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Brief Title: Trial of 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

INTRODUCTION

  • Org Study ID: HCRN GU16-287
  • Secondary ID: N/A
  • NTC ID: NCT03451331
  • Sponsor: Matthew Galsky
Hoosier Cancer Research Network Website

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.

  • Overall Status
    Active, not recruiting
  • Start Date
    May 10, 2018
  • Phase
    Phase 2
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Objective Response Rate (ORR)

Primary Outcome 1 - Timeframe: 1.5 years

CONDITION

  • Metastatic Urothelial Cancer

ELIGIBILITY

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 must have a negative serum or urine pregnancy. - Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception as stated for the timeline below. Male subjects are not required to use contraception.
NOTE: Women of childbearing potential is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.
NOTE: Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of investigational product.
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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Matthew Galsky, M.D.

Role: Principal Investigator

Affiliation: Icahn School of Medicine at Mount Sinai; Tisch Cancer Institute

Overall Contact

Name: Matthew Galsky, M.D.

Phone: N/A

Email: N/A

LOCATION

Facility Status Contact