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Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer (PrE0807)

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ClinicalTrials.gov Identifier: NCT03532451
Recruitment Status : Recruiting
First Posted : May 22, 2018
Last Update Posted : July 19, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
PrECOG, LLC.

Tracking Information
First Submitted Date  ICMJE May 10, 2018
First Posted Date  ICMJE May 22, 2018
Last Update Posted Date July 19, 2019
Actual Study Start Date  ICMJE March 22, 2019
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 10, 2018)
Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE V5.0 [ Time Frame: 30 months ]
Number of patients with Grade 3 or higher adverse events (AEs) related to nivolumab and nivolumab/lirilumab
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03532451 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2018)
  • Change in CD8+ Tumor-Infiltrating Lymphocytes (TIL) Density [ Time Frame: 54 months ]
    Change (#) in CD8+ TIL density from pre-treatment TURBT to post-treatment RC tissues in patients treated with nivolumab and nivolumab/lirilumab
  • Percent Change in CD8+ TIL Density [ Time Frame: 54 months ]
    Percent change in CD8+ TIL density from pre-treatment TURBT to post-treatment RC tissues in patients treated with nivolumab and nivolumab/lirilumab
  • Number of Patients unable to undergo RC [ Time Frame: 30 months ]
    Number of patients in each cohort who do not get RC within 6 weeks after completion of neoadjuvant treatment related to treatment-related AEs
  • Complete Response Rate [ Time Frame: 30 months ]
    Measured by pathologic complete (pT0N0) and partial (<pT2N0) response rate at time of RC in the two cohorts
  • Recurrence-Free Survival (RFS) [ Time Frame: 54 months ]
    Rate of RFS at the two-year time point from the time of registration in patients treated with nivolumab and nivolumab/lirilumab
  • Immunohistochemistry (IHC) Change [ Time Frame: 54 months ]
    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
  • Peripheral Blood Mononuclear Cell (PBMC) T-Cell Subset Change [ Time Frame: 54 months ]
    %CD4+ T-cells will be assessed via flow cytometry and the change will be measured
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer
Official Title  ICMJE Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer
Brief Summary

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Cohort 1: Nivolumab alone. 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)
Primary Purpose: Treatment
Condition  ICMJE Bladder Cancer
Intervention  ICMJE
  • Drug: Nivolumab
    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.
    Other Name: Opdivo
  • Drug: Nivolumab/Lirilumab
    Nivolumab 480 mg IV over approximately 30 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.
    Other Names:
    • Opdivo
    • BMS-986015
Study Arms  ICMJE
  • Experimental: Cohort 1: Nivolumab
    Nivolumab 480 mg IV on week 0 and week 4
    Intervention: Drug: Nivolumab
  • Experimental: Cohort 2: Nivolumab/Lirilumab
    Nivolumab 480 mg IV and Lirilumab 240 mg on week 0 and week 4
    Intervention: Drug: Nivolumab/Lirilumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 10, 2018)
43
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2022
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Carolyn Andrews, RN 267-207-4070 candrews@precogllc.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03532451
Other Study ID Numbers  ICMJE PrE0807
CA209-9DF ( Other Identifier: BMS )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Data is proprietary.
Responsible Party PrECOG, LLC.
Study Sponsor  ICMJE PrECOG, LLC.
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Study Chair: Petros Grivas, MD, PhD University of Washington
PRS Account PrECOG, LLC.
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP