Phase II Study Evaluating Combination Chemotherapy + Radiotherapy (RT) With Avelumab in Muscle Invasive Bladder Cancer
Overview
- Phase
- Phase 2
- Intervention
- Avelumab
- Conditions
- Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall
- Sponsor
- Mayo Clinic
- Enrollment
- 2
- Locations
- 3
- Primary Endpoint
- Proportion of Participants With Complete Response (At 6 Months)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This phase II trial studies the side effects of avelumab and how well it works in combination with fluorouracil and mitomycin or cisplatin and radiation therapy in treating participants with muscle-invasive bladder cancer. Monoclonal antibodies, such as avelumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as fluorouracil, mitomycin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving avelumab with chemotherapy and radiotherapy may work better in treating participants with muscle-invasive bladder cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the complete response rate of concurrent chemotherapy radiation treatment combined with avelumab for patients with muscle invasive bladder cancer. SECONDARY OBJECTIVES: I. To evaluate the safety and toxicity (adverse event profile) of concurrent chemotherapy radiation treatment combined with avelumab. II. To evaluate quality of life (QoL) at 1 year of concurrent chemotherapy radiation treatment combined with avelumab. III. To evaluate progression-free survival and relapse-free survival at 1 year with concurrent chemotherapy radiation treatment combined with avelumab. CORRELATIVE OBJECTIVES: I. To explore biomarkers that may predict response to avelumab in the muscle invasive population. II. To evaluate the association of tumor mutational burden with response to concurrent chemo- radiation and immunotherapy. III. To evaluate whether concurrent chemoradiation and immunotherapy after maximal transurethral resection of bladder tumor (TURBT) is associated with a decrease in circulating Bim+CD11a\^high PD-1+CD8+ T-cells and myeloid-derived suppressor cells (MDSCs). OUTLINE: Participants receive avelumab intravenously (IV) over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during radiation therapy (RT) and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 30 days, 6, 9, and 12 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologic proof of T2-T4a N0M0 (American Joint Committee on Cancer \[AJCC\] 8th edition) with predominant urothelial carcinoma. Mixed histologies are acceptable provided urothelial carcinoma is the predominant histology. Small cell urothelial carcinoma is excluded.
- •Cystoscopy with maximal TURBT performed =\< 70 days of study registration. NOTE: Both completely resectable or partially resectable tumors are eligible as long as the treating urologist attempted complete resection. Exam under anesthesia needs to be performed and documented.
- •Absolute neutrophil count (ANC) \>= 1500/mm\^3 =\< 28 days prior to registration.
- •Platelets (PLT) 100,000/mm\^3 =\< 28 days prior to registration.
- •Total bilirubin =\< 1.5 upper limit of normal (ULN) =\< 28 days prior to registration.
- •Aspartate transaminase (AST) =\< 2.5 x ULN (=\< 5 x ULN for patients with liver involvement) =\< 28 days prior to registration.
- •Alanine aminotransferase (ALT) =\< 2.5 x ULN (=\< 5 x ULN for patients with liver involvement) =\< 28 days prior to registration.
- •Hemoglobin (Hgb) \>= 9 gm/dl =\< 28 days prior to registration.
- •Calculated creatinine clearance must be \>= 30 ml/min using the Cockcroft-Gault formula =\< 28 days prior to registration.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS 0, 1, 2).
Exclusion Criteria
- •Patients with locally advanced unresectable (T4b) or metastatic urothelial carcinoma (N1M0-1) as assessed on baseline radiographic imaging obtained =\< 70 days prior to study registration. The required radiographic imaging includes:
- •Abdomen/pelvis computed tomography (CT) or magnetic resonance imaging (MRI) scan
- •Chest x-ray or CT scan.
- •Patients with concurrent urothelial carcinoma and/or related variants anywhere outside bladder
- •NOTE: Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.
- •A prior or concurrent malignancy of any other site or histology unless the patient has been disease-free for \> 2 years prior to registration except for:
- •Non-melanoma skin cancer and/or localized prostate cancer (T2 a or b , Gleason \< 3+4) or carcinoma in situ of the uterine cervix which has been adequately treated =\< 2 years prior to registration
- •Or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai stage 0, prostate cancer with Gleason score =\< 3+4, and prostate-specific antigen \[PSA\] =\< 10 mg/mL, etc.).
- •Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies =\< 4 weeks prior to registration, or who have not recovered from the side effects of such therapy.
- •EXCEPTION: Except single dose intravesical chemotherapy administered after TURBT.
Arms & Interventions
Treatment (avelumab, chemotherapy, radiation therapy)
Participants receive avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during RT and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Avelumab
Treatment (avelumab, chemotherapy, radiation therapy)
Participants receive avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during RT and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Cisplatin
Treatment (avelumab, chemotherapy, radiation therapy)
Participants receive avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during RT and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Fluorouracil
Treatment (avelumab, chemotherapy, radiation therapy)
Participants receive avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during RT and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Mitomycin
Treatment (avelumab, chemotherapy, radiation therapy)
Participants receive avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during RT and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Treatment (avelumab, chemotherapy, radiation therapy)
Participants receive avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during RT and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Radiation Therapy
Outcomes
Primary Outcomes
Proportion of Participants With Complete Response (At 6 Months)
Time Frame: At 6 months from registration
Patients enrolled will have non-measurable disease based on imaging at baseline. Patients will be assessed for a response after 6 months of treatment using the results of a biopsy and cytology test. A complete response (CR) is defined as having a negative biopsy and negative urine cytology at 6 months from registration after finishing of concurrent RT and immunotherapy. Imaging of abdomen and pelvis confirming no systemic disease within 4 weeks of cystoscopy will be completed. The proportion of patients reporting a CR is reported here with confidence intervals for the true success proportion using the binomial distribution.
Secondary Outcomes
- Adverse Events Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0)(Up to 12 months)
- Patient-reported Outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-30(Baseline to 12 months)
- Patient-reported Outcomes (European Organization for Research and Treatment of Cancer [EORTC] EORTCQOL-Muscle-Invasive Bladder Cancer Module [BLM]30(Baseline to 12 months)
- Progression-free Survival(From registration to time of first documentation of progression or death from any cause, assessed up to 12 months)
- Recurrence-free Survival(From documented complete response to the first documentation of recurrence, assessed up to 12 months)