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

• ClinicalTrials.gov Identifier: NCT03532451
• Recruitment Status: Completed
• First Posted: May 22, 2018
• Results First Posted: September 1, 2021
• Last Update Posted: November 8, 2022
• Sponsor: PrECOG, LLC.
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): PrECOG, LLC.

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Bladder Cancer	Drug: Nivolumab; Drug: Nivolumab/Lirilumab	Phase 1

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 that are either cisplatin-ineligible or refuse cisplatin-based chemotherapy and have MIBC (T2-T4a, N0-N1, M0).Neoadjuvant treatment must start within 10 weeks of transurethral resection of the most recent 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 (Completed November 20, 2019).

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 43 participants
• 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)
• Primary Purpose: Treatment
• Official Title: Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer
• Actual Study Start Date: March 22, 2019
• Actual Primary Completion Date: November 27, 2020
• Actual Study Completion Date: October 5, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1: Nivolumab; Nivolumab 480 mg IV on week 0 and week 4	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
Experimental: Cohort 2: Nivolumab/Lirilumab; Nivolumab 480 mg IV and Lirilumab 240 mg on week 0 and week 4	Drug: Nivolumab/Lirilumab; 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.; Other Names: Opdivo; BMS-986015

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE V5.0 [ Time Frame: 19 weeks ]
   Number of patients with Grade 3 or higher adverse events (AEs) related to nivolumab and nivolumab/lirilumab

Secondary Outcome Measures :

1. Complete Response Rate [ Time Frame: 20 months ]
   Measured by pathologic complete (pT0N0) and partial (<pT2N0) response rate at time of RC in the two cohorts
2. Two Year Recurrence-free Survival [ Time Frame: 24 months ]
   Measured by recurrence rate after 2 years following the RC in the two cohorts. Secondary Endpoints are still being followed and no results can be entered at this time.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Florida

Moffitt Cancer Center

Tampa, Florida, United States, 33612

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10461

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

United States, Ohio

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239

United States, Texas

University of TX Southwestern

Dallas, Texas, United States, 75390

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22903

United States, Washington

University of Washington

Seattle, Washington, United States, 98109

Sponsors and Collaborators

PrECOG, LLC.

Bristol-Myers Squibb

Investigators

• Study Chair: Petros Grivas, MD, PhD; University of Washington

  Study Documents (Full-Text)

Documents provided by PrECOG, LLC.:

Study Protocol  [PDF] December 10, 2019

Statistical Analysis Plan  [PDF] February 6, 2020

More Information

• Responsible Party: PrECOG, LLC.
• ClinicalTrials.gov Identifier: NCT03532451
• Other Study ID Numbers: PrE0807; CA209-9DF ( Other Identifier: BMS )
• First Posted: May 22, 2018
• Results First Posted: September 1, 2021
• Last Update Posted: November 8, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Data is proprietary.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by PrECOG, LLC.:

Muscle-Invasive; Cisplatin-Ineligible; Nivolumab; Lirilumab

Additional relevant MeSH terms:

Urinary Bladder Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action