Multi-Institutional Phase II Study of Radiation Therapy and Anti-PD-L1 Checkpoint Inhibition (Durvalumab) With or Without Anti-CTLA-4 Inhibition (Tremelimumab) in Patients With Unresectable, Muscle-Invasive or Metastatic Urothelial Bladder Cancer That Are Ineligible or Refusing Chemotherapy
Overview
- Phase
- Phase 2
- Intervention
- Radiation Therapy
- Conditions
- Bladder Cancer
- Sponsor
- Terence Friedlander, MD
- Locations
- 1
- Primary Endpoint
- Progression-free survival (PFS)
- Status
- Withdrawn
- Last Updated
- 8 years ago
Overview
Brief Summary
This is a multi-site, randomized, prospective, open-label phase II study. Patients in this study will have localized (cT3-cT4), or metastatic bladder cancer with a symptomatic, intact primary bladder tumor. In this study, patients will undergo stereotactic body radiation therapy (SBRT) to the bladder tumor and will receive durvalumab with or without tremelimumab.
Detailed Description
The study will commence with a safety lead-in phase at UCSF in which 6 patients are accrued to Regimen A1 (RT + durvalumab). If this is not tolerated then an alternative Regimen A2, containing a lower total radiation dose will accrue 6 patients. If either A1 or A2 is tolerated then patients will be accrued to Regimen B1 (durvalumab, tremelimumab x 2 doses, and RT dose determined from Regimen A) following a 3+3 design for safety. If Regimen B1 is not tolerated an alternative Regimen B2 (durvalumab, tremelimumab x 1 dose, and RT dose determined from regimen A) will accrue following a 3+3 design for safety. After the safety lead-in for each group is completed, an expansion cohort will accrue patients. In this expansion cohort, patients will be randomized 1:1 to be treated with either regimen A or regimen B dose selected from the safety lead-in stratified by patient population (localized patients and metastatic patients).
Investigators
Terence Friedlander, MD
Assistant Clinical Professor
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
- •Locally advanced (cT3 or cT4) or metastatic (N+ or M+) urothelial bladder cancer. Mixed histologies with predominant urothelial pattern are allowed
- •If metastatic disease present patients must have an intact, symptomatic bladder tumor, appropriate for palliative RT to the bladder.
- •Measurable metastatic disease according to RECIST v1.1 criteria. Thus, patients with metastatic disease must have at least 1 lesion, not previously irradiated, that can be accurately measured at baseline as at least 10 mm in the longest diameter (except lymph nodes which must have a short axis greater than or equal to 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.
- •Age greater than or equal to 18 years at time of study entry
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Life expectancy of at least 12 weeks
- •Patients with non-metastatic bladder cancer must be ineligible for cystectomy in the opinion of the treating investigator.
- •Patients must be ineligible for cisplatin-based chemotherapy. The reason for cisplatin ineligibility must be documented. Cisplatin ineligibility is defined as meeting 1 of the following criteria:
- •Creatinine clearance (calculated or measured) less than 60 mL/min
Exclusion Criteria
- •ECOG PS 2 or higher
- •Upper tract-only or urethral-only urothelial cancer
- •Prior cystectomy or definitive RT to the bladder.
- •Prior systemic chemotherapy for bladder cancer
- •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 exluded
Arms & Interventions
Safety Lead-In, Regimen A2 Durvalumab + RT
In cohort A2 the dose of radiation will be decreased to a total dose of 30 Gy administered in 5 fractions of 6 Gy. Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (30 Gy delivered as 6.0Gy x 5 fractions) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Radiation Therapy
Safety Lead-In, Regimen A1 Durvalumab + RT
Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (33Gy delivered as 6.6Gy x 5 fractions) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Durvalumab
Safety Lead-In, Regimen A1 Durvalumab + RT
Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (33Gy delivered as 6.6Gy x 5 fractions) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Radiation Therapy
Safety Lead-In, Regimen A2 Durvalumab + RT
In cohort A2 the dose of radiation will be decreased to a total dose of 30 Gy administered in 5 fractions of 6 Gy. Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (30 Gy delivered as 6.0Gy x 5 fractions) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Durvalumab
Safety Lead-In, Regimen B1 Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 2 cycles with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After two doses of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Durvalumab
Safety Lead-In, Regimen B1 Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 2 cycles with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After two doses of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Tremelimumab
Safety Lead-In, Regimen B1 Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 2 cycles with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After two doses of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Radiation Therapy
Safety Lead-In, Regimen B2 Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 1 cycle with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After one dose of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Durvalumab
Safety Lead-In, Regimen B2 Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 1 cycle with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After one dose of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Tremelimumab
Safety Lead-In, Regimen B2 Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 1 cycle with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After one dose of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Radiation Therapy
Expansion Cohort, Regimen A: Durvalumab + RT
Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (either 33Gy delivered as 6.6Gy x 5 fractions or 30 Gy delivered as 6.0 Gy x 5 fractions, as determined during the safety lead-in for Regimen B) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Durvalumab
Expansion Cohort, Regimen A: Durvalumab + RT
Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (either 33Gy delivered as 6.6Gy x 5 fractions or 30 Gy delivered as 6.0 Gy x 5 fractions, as determined during the safety lead-in for Regimen B) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Radiation Therapy
Expansion Cohort Regimen B: Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 1 or 2 cycles (as determined during the safety lead-in for Regimen B) with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After 1 or 2 doses of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Durvalumab
Expansion Cohort Regimen B: Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 1 or 2 cycles (as determined during the safety lead-in for Regimen B) with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After 1 or 2 doses of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Tremelimumab
Expansion Cohort Regimen B: Durvalumab + Tremelimumab + RT
Tremelimumab 75 mg will be administered via IV infusion q4wk for 1 or 2 cycles (as determined during the safety lead-in for Regimen B) with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After 1 or 2 doses of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.
Intervention: Radiation Therapy
Outcomes
Primary Outcomes
Progression-free survival (PFS)
Time Frame: Over the duration of the study, which is estimated to be approximately 50 months.
PFS will be determined from first day of treatment to date of progression. Progression will be defined based on RECIST 1.1
Toxicity according to NCI CTCAE v. 4.03 criteria
Time Frame: Over the duration of the study, which is estimated to be approximately 50 months.
Safety profile
Secondary Outcomes
- Local control at the primary irradiated site(Over the duration of the study, which is estimated to be approximately 50 months.)
- Pathologic Complete Response (CR) rate of primary irradiated tumor(Over the duration of the study, which is estimated to be approximately 50 months.)
- Abscopal response (in patients with metastatic disease)(Over the duration of the study, which is estimated to be approximately 50 months.)
- Overall response rate (ORR)(Over the duration of the study, which is estimated to be approximately 50 months.)
- Disease-specific survival(Over the duration of the study, which is estimated to be approximately 50 months.)
- Overall survival(Over the duration of the study, which is estimated to be approximately 50 months.)
- Duration of response(Over the duration of the study, which is estimated to be approximately 50 months.)