Nivolumab with or without Urelumab before Surgery in Treating Participants with Muscle-Invasive Bladder Urothelial Cancer

Status: Active

Description

This randomized phase II trial studies how well nivolumab with or without urelumab before surgery works in treating participants with bladder urothelial cancer that has spread into the muscle tissue. Monoclonal antibodies, such as nivolumab and urelumab, may interfere with the ability of tumor cells to grow and spread. Giving nivolumab and urelumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed muscle-invasive urothelial carcinoma of the bladder defined as T2-T4 stage; mixed histologies are acceptable provided urothelial carcinoma is the predominant histology (≥ 50%); patients with > 50% non- urothelial carcinoma histologies or any component of small cell carcinoma are not eligible; resectable clinical node-positive (N1) patients are eligible provided the lymph nodes are confined to the true pelvis and are within the planned surgical lymph node dissection template
  • Sufficient baseline tumor tissue available to perform tumor infiltrating CD8+ T-cell density assessment; (NOTE: The actual CD8+ T-cell density assessment does not need to be performed prior to registration, however the slides must be reviewed prior to registration to ensure that adequate tissue will be available for the pre-treatment tumor infiltrating CD8+ T-cell density assessment)
  • Medically fit to undergo cystectomy
  • Ineligible to receive cisplatin-based neoadjuvant chemotherapy based upon at least one of the following criteria: * Creatinine clearance < 60 ml/min * Eastern Cooperative Oncology Group (ECOG) performance status = 2 * Grade ≥ 2 hearing loss * Grade ≥ 2 neuropathy * New York Heart Association class III heart failure
  • Absolute neutrophil count (ANC) ≥ 1.5 K/mm^3 (must be stable off any growth factor within 4 weeks of first study drug administration)
  • Platelets ≥ 100 K/mm^3 (transfusion to achieve this level is not permitted within 2 weeks of first study drug administration)
  • Hemoglobin (Hgb) ≥ 9 g/dL
  • Serum total bilirubin: ≤ 1.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN
  • Serum creatinine clearance (CrCl) ≥ 30 mL/min using the Cockcroft- Gault equation
  • Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria

  • Patients with locally advanced unresectable or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 28 days prior to study registration; the required radiographic imaging includes: * Abdomen/Pelvis – computed tomography (CT) scan * Chest – chest x-ray or CT scan
  • Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma; (NOTE: Patients with history of non-invasive [Ta, Tis] upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment [i.e. cytology, biopsy, imaging] that demonstrates no evidence of residual disease are eligible)
  • Patients with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer; patients that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment
  • Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
  • Patients who have received prior therapy with immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4) or immune costimulatory molecules (e.g. anti-CD137, anti-OX40, anti-GITR) directed agents
  • Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have not recovered from radiotherapy toxicities
  • Patients who have undergone major surgery (e.g. intra-thoracic, intra- abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures (i.e. transurethral resection of bladder tumor [TURBT]), percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
  • Patients with history of alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis
  • Patient with history of prior solid organ or allogeneic bone marrow transplant
  • Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: * Clinically significant cardiac diseases, including any of the following: ** History or presence of serious uncontrolled ventricular arrhythmias ** Clinically significant resting bradycardia ** Any of the following within 3 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE) ** Uncontrolled hypertension defined by a systolic blood pressure (SBP) ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mm Hg, with or without anti-hypertensive medication(s) * Cirrhosis, chronic active hepatitis or chronic persistent hepatitis * Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) * Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy; usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted; for questions, please consult the study chair * Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
  • Pregnant or breast-feeding women
  • Women of child-bearing potential, who are biologically able to conceive, and not employing two forms of highly effective contraception; highly effective contraception must be used throughout the trial and up to 7 months after the last dose of study drug (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device); women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to starting study drug
  • Fertile males not willing to use contraception, as stated above
  • Patients unwilling or unable to comply with the protocol

Locations & Contacts

California

Los Angeles
UCLA / Jonsson Comprehensive Cancer Center
Status: Approved
Contact: Karim Chamie
Phone: 310-794-2526
Email: kchamie@mednet.ucla.edu

Colorado

Aurora
University of Colorado Hospital
Status: Approved
Contact: Elizabeth Riley Kessler
Phone: 720-848-0170
Email: Elizabeth.kessler@ucdenver.edu

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: Approved
Contact: Gary David Steinberg
Phone: 773-702-8222
Email: gsteinbe@surgery.bsd.uchicago.edu

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Noah M. Hahn
Phone: 443-287-0553
Email: nhahn4@jhmi.edu

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: Approved
Contact: Christopher Burch Anderson
Phone: 212-305-0114
Email: cba2125@cumc.columbia.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To compare the post-treatment tumor infiltrating CD8+ T-cell density at cystectomy in cisplatin-ineligible muscle invasive urothelial carcinoma of the bladder (MIBC) patients treated with neoadjuvant nivolumab plus urelumab (Arm A) versus (vs.) nivolumab alone (Arm B).

SECONDARY OBJECTIVES:

I. Describe the safety profile of nivolumab plus urelumab (Arm A) and nivolumab monotherapy (Arm B) as assessed according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).

II. Estimate and compare the proportions of patients achieving pathologic response (< pT2N0) with neoadjuvant nivolumab and urelumab (Arm A) and nivolumab monotherapy (Arm B).

III. Assess the prognostic value of tumor biopsy PD-1 and PD-L1 expression and change in expression, as assessed by immunohistochemistry (IHC) analysis, for pathologic tumor response, as defined by cystectomy pathologic staging < pT2N0, in cisplatin-ineligible MIBC patients treated with nivolumab.

IV. Estimate and compare the proportions of patients achieving pathologic complete response (pT0N0) with neoadjuvant nivolumab and urelumab (Arm A) and nivolumab monotherapy (Arm B).

V. Assess the prognostic value of tumor biopsy PD-1 and PD-L1 expression and change in expression, as assessed by immunohistochemistry (IHC) analysis, for pathologic complete response, as defined by cystectomy pathologic staging pT0N0, in cisplatin-ineligible MIBC patients treated with nivolumab.

VI. Assess the prognostic value of tumor biopsy 4-1BB (CD137) and 4-1BB ligand (CD137L) expression and change in expression, as assessed by immunohistochemistry (IHC) analysis, for pathologic tumor response, as defined by cystectomy pathologic staging < pT2N0, in cisplatin-ineligible MIBC patients treated with urelumab.

VII. Assess the prognostic value of tumor biopsy 4-1BB (CD137) expression and change in expression, as assessed by immunohistochemistry (IHC) analysis, for pathologic complete response, as defined by cystectomy pathologic staging pT0N0, in cisplatin-ineligible MIBC patients treated with urelumab.

VIII. Assess the prognostic value of peripheral blood mononuclear cell (PBMC) T- cell subset status (%CD4+ T-cells, %CD8+ T-cells, %T-regulatory (Treg) T-cells, %myeloid derived suppressor cells, %natural killer cells, etc.) and change in status, as assessed by flow cytometry analysis, for pathologic tumor response, as defined by cystectomy pathologic staging < pT2N0, in cisplatin-ineligible MIBC patients treated with nivolumab and/or urelumab.

IX. Assess the prognostic value of peripheral blood mononuclear cell (PBMC) T- cell subset status (%CD4+ T-cells, %CD8+ T-cells, %Treg T-cells, %myeloid derived suppressor cells, %natural killer cells, etc.) and change in status, as assessed by flow cytometry analysis, for pathologic complete response, as defined by cystectomy pathologic staging pT0N0, in cisplatin-ineligible MIBC patients treated with nivolumab and/or urelumab.

EXPLORATORY OBJECTIVES:

I. To compare the post-treatment %CD8+ tumor infiltrating cells at cystectomy in cisplatin-ineligible MIBC patients treated with neoadjuvant nivolumab plus urelumab (Arm A) vs. nivolumab alone (Arm B).

II. To compare the post-treatment total CD8+ T-cell density at cystectomy in cisplatin-ineligible MIBC patients treated with neoadjuvant nivolumab plus urelumab (Arm A) vs. nivolumab alone (Arm B).

III. To assess the prognostic relationship between post-treatment natural killer cell (NK-cell) activation and pathologic tumor response and pathologic complete response, defined by cystectomy pathologic staging < pT2N0 and pT0N0 respectively in cisplatin-ineligible MIBC patients treated with nivolumab and/or urelumab.

IV. Assess the prognostic value of plasma cytokine markers of interest (i.e. IFN-alpha, TGF-beta, IL-10, IL-4, IL-5, IL-13, IFN-gamma) and changes in these markers for pathologic tumor response and pathologic complete response, defined by cystectomy pathologic staging < pT2N0 and pT0N0 respectively, in cisplatin- ineligible MIBC patients treated with nivolumab and/or urelumab.

V. Assess the prognostic value of tumor and/or tumor infiltrating lymphocyte gene mutation, expression, and methylation signatures for pathologic tumor response and pathologic complete response, defined by cystectomy pathologic staging < pT2N0 and pT0N0 respectively, in cisplatin-ineligible MIBC patients treated with nivolumab and/or urelumab.

VI. Assess the prognostic value of serum circulating antibody profiles on pathologic tumor response and pathologic complete response defined by cystectomy pathology staging < pT2N0 and pT0N0 respectively in cisplatin- ineligible MIBC patients treated with nivolumab and/or urelumab.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM A: Participants receive nivolumab intravenously (IV) over approximately 60 minutes on days 1 and 15 and urelumab IV over approximately 60 minutes on day 1. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Participants then undergo cystectomy within 42 days of the completion of nivolumab and urelumab.

ARM B: Participants receive nivolumab as in Arm A. Participants then undergo cystectomy within 42 days of the completion of nivolumab.

After completion of study treatment, participants are followed up at 1 and 3 months, and then every 3 months for up to 2 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Noah M. Hahn

Trial IDs

Primary ID J1682
Secondary IDs NCI-2018-00385, IRB00103062, CRMS-64455
Clinicaltrials.gov ID NCT02845323