Clinical Trials /

Nivolumab and Radiation Therapy in Treating Patients With Localized/Locally Advanced Urothelial Bladder Cancer Ineligible for Chemotherapy

NCT03421652

Description:

This phase II trial studies how well nivolumab works with radiation therapy in treating patients with urothelial bladder cancer that has spread from its original site of growth to nearby tissues or lymph nodes and are ineligible for chemotherapy. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab and radiation therapy may work better in treating patients with urothelial bladder cancer.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Radiation Therapy in Treating Patients With Localized/Locally Advanced Urothelial Bladder Cancer Ineligible for Chemotherapy
  • Official Title: Phase II Trial of Concurrent Nivolumab in Urothelial Bladder Cancer With Radiation Therapy in Localized/Locally Advanced Disease for Chemotherapy Ineligible Patients [NUTRA]

Clinical Trial IDs

  • ORG STUDY ID: 2016-195
  • NCT ID: NCT03421652

Conditions

  • Stage II Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage III Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage IV Bladder Urothelial Carcinoma AJCC v7

Interventions

DrugSynonymsArms
Nivolumab946414-94-4, BMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, radiation therapy)

Purpose

This phase II trial studies how well nivolumab works with radiation therapy in treating patients with urothelial bladder cancer that has spread from its original site of growth to nearby tissues or lymph nodes and are ineligible for chemotherapy. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab and radiation therapy may work better in treating patients with urothelial bladder cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the 12-month rate of progression-free survival (PFS) achieved with the
      combination of nivolumab, a programmed death (PD-1) inhibitor, and radiation therapy in
      localized/locally advanced urothelial cancer patients, who are chemotherapy ineligible, to a
      historical control reference 12-month PFS rate.

      SECONDARY OBJECTIVES:

      I. To assess the toxicity of concurrent nivolumab and radiation therapy in urothelial cancer.

      II. To determine overall response rate (ORR). III. To determine metastasis-free survival
      (MFS). IV. To determine overall survival (OS). V. To evaluate the quality of life and bladder
      functioning during and after the therapy.

      VI. To explore the relationships of PD-1 expression, PDL-1 expression, and the Th1/Th2
      cytokine ratio to clinical outcomes (response, PFS, MFS, and OS).

      OUTLINE:

      Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
      every 14 days (2 weeks) for up to 14 courses (6 months) in the absence of disease progression
      or unacceptable toxicity. Beginning 3 days of course 1, patients undergo radiation therapy
      over 32-35 on weeks 1, 3, 5, 7 and 9.

      After completion of study treatment, patients are followed up every 3 months for 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, radiation therapy)ExperimentalGiven IV
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

        - Localized urothelial cancer of bladder with presence of transitional cell carcinoma (TCC)
        component; mixed histologies are allowed Clinical or pathologic stage T2 -T4 disease
        including T4a and 4b if feasible to treat with radiation therapy Locoregional lymph node
        metastases are permitted but patients with distant metastases are ineligible; imaging to
        evaluate for distant metastases should consist of a minimum of computed tomography
        (CT)/magnetic resonance imaging (MRI) of abdomen/pelvis or CT urogram and a chest x-ray
        (CXR) or CT chest; patients for which there is clinical suspicion or symptoms of bone
        metastasis should have a bone scan completed to rule out metastatic disease prior to
        enrollment on study Agreeable to consider radiation therapy (RT) for the urothelial cancer:
        patients have to be evaluated by a radiation oncologist and deemed to be candidates for RT

        The patients must not be candidates for chemotherapy due to at least one of the following
        reasons:

          -  Performance status of 2

          -  Creatinine clearance =< 60 ml/min as calculated by the Cockcroft-Gault formula

          -  Cardiac disease such as New York Heart Association (NYHA) class III or IV heart
             failure or cardiac ischemia within the last 12 months, grade 2 or greater neuropathy,
             or other comorbidities based on which patient is not considered a candidate for
             chemotherapy Alkaline phosphatase =< 3 x upper limit of normal Aspartate
             aminotransferase (AST) =< 3 x upper limit of normal Alanine aminotransferase (ALT) =<
             3 x upper limit of normal Bilirubin < 1.5 x upper limit of normal (ULN) Absolute
             neutrophil count >= 1500/mm^3 Hemoglobin >= 9 g/dL Platelets >= 100 K/mm^3 Performance
             score (PS) of 0-2 by Zubrod score Life expectancy of 12 months Willingness to sign
             informed consent Patients cannot have active autoimmune disease or immunosuppressive
             conditions Serum creatinine =< 1.5 X institutional ULN or creatinine clearance > 40
             ml/min as calculated by the Cockcroft-Gault formula In females with childbearing
             potential, or men with partners of child bearing potential, willingness to use
             adequate contraception for a minimum duration of 155 days in females and 215 days in
             males, after last dose of nivolumab Maximal tumor resection has been performed as
             feasible

        Exclusion Criteria:

        - The subject has received cytotoxic chemotherapy (including investigational cytotoxic
        chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 4 weeks, or
        intravesical Bacillus Calmette-Guerin (BCG) within 6 weeks of the first dose of study
        treatment Prior treatment with any PD-1 or PDL-1 inhibitor

        The subject has received therapeutic radiation:

          -  To the bladder/prostate/rectum pelvis

          -  To any other site(s) within 28 days of the first dose of study treatment Obstructive
             renal failure that is not relieved with stents or nephrostomy tube/s The subject has
             received any other type of investigational agent within 28 days before the first dose
             of study treatment Steroid doses greater than an equivalent of prednisone 10 mg daily
             The subject has prothrombin time (PT)/international normalized ratio (INR) or partial
             thromboplastin time (PTT) test results at screening >= 2 x the laboratory ULN
             Uncontrolled hematuria

        The subject has uncontrolled, significant intercurrent or recent illness including, but not
        limited to, the following conditions:

          -  Cardiovascular disorders such as uncontrolled arrhythmias or uncontrolled congestive
             heart failure

          -  Gastrointestinal disorders particularly those associated with a high risk of
             perforation or fistula formation including:

               -  Any of the following at the time of screening

                    -  Active peptic ulcer disease,

                    -  Active inflammatory bowel disease (including ulcerative colitis and Crohn's
                       disease), diverticulitis, cholecystitis, symptomatic cholangitis or
                       appendicitis

               -  Any of the following within 6 months before the first dose of study treatment:

                    -  History of abdominal fistula

                    -  Bowel perforation The subject has a previously identified allergy or
                       hypersensitivity to components of the study treatment formulation The
                       subject is unable or unwilling to abide by the study protocol or cooperate
                       fully with the investigator or designee Presence of another invasive
                       malignancy, which required systemic therapy within 12 months of protocol
                       enrollment, except for resected skin cancers or prostate cancer that is in
                       remission Pregnant or nursing women Patient is a candidate for radical
                       cystectomy as a potentially curative option Patients with inherited
                       syndromes associated with hypersensitivity to ionizing radiation (e.g.,
                       ataxia-telangiectasia, Nijmegen breakage syndrome)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From date of registration to date of first documented disease relapse/progression, or death from urothelial cancer whichever occurs first, assessed up to 12 months
Safety Issue:
Description:PFS distribution will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for PFS will be generated along with the Hall-Wellner 95% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (12-month PFS rate, median PFS, etc.) will be calculated from the K-M life table, each one with its respective 95% confidence interval (CI).

Secondary Outcome Measures

Measure:Incidence of adverse events graded per Common Terminology Criteria for Adverse Events version 4.0.
Time Frame:Up to 12 months
Safety Issue:
Description:Frequency distributions of each toxicity type by severity grade will be generated. For a given grade(s), the point estimate of the toxicity rate will be computed, along with its 95% (Wilson type) CI.
Measure:Overall response rate (ORR)
Time Frame:Up to 12 months
Safety Issue:
Description:ORR will be estimated among the response evaluable patients and among all patients. Frequency distributions of best response will be generated for each of those sets of patients. The point estimate of the ORR will be computed, along with its 95% (Wilson type) CI.
Measure:Metastasis-free survival (MFS)
Time Frame:From registration to the appearance of metastases or cancer related death, assessed up to 12 months
Safety Issue:
Description:Summary statistics of MFS will be calculated from the K-M life tables. K-M graphs of the censored MFS distributions will also be generated.
Measure:Overall survival (OS)
Time Frame:From date of registration to death or last follow up, assessed up to 12 months
Safety Issue:
Description:Summary statistics of OS will be calculated from the K-M life tables. K-M graphs of the censored OS distributions will also be generated.
Measure:Quality of life (QOL) and bladder functioning questionnaires assessment
Time Frame:Up to 12 months
Safety Issue:
Description:The QOL score will be measured pre therapy, during therapy and after therapy to compare the changes.
Measure:PD-1 and PDL-1 expression analysis using immunohistochemistry (IHC)
Time Frame:Up to 12 months
Safety Issue:
Description:PDL-1 status will be checked on pre-therapy tumor tissue and will be correlated with the primary endpoint.
Measure:Th1/Th2 cytokine ratio analysis
Time Frame:Up to 12 months
Safety Issue:
Description:The continuous markers (e.g., tumor infiltrating lymphocyte [TIL]s, Th1/Th2 cytokine ratio, etc.) will be summarized with standard descriptive statistics. These descriptive analyses of the serum markers will be performed for each time point at which the each marker is determined. Response (CR/PR vs not) will be modeled as a function of a dichotomized version of pre-study the continuous (ungrouped) markers (e.g., TILs from tissue, and the Th1/Th2 cytokine ratio from serum). The statistical goal of these exploratory analyses is to obtain the point and 95% CI estimates of the OR, and to simply determine the direction and approximate magnitude of these associations for use in planning a subsequent study. Censored PFS will be modeled as a function of a dichotomized version of the continuous (ungrouped) markers (e.g., TILs from tissue, and the Th1/Th2 cytokine ratio using Cox modelling strategy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Barbara Ann Karmanos Cancer Institute

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