Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer
Condition: Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms
Intervention: Nivolumab; Nivolumab/Lirilumab
Intervention description: Nivolumab 480 mg intravenously (IV) over approximately 30 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) followed by RC with bilateral (standard or extended) PLND as soon as possible but within 6 weeks after the last neoadjuvant infusion.; Nivolumab 480 mg IV over approximately 60 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) with at least a 30 minute rest between infusions followed by lirilumab 240 mg IV over approximately 60 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) followed by RC with bilateral (standard or extended) PLND as soon as possible but within 6 weeks after the last neoadjuvant infusion.
Intervention MeSH terms: Nivolumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Cohort 1: Nivolumab alone (Completed November 20, 2019). In the absence of the occurrence of high rate of treatment related adverse events, the study will proceed with enrollment into Cohort 2: Nivolumab/Lirilumab.
Masking: None (Open Label)
Enrollment: 43.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Muscle-Invasive; Cisplatin-Ineligible; Nivolumab; Lirilumab

Summary:

      Patients with muscle-invasive bladder cancer (MIBC) who can not receive cisplatin or refuse
      cisplatin therapy will receive nivolumab or nivolumab/lirilumab before a planned surgical
      procedure called a radical cystectomy (RC) to remove the bladder.

      Nivolumab works by attaching to and blocking a molecule called Programmed Death-1 (PD-1).
      Lirilumab attaches to and blocks a group of molecules called Killer Cell Immunoglobulin-Like
      Receptor (KIR). PD-1 and KIR are proteins present mainly on immune system cells, and each
      controls part of the immune system by shutting it down. It is hoped that by binding to and
      inactivating these proteins, these drugs can enhance the body's ability to detect, attack and
      destroy cancer cells.

      The purpose of this research study is to see whether nivolumab alone or combination of
      nivolumab and lirilumab given before surgery is effective in treating people who have bladder
      cancer, and to examine the side effects, good and bad, associated with nivolumab and
      lirilumab.
    

Eligibility criteria:

        -  Patients must have histologically confirmed MIBC (T2-T4a, N0-N1, M0 per American Joint
             Commission on Cancer [AJCC]) pure or mixed histology urothelial carcinoma. Clinical
             node-positive (N1) patients are eligible provided the lymph nodes (LNs) are confined
             to the true pelvis and are within the planned surgical LN dissection template.

          -  The most recent TURBT that showed muscularis propria invasion should be within 10
             weeks prior to beginning study therapy. Patients must have sufficient baseline tumor
             tissue from either initial or repeat TURBTs. The local site pathologist will be asked
             to estimate and record the rough approximate percentage of viable tumor in the TURBT
             sample (initial or repeat TURBT with highest tumor content) to document at least 20%
             viable tumor content prior to registration.

          -  Patients must be ineligible for cisplatin-based chemotherapy due to any of the
             following below OR refused cisplatin-based chemotherapy:

               -  Creatinine clearance(CrCl) <60 mL/min with Easter Cooperative Oncology Group
                  (ECOG) Performance Status (PS) 0-1

               -  Creatinine clearance(CrCl) ≥ 60 mL/min with ECOG PS 2 (if patient fit for RC)

               -  Hearing impaired ≥ Grade 2 by CTCAE criteria

               -  Neuropathy ≥ Grade 2 by CTCAE criteria

               -  Patient refused cisplatin-based chemotherapy?

          -  Patients must be medically fit for TURBT and RC.

          -  Age ≥ 18 years.

          -  Ability to understand and willingness to sign Institutional Review Board
             (IRB)-approved informed consent.

          -  Willing to provide tumor tissue, blood, and urine samples for research.

          -  Adequate organ function as measured by the following criteria, obtained ≤ 4 weeks
             prior to registration:

               -  Absolute Neutrophil Count (ANC) ≥ 1000/mm³ (stable off growth factor within 4
                  weeks of first study drug administration)

               -  Platelets ≥ 100,000/mm³

               -  Hemoglobin ≥ 8 g/dL

               -  Serum Creatinine Clearance ≥ 30 mL/min using the Cockcroft-Gault formula

               -  Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x Upper
                  Limit of Normal (ULN)

               -  Total Bilirubin ≤ 1.5x ULN (in the absence of previously diagnosed Gilbert's
                  disease)

          -  Women must not be pregnant or breastfeeding since we do not know the effects of
             nivolumab and lirilumab on the fetus or breastfeeding child.

          -  Sexually active women of child-bearing potential with a non-sterilized male partner
             and sexually active men must agree to use 2 methods of adequate contraception
             (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the
             duration of study participation, and for 5 months for women and 7 months for men
             following last dose of study drugs.

          -  Active or prior documented autoimmune disease within the past 2 years prior to
             Screening or other immunosuppressive agent within 14 days of study treatment.

          -  Patients may not have locally advanced unresectable or metastatic urothelial carcinoma
             as assessed on baseline radiographic imaging obtained within 28 days prior to study
             registration.

          -  Patients may not have concurrent upper urinary tract (i.e. ureter, renal pelvis)
             invasive urothelial carcinoma. 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 may not have another malignancy that could interfere with the evaluation of
             safety or efficacy of the study drugs. Patients with a prior malignancy will be
             allowed without study chair approval in the following circumstances:

               -  Not currently active and diagnosed at least 3 years prior to the date of
                  registration.

               -  Non-invasive diseases such as low risk cervical cancer or any cancer in situ.

               -  Localized (early stage) cancer treated with curative intent (without evidence of
                  recurrence and intent for further therapy), and in which no systemic chemotherapy
                  was indicated.(e.g. low/intermediate risk prostate cancer, etc.).

          -  Patients may not have received any prior immune checkpoint inhibitor (i.e. anti-KIR,
             anti-PD-1, anti-PD-L1, or other).

          -  Patients may not have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
             intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer
             treatment ≤ 4 weeks prior to starting study drug, or patients who have had
             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 must not have clinically significant cardiac disease.

          -  Patients may not have chronic active liver disease or evidence of acute or chronic
             Hepatitis B Virus (HBV) or Hepatitis C (HCV).

          -  Patients may not have known diagnosis of human immunodeficiency virus (HIV) infection.
             Testing is not required in absence of clinical suspicion.

          -  Patients may not have known diagnosis of any condition (e.g. post-hematopoietic or
             solid visceral organ transplant, pneumonitis, 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.

          -  Patients with any serious and/or uncontrolled concurrent medical conditions (e.g.
             active or uncontrolled infection, uncontrolled diabetes) or psychiatric illness that
             could, in the investigator's opinion, cause unacceptable safety risks or potentially
             interfere with the completion of the treatment according to the protocol are not
             eligible.

          -  Patients may not have any live viral vaccine used for prevention of infectious
             diseases within 4 weeks prior to study drug(s).

          -  Patients unwilling or unable to comply with the protocol.