Phase II Study of Radiation Therapy and Anti-PD-L1 Checkpoint Inhibitor (Durvalumab) With or Without Anti-CTLA-4 Inhibition (Tremelimumab) in Patients With Unresectable, Locally Advanced, or Metastatic Urothelial Bladder Cancer That Are Ineligible or Refusing Chemotherapy
Overview
- Phase
- Phase 2
- Intervention
- Durvalumab
- Conditions
- Bladder Urothelial Carcinoma
- Sponsor
- Jonsson Comprehensive Cancer Center
- Enrollment
- 13
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.03 criteria (Safety lead-in cohort)
- Status
- Active, Not Recruiting
- Last Updated
- last year
Overview
Brief Summary
This phase II trial studies the side effects and how well radiation therapy and durvalumab with or without tremelimumab work in treating participants with bladder cancer that cannot be removed by surgery, has spread to nearby tissue or lymph nodes, or that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and durvalumab with or without tremelimumab will work better in treating participants with bladder cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety profile of radiation therapy (RT) and durvalumab with or without tremelimumab. (Safety lead-in cohort) II. To determine the median progression-free survival with RT and durvalumab with or without tremelimumab. (Expansion cohort) SECONDARY OBJECTIVES: I. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of local control of irradiated bladder tumor. II. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of pathologic complete response (CR) rate of irradiated bladder tumor. III. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms overall response rate. IV. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of abscopal response rate. V. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of duration of response. VI. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of disease specific survival. VII. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of overall survival. VIII. To further determine the safety and tolerability of RT + durvalumab with or without tremelimumab (expansion cohorts). EXPLORATORY OBJECTIVES: I. To explore the immunologic changes associated with the combination of durvalumab and RT +/- tremelimumab. OUTLINE: Participants are randomized to 1 of 2 regimens. REGIMEN A: Participants receive durvalumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Participants also undergo external beam radiation therapy (EBRT) for 5 fractions beginning on day 8 of course 1. REGIMEN B: Participants receive tremelimumab IV over 60 minutes on day 1 for up to 2 courses and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression of unacceptable toxicity. Participants also receive undergo EBRT for 5 fractions beginning on day 8 of course 1. After completion of study treatment, participants are followed up at 8 weeks and then every 12 and 16 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
- •cT2 - T4 or metastatic (N+ or M+) urothelial bladder cancer. Mixed histologies with predominant urothelial pattern are allowed. Patients with localized disease must either refuse cystectomy or be deemed not ideal cystectomy candidates.
- •If metastatic disease present patients must have an intact, symptomatic bladder tumor, appropriate for palliative RT to the bladder.
- •Measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria. Thus, patients with metastatic disease must have at least 1 lesion, not previously irradiated, that can be accurately measured at baseline as \>= 10 mm in the longest diameter (except lymph nodes which must have a short axis \>= 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurement as per RECIST v1.1 guidelines.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1/
- •Life expectancy of \>= 12 weeks.
- •Patients must be ineligible for or refuse cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting 1 of the following criteria:
- •Creatinine clearance (calculated or measured) \< 60 mL/min
- •Common Terminology Criteria for Adverse Events (CTCAE) grade \>= 2 audiometric hearing loss
- •CTCAE grade 2 or higher peripheral neuropathy
Exclusion Criteria
- •ECOG PS 2 or higher.
- •Prior cystectomy or definitive RT to the bladder.
- •History of autoimmune disease, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegner?s granulomatosis, Sjogren?s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
- •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
- •Subjects with childhood atopy or asthma, vitiligo, alopecia, Hashimoto syndrome, Grave?s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
- •Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are not excluded.
- •Patients with controlled type 1 diabetes mellitus on a stable dose of insulin regimen are not excluded.
- •Any chronic skin condition that does not require systemic therapy are not excluded.
- •Patients without active autoimmune disease in the last 5 years may be included after consultation with the study physician.
- •Patients with human immunodeficiency virus (HIV), active hepatitis B (HBV) or active hepatitis C (HCV)
Arms & Interventions
Regimen A (radiation therapy and durvalumab)
Participants receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Participants also undergo EBRT for 5 fractions beginning on day 8 of course 1.
Intervention: Durvalumab
Regimen A (radiation therapy and durvalumab)
Participants receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Participants also undergo EBRT for 5 fractions beginning on day 8 of course 1.
Intervention: External Beam Radiation Therapy
Regimen B (radiation therapy, durvalumab, tremelimumab)
Participants receive tremelimumab IV over 60 minutes on day 1 for up to 2 courses and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression of unacceptable toxicity. Participants also receive undergo EBRT for 5 fractions beginning on day 8 of course 1.
Intervention: Durvalumab
Regimen B (radiation therapy, durvalumab, tremelimumab)
Participants receive tremelimumab IV over 60 minutes on day 1 for up to 2 courses and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression of unacceptable toxicity. Participants also receive undergo EBRT for 5 fractions beginning on day 8 of course 1.
Intervention: External Beam Radiation Therapy
Regimen B (radiation therapy, durvalumab, tremelimumab)
Participants receive tremelimumab IV over 60 minutes on day 1 for up to 2 courses and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression of unacceptable toxicity. Participants also receive undergo EBRT for 5 fractions beginning on day 8 of course 1.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.03 criteria (Safety lead-in cohort)
Time Frame: Up to 90 days after last dose of investigation product
Observed toxicities will be tabulated using frequencies and percentages based on the CTCAE v 4.03.
Progression- free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 (Expansion cohort)
Time Frame: From the first day of the treatment to the first occurrence of disease progression or death, assessed up to 3 years
PFS will be estimated in each study arm by Kaplan-Meier estimate, where PFS is a composite endpoint based on radiologic progression, clinical deterioration or death. A log rank test will be used to test if there is significant difference in PFS between two arms. PFS will be also estimated for localized patients and metastatic patients separately within each arm and stratified log rank test will be used as well.
Secondary Outcomes
- Local control at the primary irradiate site determined by RECIST v 1.1(Up to 3 years)
- Incidence of adverse events assessed by National Cancer Institute CTCAE v4.0(Up to 3 years)
- Overall response rate (ORR) defined as the number (%) of patients with at least 1 visit response of CR or partial response (PR) determined by RECIST v 1.1(Up to 3 years)
- Abscopal response (in patients with metastatic disease) determined by RECIST v 1.1 with response (PR and CR) sites away from the primary irradiated tumor(Up to 3 years)
- Duration of response(From date of the first documented response until the first date of documented progression or death, assessed up to 3 years)
- Disease-specific survival(From the date of randomization to the date of death related to treatment and/or disease determined, assessed up to 3 years)
- Overall survival(From the date of randomization to the date of to the date of death due to any cause, assessed up to 3 years)
- Pathologic complete rate (CR) of primary irradiated tumor(Up to 3 years)