This phase II trial studies the side effects of atezolizumab with or without eribulin mesylate and how well they work in treating patients with urothelial cancer that has come back (recurrent), spread to nearby tissues or lymph nodes (locally advanced), or spread from where it first started (primary site) to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as eribulin mesylate, 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. Giving atezolizumab and eribulin mesylate may work better at treating urothelial cancer compared to atezolizumab alone.
PRIMARY OBJECTIVES: I. To confirm that eribulin mesylate (eribulin), at or close to the single agent recommended phase 2 dose, and atezolizumab at the single agent recommended phase 2 dose, can be given together with an acceptable toxicity profile. (Safety/Run-in) II. To estimate the objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for eribulin and atezolizumab in combination, and compare that to the ORR of atezolizumab alone. (Phase 2) SECONDARY OBJECTIVES: I. To summarize and characterize the toxicity associated with this 2-drug combination. II. To estimate the best overall response rate (immune-related best overall response \[irBOR\] rate) using the immune-related response criteria (irRC). III. To estimate the disease control rate (DCR: complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]) based on RECIST 1.1. IV. To estimate the duration of response and the duration of stable disease. V. To summarize the progression-free survival (PFS). VI. To summarize the overall survival (OS). VII. To evaluate efficacy in subsets of patients determined by PD-L1, CD3 and CD8 expression. EXPLORATORY OBJECTIVES: I. To assess the pharmacodynamic (PD) profile of eribulin when it is given in combination with atezolizumab, specifically exploring the expression of putative tumor, circulating microenvironment and computed tomography (CT) radiomic correlatives of epithelial-mesenchymal transition (EMT)/ (mesenchymal-epithelial transition) MET phenotype at baseline and 6 weeks on therapy. II. To ascertain the role of expression of PD-L1 using the SP142 assay and potentially other methods as a predictive biomarker for response to treatment with atezolizumab in combination with eribulin. III. To identify clinical biomarkers that may predict for efficacy and toxicity in this population and with this treatment combination. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and CT with contrast throughout the trial. Patients may undergo biopsy during screening and on study. ARM II: Patients receive atezolizumab IV over 30-60 minutes on day 1 of each cycle and eribulin mesylate IV over 2-3 minutes on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and CT with contrast throughout the trial. Patients may undergo biopsy during screening and on study. After completion of study treatment, patients are followed up every 3 or 6 months for 52 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
72
Given IV
Undergo biopsy
Undergo blood sample collection
Undergo CT scan
Given IV
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Keck Medicine of USC Buena Park
Buena Park, California, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
City of Hope at Irvine Lennar
Irvine, California, United States
Keck Medicine of USC Koreatown
Los Angeles, California, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
Keck Medical Center of USC Pasadena
Pasadena, California, United States
...and 11 more locations
Incidence of adverse events (Safety/Run-In)
Will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Tables will be created to summarize the numbers of patients who experienced toxicities by arm, toxicity system, type, grade and attribution. If helpful, cumulative incidence curves will be constructed to summarize the onset of selected adverse events.
Time frame: Up to 52 weeks
Overall response rate (probability of complete response [CR] or partial response [PR]) (Phase II)
Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The two arms will be compared using a one-sided, 0.10-level Mantel-Haenszel, stratifying by (a) cisplatin ineligible first line vs. having received prior platinum therapy, and PD-L1 status in archival tumor tissue (immunohistochemistry \[IHC\] 0-1 versus \[vs\] 2-3). Two-sided 80% confidence intervals will be constructed for the probability of response in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 versus \[vs\] 3-4).
Time frame: Up to 52 weeks
Incidence of adverse events
Tables will be created to summarize the numbers of patients who experienced toxicities (graded according to the CTCAE version 5.0), by arm, toxicity system, type, grade and attribution. If helpful, cumulative incidence curves will be constructed to summarize the onset of selected adverse events.
Time frame: Up to 52 weeks
Best overall response rate (immune-related best overall response [irBOR] rate) using the immune-related response criteria
Analysis of the irBOR will be based on a modified intention-to-treat analysis which will include all eligible, randomized patients who receive any amount of either atezolizumab or eribulin. The proportion of patients in each of the 5 categories above will be calculated for each arm and two-sided 80% confidence intervals will be constructed. Two-sided 80% confidence intervals will be constructed for the probability of response in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).
Time frame: Up to 52 weeks
Disease control rate (DCR: CR + PR + stable disease)
Will be assessed based on RECIST 1.1. The two arms will be compared in terms of the DCR using a one-sided, 0.10-level Mantel-Haenszel, stratifying by (a) cisplatin ineligible first line vs having received prior platinum therapy, and PD-L1 status in archival tumor tissue (IHC 0-1 vs 2-3). Two-sided 80% confidence intervals will be constructed for the probability of DCR in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).
Time frame: Up to 52 weeks
Progression-free survival (PFS)
Will be displayed using Kaplan-Meier plots. Median PFS will be estimated and 80% confidence intervals constructed; PFS at 6 months and 12 months will be estimated and 80% confidence intervals constructed. The two arms will be compared using a one-sided, 0.10-level, stratified logrank test. If numbers permit, Kaplan-Meier plots will be drawn for patients grouped by the stratification variables. In addition, also, if numbers permit, a Cox proportional hazards regression be used to estimate the hazards ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).
Time frame: From randomization until progression or death, whichever occurs first, assessed up to 52 weeks
Overall survival (OS)
OS will be displayed using Kaplan-Meier plots. Median OS will be estimated and 80% confidence intervals constructed; OS at 6 months and 12 months will be estimated and 80% confidence intervals constructed. The two arms will be compared using a one-sided, 0.10-level, stratified logrank test. If numbers permit, Kaplan-Meier plots will be drawn for patients grouped by the stratification variables. In addition, also, if numbers permit, a Cox proportional hazards regression be used to estimate the hazards ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).
Time frame: From randomization until death or date last known to be alive, assessed up to 52 weeks
Duration of response (DOR)
Will be displayed using Kaplan-Meier plots. Median DOR will be estimated and 80% confidence intervals constructed; DOR at 6 months will be estimated and 80% confidence intervals constructed.
Time frame: From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that progressive disease is objectively documented, assessed up to 52 weeks
Analysis based on PD-L1 expression
The analyses described for ORR, DCR, irBOR, PFS, and OS will be repeated, examining patients whose tumors are PD-L1 "positive" (IHC = 2-3) and those whose tumors are PD-L1 "negative (IHC = 0-1). Although numbers will be small, the odds ratio's and hazard ratio's will be compared (using the logistic or Cox regression models) to ascertain whether the impact of eribulin is different based on the PD-L1 status.
Time frame: Up to 52 weeks
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