Clinical trial NCT03451331: Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Urothelial Cancer
Keywords: cisplatin-ineligible
gemcitabine
carboplatin
nivolumab
oxaliplatin
Lead sponsor: Hoosier Cancer Research Network
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: Hoosier Cancer Research Network
First posted: 2018-03-01
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

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. 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

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to a maximum of 50 months
Secondary outcomes:
measure: Adverse Events
timeFrame: AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 19 months.
measure: Duration of Response (DOR)
timeFrame: Up to a maximum of 50 months
measure: Progression-Free Survival (PFS)
timeFrame: Up to maximum of 50 months
measure: Overall Survival (OS)
timeFrame: Up to a maximum of 53 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Hackensack
country: United States
facility: John Theuer Cancer Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: Icahn School of Medicine: Tisch Cancer Institute at Mount Sinai Medical Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute University of Utah
state: Utah
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai; Tisch Cancer Institute
name: Matthew Galsky, M.D.
role: PRINCIPAL_INVESTIGATOR
References: