Clinical Trials /

Neoadjuvant Nivolumab With and Without Urelumab in Cisplatin-Ineligible or Chemotherapy-refusing Patients With Muscle-Invasive Urothelial Carcinoma of the Bladder

NCT02845323

Description:

This study evaluates the post cystectomy CD8+ tumor response of patients receiving Nivolumab plus Urelumab versus Nivolumab alone. Half the patients will receive Nivolumab plus Urelumab, while the other half will receive Nivolumab alone.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Nivolumab With and Without Urelumab in Patients With Cisplatin-Ineligible Muscle-Invasive Urothelial Carcinoma of the Bladder
  • Official Title: Randomized Phase II Study of Neoadjuvant Nivolumab With and Without Urelumab in Patients With Cisplatin-Ineligible Muscle-Invasive Urothelial Carcinoma of the Bladder

Clinical Trial IDs

  • ORG STUDY ID: J1682
  • SECONDARY ID: IRB00103062
  • NCT ID: NCT02845323

Conditions

  • Urothelial Carcinoma
  • Bladder Cancer

Interventions

DrugSynonymsArms
Nivolumab in combination with UrelumabOpdivoNivolumab in combination with Urelumab
Nivolumab monotherapyNivolumab monotherapy

Purpose

This study evaluates the post cystectomy CD8+ tumor response of patients receiving Nivolumab plus Urelumab versus Nivolumab alone. Half the patients will receive Nivolumab plus Urelumab, while the other half will receive Nivolumab alone.

Detailed Description

      This is phase II clinical trial design randomizing patients with cisplatin-ineligible MIBC
      (stages T2-T4, N0-1, M0) to one of two treatment arms: Arm A - Nivolumab in combination with
      Urelumab or Arm B - Nivolumab monotherapy.

      The study population will include male and female patients over the age of 18 with muscle
      invasive urothelial carcinoma of the bladder (MIBC) who are not suitable for cisplatin-based
      chemotherapy, but are fit to undergo surgical resection of their cancer by cystectomy.
      Patients with resectable clinical node positive disease within the true pelvis (N1) are
      eligible.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab in combination with UrelumabExperimentalNivolumab and Urelumab combination: Nivolumab 240 mg will be administered by 1 hour intravenous infusion on day 1 and day 15 for two cycles Urelumab 8mg will be administered by 1 hour intravenous infusion on day 1 for two cycles
  • Nivolumab in combination with Urelumab
Nivolumab monotherapyActive ComparatorNivolumab 240 mg will be administered by 1 hour intravenous infusion on day 1 and day 15 for two cycles
  • Nivolumab monotherapy

Eligibility Criteria

        Inclusion Criteria:

          -  Ineligible to receive cisplatin-based neoadjuvant chemotherapy based upon at least one
             of the following criteria:

          -  Creatinine clearance < 60 ml/min

          -  ECOG status =2

          -  Grade > 2 hearing loss

          -  Grade > 2 neuropathy

          -  New York Heart Association Class III heart failure

          -  Age ≥ 18 years old at time of consent

          -  Patients must have the following laboratory values:

             a) Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 (must be stable off any growth factor
             within 4 weeks of first study drug administration) b) Platelets ≥ 100 K/mm3
             (transfusion to achieve this level is not permitted within 2 weeks of first study drug
             administration) c) Hemoglobin (Hgb) ≥ 9 g/dL d) Serum total bilirubin: ≤ 1.5 x ULN e)
             ALT and AST ≤ 3.0 x ULN f) Serum creatinine clearance (CrCl) ≥ 30 mL/min using the
             Cockcroft-Gault equation, see formula below:

          -  CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if patient is female
             multiply the above by 0.85)

          -  Patients who give a written informed consent obtained according to local guidelines

        Exclusion Criteria:

          -  Patients with locally advanced unresectable or metastatic urothelial carcinoma as
             assessed on baseline radiographic imaging obtained within 28 days prior to study
             registration. The required radiographic imaging includes:

             a) Abdomen/Pelvis - CT scan b) Chest - chest x-ray or CT scan

          -  Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive
             urothelial carcinoma.

          -  Patients with another active second malignancy other than non-melanoma skin cancers
             and biochemical relapsed prostate cancer

          -  Patients who have received the last administration of an anti-cancer therapy including
             chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting
             study drug, or who have not recovered from the side effects of such therapy

          -  Patients who have received prior therapy with immune checkpoint inhibitors (e.g.
             anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4) or immune costimulatory molecules (e.g.
             anti-CD137, anti-OX40, anti-GITR) directed agents.

          -  Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have
             not recovered from radiotherapy toxicities

          -  Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
             intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting
             study drug, or patients who have had minor procedures (i.e. TURBT), 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 with history of alcoholic or non-alcoholic steatohepatitis (NASH),
             auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis.

          -  Patient with history of prior solid organ or allogeneic bone marrow transplant.

          -  Patients with any of the following concurrent severe and/or uncontrolled medical
             conditions which could compromise participation in the study:

               1. Clinically significant cardiac diseases, including any of the following:

             i. History or presence of serious uncontrolled ventricular arrhythmias

        ii.Clinically significant resting bradycardia

        iii.Any of the following within 3 months prior to starting study drug: myocardial
        infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive
        Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA),
        Pulmonary Embolism (PE)

        iv.Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or
        without anti-hypertensive medication(s)

        b) Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

        c) Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
        mandatory)

        d) Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant,
        rheumatoid arthritis, systemic lupus erythematosus, 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. For questions, please consult the study chair.

        e) Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active
        or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety
        risks or compromise compliance with the protocol

          -  Pregnant or breast-feeding women

          -  Women of child-bearing potential, who are biologically able to conceive, and not
             employing two forms of highly effective contraception. Highly effective contraception
             must be used throughout the trial and up to 8 weeks after the last dose of study drug
             (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device).
             Women of child-bearing potential, defined as sexually mature women who have not
             undergone a hysterectomy or who have not been naturally postmenopausal for at least 12
             consecutive months (i.e., who has had menses any time in the preceding 12 consecutive
             months), must have a negative serum pregnancy test ≤ 14 days prior to starting study
             drug

          -  Fertile males not willing to use contraception, as stated above

          -  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:Immune response to treatment with Nivolumab and Urelumab compared to Nivolumab monotherapy measured by tumor infiltrating CD8+ T cell density at cystectomy
Time Frame:2 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To evaluate the number of participants with treatment-related adverse events as assessed by CTCAE v 4.0
Time Frame:2 years
Safety Issue:
Description:
Measure:Proportion of patients achieving pathologic response (<pT2N0) with Nivolumab and Urelumab and the use of Urelumab alone
Time Frame:2 years
Safety Issue:
Description:
Measure:Prognostic value of tumor biopsy PD-1 and PD-L1 expression and change in expression for pathologic tumor response as defined by cystectomy pathologic staging <pT2 N0 in patients treated with Nivolumab
Time Frame:2 years
Safety Issue:
Description:
Measure:Change in expression for pathologic tumor response as defined by cystectomy pathologic staging <pT2 N0 in patients treated with Nivolumab
Time Frame:2 years
Safety Issue:
Description:
Measure:Prognostic value of tumor bx 4-1BB (CD137)& 4-1BB ligand (CD137L) expression
Time Frame:2 years
Safety Issue:
Description:
Measure:Change in expression, assessed by (IHC) analysis, for tumor response, defined by cystectomy staging < pT2N0, in cisplatin-ineligible MIBC pts tx w/Urelumab.
Time Frame:2 years
Safety Issue:
Description:
Measure:Prognostic value of tumor biopsy 4-1BB expression
Time Frame:2 years
Safety Issue:
Description:
Measure:Change in expression, assessed by (IHC) analysis, for pathologic CR response, defined by cystectomy staging pT0N0, in cisplatin-ineligible MIBC pts tx w/ Urelumab.
Time Frame:2 years
Safety Issue:
Description:
Measure:Proportion of patients achieving pathologic complete response with neoadjuvant Nivolumab and Urelumab (Arm A) and Nivolumab monotherapy (Arm B).
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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