Gemcitabine Hydrochloride and Nivolumab with Carboplatin or Oxaliplatin in Treating Patients with Locally Advanced or Metastatic Urothelial Cancer
- Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
- 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 transitional cell cancer [TCC] or urothelial cell cancer [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 but =< 60 mL/min (Cockcroft-Gault) * ECOG performance status = 2 * CTCAE v4 grade >= 2 audiometric hearing loss
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained within 28 days prior to registration)
- Hemoglobin (Hgb) >= 9 g/dL (obtained within 28 days prior to registration)
- Platelets >= 100 x 10^9/L (obtained within 28 days prior to registration)
- Calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior to registration)
- Bilirubin =< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL) (obtained within 28 days prior to registration)
- Aspartate aminotransferase (AST) =< 3 x ULN (obtained within 28 days prior to registration)
- Alanine aminotransferase (ALT) =< 3 x ULN (obtained within 28 days prior to registration)
- 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 * 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. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days * HIGHLY EFFECTIVE METHODS OF CONTRACEPTION ** Male condoms with spermicide ** Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject’s WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug ** Nonhormonal IUDs, such as ParaGard ** Tubal ligation ** Vasectomy ** Complete Abstinence *** Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence * LESS EFFECTIVE METHODS OF CONTRACEPTION ** Diaphragm with spermicide ** Cervical cap with spermicide ** Vaginal sponge ** Male Condom without spermicide ** Progestin only pills by WOCBP subject or male subject’s WOCBP partner ** Female condom (a male and female condom must not be used together)
- Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year
- 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 (National Cancer Institute [NCI] CTCAE version 4)
- Positive 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
Salt Lake City
I. Estimate the objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) to treatment with gemcitabine hydrochloride (gemcitabine) + carboplatin + nivolumab and gemcitabine + oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer.
I. Determine the safety of gemcitabine + carboplatin + nivolumab and gemcitabine + oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer (Common Terminology Criteria for Adverse Events [CTCAE] version [v]4).
II. Estimate the duration of response to treatment with gemcitabine + carboplatin + nivolumab and gemcitabine + oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer.
III. Estimate the progression-free survival.
IV. Estimate the overall survival.
I. Explore the effects of treatment on peripheral blood biomarkers of immune modulation and immunogenic cell death.
II. Explore the impact of genomic/genetic alterations, including deoxyribonucleic acid (DNA) damage response gene alterations, on clinical outcomes.
III. Explore the tumor immune microenvironment including the composition and frequency of immune cells and expression of immune checkpoints in archival tumor tissue and the relationship with clinical outcomes.
OUTLINE: Participants are randomized into 1 of 2 arms.
ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, gemcitabine hydrochloride IV on days 1 and 8, and carboplatin IV on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity. Patients with at least stable disease continue to receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unaccepted toxicity.
ARM B: Patients receive nivolumab IV over 30 minutes on day 1, gemcitabine hydrochloride IV on days 1 and 8, and oxaliplatin IV on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity. Participants with at least stable disease continue to receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unaccepted toxicity.
After completion of study treatment, participants are followed up at 30 days, every 3 months for 1.5 years, every 6 months for 1.5 years, yearly for 2 years, and then every 6 months for 2 years.
Trial Phase Phase II
Trial Type Treatment
Icahn School of Medicine at Mount Sinai
Matthew David Galsky
- Primary ID 17-2064
- Secondary IDs NCI-2018-01332, HCRN GU16-287
- Clinicaltrials.gov ID NCT03451331