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

• ClinicalTrials.gov Identifier: NCT03451331
• Recruitment Status: Recruiting
• First Posted: March 1, 2018
• Last Update Posted: March 8, 2021
• 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

• 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, 2021
• Estimated Study Completion Date: December 1, 2022

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

• 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 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

Contacts and Locations

Contacts

Contact: Matthew Galsky, M.D.; 212-824-5452; matthew.galsky@mssm.edu

Contact: Ahran Lee; 317.634.5842 ext 14; alee@hoosiercancer.org

Locations

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

• 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 

• Responsible Party: Matthew Galsky, Sponsor-Investigator, Hoosier Cancer Research Network
• ClinicalTrials.gov Identifier: NCT03451331
• Other Study ID Numbers: HCRN GU16-287
• First Posted: March 1, 2018
• Last Update Posted: March 8, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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:

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