This phase II trial studies the best dose of atezolizumab in treating patients with bladder cancer that has not spread to other places in the body. Immunotherapy with monoclonal antibodies may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
PRIMARY OBJECTIVES: I. To assess the intratumoral immune response associated with increasing numbers of atezolizumab (MPDL3280A) treatments. (Multi-dose cohorts, Cohort A). II. To assess the anti-tumor activity of MPDL3280A as determined by the pathologic T0 rate (pT0) at the time of cystectomy. (Expansion cohorts, Cohort A). SECONDARY OBJECTIVES: I. To evaluate the safety and feasibility of administering up to 3 cycles of atezolizumab pre-operatively to patients with resectable urothelial bladder cancer (Multi-dose cohorts). II. To assess the anti--tumor activity of neoadjuvant treatment as determined by the pathologic partial response (\< pT2N0) assessed at the time of radical cystectomy (Expansion cohorts). III. To determine the 2-year relapse-free survival (RFS) rate and median RFS from time of radical cystectomy in patients treated with neoadjuvant therapy (Expansion cohorts). IV. To determine the 2-year overall survival (OS) and median OS from time of radical cystectomy in patients treated with neoadjuvant therapy (Expansion cohorts). V. To assess the intratumoral immune response of neoadjuvant by comparing pre-treatment transurethral resection of bladder tumor (TURBT) with post-treatment cystectomy tumor specimens (Expansion cohorts). EXPLORATORY (CORRELATIVE) OBJECTIVES: I. To assess for tumor-based biomarkers of response and resistance to this combination therapy using single-cell RNA sequencing (scRNA-seq) and high-dimensional flow cytometry. II. To assess the presence of antigen-specific immune responses to a broad panel of candidate tumor antigens. OUTLINE: This is a dose-escalation study of atezolizumab. COHORT A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 3 doses prior to cystectomy in the absence of disease progression or unacceptable toxicity. COHORT B: Cohort B was never opened for enrollment. After all neoadjuvant study therapy is administered, each subject will undergo cystectomy to evaluate pathologic response to treatment and for immunologic characterization in the resected tissue. Serum and urine will be obtained as well to characterize circulating immune responses. After completion of study treatment, patients are followed for up every 4 weeks for 12 weeks and then every 12 weeks for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
23
1200 mg Given IV
University of California, San Francisco
San Francisco, California, United States
Mean log2 (Fold Change of CD3+ T-Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the Cluster of differentiation 3 positive (CD3+) T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Time frame: Up to 1 year
Mean log2 (Fold Change of CD3+ Ki67+ Proliferative T Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the CD3+ Ki67+ proliferative T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Time frame: Up to 1 year
Mean log2 (Fold Change of CD4+ FoxP3- Helper T Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the cluster of differentiation 4 positive (CD4+) FoxP3- helper T cells count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Time frame: Up to 1 year
Mean log2 (Fold Change of CD4+ FoxP3+ Regulatory T Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the CD4+ FoxP3+ regulatory T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Time frame: Up to 1 year
Mean log2 (Fold Change of CD8+ Cytotoxic T Cell Count/µm2) Over Time
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The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the cluster of differentiation 8 positive (CD8+) cytotoxic T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Time frame: Up to 1 year
Percentage of Participants With a Treatment-related Delay
The percentage of participants requiring a treatment-related delay in surgery beyond 12 weeks from study start will be summarized using descriptive statistics.
Time frame: Up to 2 years
Number of Participants With Maximum Grade Treatment-related Toxicities Prior to Surgery
Treatment-related adverse events occurring prior to surgery will be summarized by maximum toxicity grade for all participants treated with a particular regimen. The grade of toxicity will be calculated using NCI CTCAE version 4.0.
Time frame: Up to 2 years
Near Complete Pathologic Response Rate
Point estimates and 95% confidence intervals of the near complete pathologic response rate, defined as the presence of only pTa or pTis in patients with T2 or greater disease at baseline.
Time frame: Up to 2 years
Relapse-free Survival (RFS) Rate Intention-To-Treat (ITT) Population
The percentage of participants with a two- year RFS defined from study start until recurrence of disease or death from any cause, will be obtained using the Kaplan Meier method for the ITT population.
Time frame: Up to 2 years
Overall Survival Rate
Overall survival rate will be reported as the percentage of participants from study start until death from any cause obtained by Kaplan Meier method for the ITT population.
Time frame: Up to 2 years
Association of Tumor and T-cell PD-L1/PD-1 Immunohistochemical Expression With Disease Response
Fisher's exact test will be used to test the association of baseline tumor and T-cell programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immunohistochemical expression with disease response.
Time frame: Up to 2 years