A Randomized, Phase 2 Trial to Evaluate the Safety and Efficacy of Eribulin Mesylate in Combination With Atezolizumab Compared to Atezolizumab Alone in Subjects With Locally Advanced or Metastatic Transitional Cell Urothelial Cancer Where Cisplatin-Based Treatment is Not an Option
概览
- 阶段
- 2 期
- 干预措施
- Atezolizumab
- 疾病 / 适应症
- Locally Advanced Bladder Urothelial Carcinoma
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 72
- 试验地点
- 21
- 主要终点
- Overall response rate (probability of complete response [CR] or partial response [PR]) (Phase II)
- 状态
- 进行中（未招募）
- 最后更新
- 19天前
概览
简要总结
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.
详细描述
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.
研究者
入排标准
入选标准
- •Males or females age \> or = 18 years at the time of informed consent. Because no dosing or adverse event data are currently available on the use of atezolizumab in combination with eribulin in patients \< 18 years of age, children are excluded from this study
- •Histologically- or cytologically-confirmed diagnosis of locally advanced/unresectable (inoperable or not amenable to surgical treatment) and/or metastatic transitional cell urothelial cancer of the renal pelvis, ureter, urinary bladder, or urethra
- •Presence of measurable disease meeting the following criteria:
- •At least one lesion of \>= 1.0 cm in long axis diameter for non-lymph nodes or \>= 1.5 cm in short axis diameter for lymph nodes that is serially measurable according to RECIST 1.1 using either computerized tomography or magnetic resonance imaging or panoramic and close-up color photography with caliper measurement; if there is only one target lesion and it is a not a lymph node, it should have a long-axis diameter of at least 1.5 cm
- •Lesions that have had radiotherapy must show radiographic evidence of disease progression based on RECIST 1.1 may be deemed a target lesion
- •Archival paraffin-embedded invasive tumor tissue or newly obtained biopsy must be available prior to the first dose of study drug for biomarker analysis; patients must be offered sequential biopsies at baseline and 6 weeks unless in the opinion of the trial principal investigator (PI) this would be hazardous; recent data suggest discordance between primary tumor and tumor from recurrence or metastasis with high percentages of PD-L1 SP142 positive immune cells after recurrence
- •PD-L1 status determined centrally by HistogeneX, which is funded by the study, must be available before randomization of the patient to allow for stratification; COMMERCIAL ASSESSMENT OF PD-L1 STATUS OBTAINED LOCALLY AT THE SITE WILL NOT SATISFY ELIGIBILITY CRITERIA
- •New, progressive or recurrent disease occurring
- •During or within 12 months of treatment with a platinum containing regimen (cisplatin or carboplatin or novel platinum) in either in the metastatic or perioperative setting
- •In first-line patients defined as cisplatin-ineligible based on renal impairment (creatinine clearance calculated by Cockcroft-Gault method \< 60 ml/min), at least grade 2 hearing loss and/or Eastern Cooperative Oncology Group (ECOG) status of 2; these patients will be chemotherapy naive or have received platinum based therapy in the adjuvant or neoadjuvant setting more than 12 months prior to study entry
排除标准
- •Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
- •Patients who have had chemotherapy within 3 weeks or radiotherapy or targeted therapy 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier; however, the following therapies are allowed:
- •Hormone-replacement therapy or oral contraceptives
- •Herbal therapy \> 1 week prior to cycle 1, day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1)
- •Palliative radiotherapy for bone metastases \> 2 weeks prior to cycle 1, day 1
- •Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents or eribulin
- •Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met:
- •Minimum of 12 weeks from the first dose of anti-CTLA-4 and \> 6 weeks from the last dose
- •No history of severe immune-related adverse effects from anti-CTLA-4 (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0)
- •Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1
研究组 & 干预措施
Arm I (atezolizumab)
Patients receive atezolizumab 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.
干预措施: Atezolizumab
Arm I (atezolizumab)
Patients receive atezolizumab 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.
干预措施: Biopsy Procedure
Arm I (atezolizumab)
Patients receive atezolizumab 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.
干预措施: Biospecimen Collection
Arm I (atezolizumab)
Patients receive atezolizumab 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.
干预措施: Computed Tomography with Contrast
Arm II (atezolizumab, eribulin mesylate)
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.
干预措施: Atezolizumab
Arm II (atezolizumab, eribulin mesylate)
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.
干预措施: Biospecimen Collection
Arm II (atezolizumab, eribulin mesylate)
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.
干预措施: Computed Tomography with Contrast
Arm II (atezolizumab, eribulin mesylate)
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.
干预措施: Eribulin Mesylate
Arm II (atezolizumab, eribulin mesylate)
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.
干预措施: Biopsy Procedure
结局指标
主要结局
Overall response rate (probability of complete response [CR] or partial response [PR]) (Phase II)
时间窗: Up to 52 weeks
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).
Incidence of adverse events (Safety/Run-In)
时间窗: Up to 52 weeks
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.
次要结局
- Best overall response rate (immune-related best overall response [irBOR] rate) using the immune-related response criteria(Up to 52 weeks)
- Analysis based on PD-L1 expression(Up to 52 weeks)
- Incidence of adverse events(Up to 52 weeks)
- Overall survival (OS)(From randomization until death or date last known to be alive, assessed up to 52 weeks)
- Disease control rate (DCR: CR + PR + stable disease)(Up to 52 weeks)
- Duration of response (DOR)(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)
- Progression-free survival (PFS)(From randomization until progression or death, whichever occurs first, assessed up to 52 weeks)