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Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

NCT03532451

Description:

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.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer
  • Official Title: Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

Clinical Trial IDs

  • ORG STUDY ID: PrE0807
  • SECONDARY ID: CA209-9DF
  • NCT ID: NCT03532451

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
NivolumabOpdivoCohort 1: Nivolumab
Nivolumab/LirilumabOpdivo, BMS-986015Cohort 2: Nivolumab/Lirilumab

Purpose

Patients with muscle-invasive bladder cancer (MIBC) who can not receive 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.

Detailed Description

      Bladder cancer (BC) is the 6th most common malignancy in the United States with an estimated
      79,030 new cases and 16,870 deaths in 2017. It is the 4th most common cancer in men and there
      are presently >500,000 BC patients alive in the US. It accounts for about 5% of all new
      cancers in the US. It is also the most expensive cancer to treat from diagnosis to death.
      Almost a third of BC patients present with MIBC.

      This is a Phase Ib open-label clinical trial for patients with cisplatin-ineligible MIBC
      (Stage T2-T4a, N0-N1, M0). Neoadjuvant treatment must start within 8 weeks of transurethral
      resection of the first transurethral resection of bladder tumor (TURBT) that showed
      muscularis propria invasion.

      Patients must have sufficient baseline tumor tissue. Tumor tissue content for CD8+ T-cell
      density assessment must be qualified as sufficient (≥ 20% tumor content in the specimen) for
      analysis and must be documented by the local pathologist prior to registration.

      The first 12 patients will be enrolled into Cohort 1 and treated with nivolumab before a
      planned RC.

      In the absence of the occurrence of high rate of treatment related Adverse Events (AEs) with
      nivolumab, the study will proceed with enrollment into Cohort 2 with the combination of
      nivolumab/lirilumab before a planned RC.

      Each group will receive a total of 2 doses (week 0 and 4) of nivolumab (Cohort 1) or
      nivolumab/lirilumab (Cohort 2) therapy followed by RC with bilateral (standard or extended)
      pelvic lymph node dissection (PLND).

      Mandatory tumor tissue at Screening (archived tumor tissue from Transurethral Resection of
      Bladder Tumor [TURBT] may be used) and at time of RC. Peripheral blood and urine samples are
      also required.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: NivolumabExperimentalNivolumab 480 mg IV on week 0 and week 4
  • Nivolumab
Cohort 2: Nivolumab/LirilumabExperimentalNivolumab 480 mg IV and Lirilumab 240 mg on week 0 and week 4
  • Nivolumab/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 initial TURBT that showed muscularis propria invasion should be within 8 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:

               -  Creatinine clearance(CrCl) <60 mL/min with Easter Cooperative Oncology Group
                  (ECOG) Performance Status (PS) 0-1

               -  Hearing impaired ≥ Grade 2 by CTCAE criteria

               -  Neuropathy ≥ Grade 2 by CTCAE criteria

               -  Heart failure New York Heart Association (NYHA) ≥ III

          -  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 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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE V5.0
Time Frame:30 months
Safety Issue:
Description:Number of patients with Grade 3 or higher adverse events (AEs) related to nivolumab and nivolumab/lirilumab

Secondary Outcome Measures

Measure:Change in CD8+ Tumor-Infiltrating Lymphocytes (TIL) Density
Time Frame:54 months
Safety Issue:
Description:Change (#) in CD8+ TIL density from pre-treatment TURBT to post-treatment RC tissues in patients treated with nivolumab and nivolumab/lirilumab
Measure:Percent Change in CD8+ TIL Density
Time Frame:54 months
Safety Issue:
Description:Percent change in CD8+ TIL density from pre-treatment TURBT to post-treatment RC tissues in patients treated with nivolumab and nivolumab/lirilumab
Measure:Number of Patients unable to undergo RC
Time Frame:30 months
Safety Issue:
Description:Number of patients in each cohort who do not get RC within 6 weeks after completion of neoadjuvant treatment related to treatment-related AEs
Measure:Complete Response Rate
Time Frame:30 months
Safety Issue:
Description:Measured by pathologic complete (pT0N0) and partial (<pT2N0) response rate at time of RC in the two cohorts
Measure:Recurrence-Free Survival (RFS)
Time Frame:54 months
Safety Issue:
Description:Rate of RFS at the two-year time point from the time of registration in patients treated with nivolumab and nivolumab/lirilumab
Measure:Immunohistochemistry (IHC) Change
Time Frame:54 months
Safety Issue:
Description:Change in expression for pathologic partial and complete tumor response (defined by cystectomy pathologic staging <pT2N0 and pT0N0, respectively), in patients treated with nivolumab and nivolumab/lirilumab
Measure:Peripheral Blood Mononuclear Cell (PBMC) T-Cell Subset Change
Time Frame:54 months
Safety Issue:
Description:%CD4+ T-cells will be assessed via flow cytometry and the change will be measured

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:PrECOG, LLC.

Trial Keywords

  • Muscle-Invasive
  • Cisplatin-Ineligible
  • Nivolumab
  • Lirilumab

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