Clinical Trials /

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

NCT03451331

Description:

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.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU16-287
  • NCT ID: NCT03451331

Conditions

  • Metastatic Urothelial Cancer

Interventions

DrugSynonymsArms
NivolumabOPDIVO®Arm A
GemcitabineGemzarArm A
CarboplatinParaplatin®Arm A
OxaliplatinEloxatinArm B

Purpose

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 metastasis status (lymph node only vs. other metastatic sites).

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalGemcitabine plus carboplatin plus nivolumab
  • Nivolumab
  • Gemcitabine
  • Carboplatin
Arm BExperimentalGemcitabine plus oxaliplatin plus nivolumab
  • Nivolumab
  • Gemcitabine
  • Oxaliplatin

Eligibility Criteria

        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 but </= 60 mL/min (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 30-60 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Matthew Galsky

Trial Keywords

  • cisplatin-ineligible
  • gemcitabine
  • carboplatin
  • nivolumab
  • oxaliplatin

Last Updated

April 23, 2018