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

NCT03532451 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: PrE0807CA209-9DF
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 8

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.

Conditions

Bladder Cancer

Keywords

Muscle-Invasive; Cisplatin-Ineligible; Nivolumab; Lirilumab

Outcome Measures

Primary Outcomes (1)

• Grade 3 or Higher Treatment Related Adverse Events as Assessed by CTCAE V5.0

  To assess safety of treatment according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) manifested as the rate of Grade 3 or higher treatment related adverse events in patients treated with nivolumab (Cohort 1) or combination of nivolumab/lirilumab (Cohort 2). The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. Toxicity graded by CTCAE v5.0 scaling from 1-5 (mild to death). Grade 3 or higher events are those that are graded '3- severe or medically significant', 4- life-threatening consequences; urgent intervention indicated' or '5-Death related to AE'.

  16 months

Secondary Outcomes (5)

• Percentage of Participants With Pathologic Complete and Partial Response

  Responses was assessed at baseline and time of radical cystectomy (within 6 weeks after the last treatment), up to 6 months.

• Two Year Recurrence-free Survival

  24 months

• Rate of no RC Due to TRAEs

  from completion of neoadjuvant treatment to 6 weeks after

• Change in CD8+ TIL Density

  From pre-treatment Transurethral Resection of Bladder Tumor (TURBT) which happens 10 weeks (at most) before treatment to post-treatment Radical Cystectomy (RC), up to 6 months. RC was scheduled within 6 weeks after the last neoadjuvant infusion

• Percentage Change in CD8+ TIL Density

  The outcome was measured from pre-treatment Transurethral Resection of Bladder Tumor (TURBT) to Radical Cystectomy (RC), up to 6 months.TURBT was scheduled 10 weeks at most before the treatment. RC was scheduled within 6 weeks after the last treatment.

Study Arms (2)

Cohort 1: Nivolumab

EXPERIMENTAL

Nivolumab 480 mg IV on week 0 and week 4

Drug: Nivolumab

Cohort 2: Nivolumab/Lirilumab

EXPERIMENTAL

Nivolumab 480 mg IV and Lirilumab 240 mg on week 0 and week 4

Drug: Nivolumab/Lirilumab

Interventions

Nivolumab DRUG

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.

Also known as: Opdivo

Cohort 1: Nivolumab

Nivolumab/Lirilumab DRUG

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.

Also known as: Opdivo, BMS-986015

Cohort 2: Nivolumab/Lirilumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

* 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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• PrECOG, LLC.: lead
• Bristol-Myers Squibb: collaborator

Study Sites (8)

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

University of TX Southwestern

Dallas, Texas, 75390, United States

Location

University of Virginia

Charlottesville, Virginia, 22903, United States

Location

University of Washington

Seattle, Washington, 98109, United States

Location

Related Publications (1)

• Grivas P, Koshkin VS, Chu X, Cole S, Jain RK, Dreicer R, Cetnar JP, Sundi D, Gartrell BA, Galsky MD, Woo B, Li-Ning-Tapia E, Hahn NM, Carducci MA. PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy. Eur Urol Oncol. 2024 Aug;7(4):914-922. doi: 10.1016/j.euo.2023.11.022. Epub 2023 Dec 27.

  PMID: 38155060 RESULT

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

Nivolumab; lirilumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Xiangying Chu
• Organization: ECOG Stats Center

xchu@ds.dfci.harvard.edu

3472770190

Study Officials

• Petros Grivas, MD, PhD

  University of Washington

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 10, 2018
• First Posted: May 22, 2018
• Study Start: March 22, 2019
• Primary Completion: November 27, 2020
• Study Completion: October 5, 2022
• Last Updated: September 19, 2024
• Results First Posted: September 1, 2021

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (8)