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

• Sponsor: Matthew Galsky
• Collaborators: Bristol-Myers Squibb; Hoosier Cancer Research Network
• Information provided by (Responsible Party): Matthew Galsky, Hoosier Cancer Research Network

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Metastatic Urothelial Cancer	Drug: Nivolumab; Drug: Gemcitabine; Drug: Carboplatin; Drug: Oxaliplatin	Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	48 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Masking Description:	Open-label
Primary Purpose:	Treatment
Official Title:	Randomized Phase 2 Trial of Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer
Actual Study Start Date :	May 10, 2018
Estimated Primary Completion Date :	May 1, 2020
Estimated Study Completion Date :	December 1, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) [ Time Frame: 1.5 years ]
   (RECIST 1.1) to treatment with gemcitabine + carboplatin + nivolumab and gemcitabine + oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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 (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 (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

Contacts and Locations

Contacts

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Contact: Matthew Galsky, M.D.	212-824-5452	matthew.galsky@mssm.edu
Contact: Ahran Lee	317.634.5842 ext 14	alee@hoosiercancer.org

Locations

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United States, Maryland
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Recruiting
Baltimore, Maryland, United States, 21287
Contact: Victoria Sinibaldi 410-614-3209 sinibvi@jhmi.edu
Principal Investigator: Jean Hoffman-Censits, MD
United States, New Jersey
John Theuer Cancer Center	Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Peter O'Rourke 551-996-5954 PORourke@Hackensackumc.org
Principal Investigator: Robert Alter, MD
Rutgers Cancer Institute of New Jersey	Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Tracie Saunders 732-235-8861 ks13@cinj.rutgers.edu
Principal Investigator: Tina Mayer, MD
United States, New York
Icahn School of Medicine: Tisch Cancer Institute at Mount Sinai Medical Center	Recruiting
New York, New York, United States, 10029
Contact: Matthew Galsky, M.D. 212-241-8214 matthew.galsky@mssm.edu
United States, Tennessee
Vanderbilt-Ingram Cancer Center	Recruiting
Nashville, Tennessee, United States, 37232
Contact: Matthew Fister 615-875-9979 matthew.c.fister@vumc.org
Principal Investigator: David Chism, MD
United States, Utah
Huntsman Cancer Institute University of Utah	Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Jamie White 801-213-6106 Jamie.White@hci.utah.edu
Principal Investigator: Benjamin Maughan, MD

Sponsors and Collaborators

Matthew Galsky

Bristol-Myers Squibb

Hoosier Cancer Research Network

Investigators

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Principal Investigator:	Matthew Galsky, M.D.	Icahn School of Medicine at Mount Sinai; Tisch Cancer Institute

More Information

Additional Information:

Hoosier Cancer Research Network Website 

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Responsible Party:	Matthew Galsky, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier:	NCT03451331 History of Changes
Other Study ID Numbers:	HCRN GU16-287
First Posted:	March 1, 2018
Last Update Posted:	February 8, 2019
Last Verified:	February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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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

Keywords provided by Matthew Galsky, Hoosier Cancer Research Network:

cisplatin-ineligible; gemcitabine; carboplatin; nivolumab; oxaliplatin

Additional relevant MeSH terms:

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Cisplatin; Gemcitabine; Carboplatin; Oxaliplatin; Nivolumab; Antineoplastic Agents; Antimetabolites, Antineoplastic; Antimetabolites	Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents, Immunological