bristol-Myers Squibb; Hoosier Cancer Research Network
• Investigators: Principal Investigator: Matthew Galsky, M.D., Icahn School of Medicine at Mount Sinai; Tisch Cancer Institute

Publications and helpful links

Helpful Links

• Hoosier Cancer Research Network Website

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2018
• Primary Completion (Actual): June 7, 2023
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: February 23, 2018
• First Submitted That Met QC Criteria: February 28, 2018
• First Posted (Actual): March 1, 2018

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: oxaliplatin; carboplatin; gemcitabine; nivolumab; cisplatin-ineligible
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Carboplatin; Oxaliplatin; Nivolumab; Gemcitabine
• Other Study ID Numbers: HCRN GU16-287

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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