Details

Details

Title A Phase 3, Randomized, Study of Neoadjuvant Chemotherapy alone versus Neoadjuvant Chemotherapy plus Nivolumab or Nivolumab and BMS-986205, Followed by Continued Post-Surgery Therapy with Nivolumab or Nivolumab and BMS-986205 in Participants with Muscle-Invasive Bladder Cancer

IRB BRMY 1819

CC 19-1212

Hospital Main Campus

Stage Stage 2, Stage 3, Stage 4

Phase Phase 3

Disease Bladder

Drug BMS-986205 , Nivolumab

Description

Description

Primary Objectives

To compare the pCR rate of neoadjuvant nivolumab + GC to neoadjuvant GC alone in all randomized participants (Arm B vs. Arm A).

To compare EFS of neoadjuvant nivolumab + GC followed by continued nivolumab after RC versus neoadjuvant SOC GC followed by RC in all randomized participants (Arm B vs. Arm A).

Secondary Objectives

To compare overall survival (OS) of neoadjuvant nivolumab + GC followed by continued nivolumab therapy after RC versus neoadjuvant SOC GC followed by RC in all randomized participants (Arm B vs Arm A).

To describe the safety and tolerability of nivolumab and nivolumab in combination with GC chemotherapy.

Inclusion Criteria

Inclusion Criteria

  1. Signed Written Informed Consent
    • Participants must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care.
    • Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, tumor biopsies, and other requirements of the study.
  2. Type of Participant and Target Disease Characteristics
    • Participants with MIBC, clinical stage T2-T4a, N0 (<10 mm on CT or MRI), M0, diagnosed at TURBT and confirmed by radiographic imaging. Variant histology is acceptable if there is a predominant (> 50%) urothelial component.
      • Note: H&E stained slides from the TURBT or tumor biopsy must be submitted to the vendor for confirmation of MIBC prior to randomization for participants in the main study (not required for participants in the safety lead-in portion)
    • Participant must be deemed eligible for RC by his/her oncologist and/or urologist, and must agree to undergo RC after completion of neoadjuvant therapy.
    • Prior BCG or other intravesical treatment of NMIBC is permitted if completed at least 6 weeks prior to initiating study treatment.
    • ECOG Performance Status 0 or 1
    • Life expectancy ≥ 6 months
    • Documentation of PD-L1 status by immunohistochemistry (IHC) performed by the central lab during the screening period; the results must be submitted to IRT prior to randomization. Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or 20 unstained tumor tissue sections [minimum of 15 slides acceptable], with an associated pathology report, must be submitted for biomarker evaluation prior to treatment. The tumor tissue sample may be fresh or archival (≤ 4 months old), and should be from the TURBT or biopsy that made the diagnosis of MIBC. No systemic therapy (eg, adjuvant or neoadjuvant chemotherapy) should be given after the sample was obtained. PD-L1 results are not required prior to beginning treatment on the safety lead-in.
    • Re-enrollment: This study permits the re-enrollment of a participant that has discontinued the study as a pre-treatment failure (ie, participant has not been randomized (or treated in the safety lead-in). If re-enrolled, the participant must be re-consented and inclusion/exclusion criteria reassessed.
  3. Age and Reproductive Status
    • Males and females, ages ≥ 18 years or age of majority
    • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment.
    • Women must not be breastfeeding.
    • WOCBP must agree to follow instructions for methods(s) of contraception for the duration of any study drugs (including chemotherapy) and 6 months after the last dose of any study drugs (including chemotherapy).
    • Males who are sexually active with WOCBP must agree to use a latex or synthetic condom during sexual activity (see Appendix 4) for the duration of treatment with study treatment plus 7 months after the last dose of the study treatment (ie, 90 days [duration of sperm turnover] plus the time required for nivolumab to undergo approximately 5 half-lives). This criterion applies to azoospermic males as well.
    • WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in these sections.Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception (Appendix 4) which have a failure rate of < 1% when used consistently and correctly. Hormonal contraceptives are considered highly effective methods of contraception for participants in this study who are WOCBP in Arms A. Hormonal contraceptives are not considered highly effective methods of contraception for participants receiving BMS-986205 on this study, eg, those who are WOCBP in the safety lead-in or in one of the arms receiving blinded BMS-986205/matching placebo (ie Arms B and C)
Exclusion Criteria

Exclusion Criteria

  1. Target Disease Exceptions
    • Clinical evidence of pathologic LN (≥ 10 mm in short axis) or metastatic bladder cancer
  2. Medical Conditions
    • Ineligible to receive cisplatin due to Grade 2 or higher peripheral neuropathy or audiometric hearing loss, or calculated (Cockcroft-Gault formula) or measured (24-hour urine) creatinine clearance (CrCl) < 50 mL/min
    • Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
    • Participants with conditions known to interfere significantly with the absorption of oral medication, as per investigator judgement.
    • Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
    • Participants with uncontrolled adrenal insufficiency.
    • Unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, history of myocardial infarction or stroke within 6 months (Appendix 8).
    • Evidence of bleeding diathesis or coagulopathy. Therapeutic anticoagulation is permitted, but participants must be on a stable dose.
    • Participants with a personal or family (ie, in a first-degree relative) history or presence of cytochrome b5 reductase deficiency (previously called methemoglobin reductase deficiency) or other diseases that puts them at risk of methemoglobinemia. All participants will be screened for methemoglobin levels prior to randomization.
    • Participants with a history of G6PD deficiency or other congenital or autoimmune hemolytic disorders. All participants will be screened for G6PD deficiency prior to randomization.
    • Prior history of serotonin syndrome
    • Participants with active interstitial lung disease (ILD) or pneumonitis or with recent history of ILD or pneumonitis requiring steroids (excluding radiation pneumonitis)
    • Known medical condition that, in the Investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results
    • Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, prostate cancer with evidence of undetectable Prostate Specific Antigen (PSA), or carcinoma in situ of the prostate, cervix, or breast
    • Major surgical procedure within 14 days prior to initiating study treatment or anticipation of the need for a major surgical procedure (other than RC) during the course of the study
  3. Prior/Concomitant Therapy
    • Prior treatment of bladder cancer (including MIBC) with systemic chemotherapy, immunotherapy, radiation therapy, or surgery for bladder cancer other than TURBT or biopsies. Prior intravesical BCG or chemotherapy is permitted if completed at least 6 weeks before initiating study treatment.
    • Participants may not have received live/attenuated vaccines (eg, yellow fever) within 30 days of first treatment.
    • Use of an investigational agent within 4 weeks of the start of study treatment.
    • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
    • Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization. Refer to Section 7.7.1 for additional notes.
  4. Physical and Laboratory Test Findings
    • WBC < 2000/μL
    • Neutrophils < 1500/μL
    • Platelets < 100 x 103/μL
    • Hemoglobin < 9.0 g/dL (transfusion to achieve this level is not permitted within 1 week of this laboratory assessment)
    • CrCl < 50 mL/min (measured or calculated using the Cockcroft-Gault formula)
    • AST or ALT > 3.0 x ULN
    • Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN)
    • Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, eg, Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV RNA negative)
    • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Note: Testing for HIV must be performed at sites where mandated locally.
    • Quantitative or qualitative G6PD assay results suggesting underlying G6PD deficiency
    • Blood methemoglobin > ULN, assessed in an arterial or venous blood sample
    • Positive pregnancy test at enrollment or prior to administration of study medication
  5. Allergies and Adverse Drug Reaction
    • History or presence of hypersensitivity or idiosyncratic reaction to methylene blue
    • History of allergy or hypersensitivity to any study treatment components
    • Any contraindications to any of the study drugs. Investigators should refer to local package insert or summary of product characteristics (SmPC).
  6. Other Exclusion Criteria
    • Prisoners or participants who are involuntarily incarcerated. (Note: under specific circumstances and only in countries where local regulations permit, a person who has been imprisoned may be included as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.).
    • Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness