This phase II/III trial compares the effect of adding durvalumab to chemotherapy versus chemotherapy alone before surgery in treating patients with upper urinary tract cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, 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 methotrexate, vinblastine, doxorubicin, cisplatin, and gemcitabine 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. Durvalumab in combination with chemotherapy before surgery may enhance the shrinking of the tumor compared to chemotherapy alone.
PRIMARY OBJECTIVES: I. To compare event-free survival (EFS) between patients with upper tract urothelial cancer (UTUC) randomized to neoadjuvant accelerated methotrexate, vinblastine, adriamycin, cisplatin (aMVAC) alone or in combination with durvalumab. (Cisplatin eligible patients \[Arms A and B\]) II. Evaluation of pathologic complete response at radical nephroureterectomy (RNU) (pathologic complete response \[pCR\], ypT0N0/ Nx). (Cisplatin ineligible patients \[Arm C\]). SECONDARY OBJECTIVES: I. To assess pathologic complete response (pCR) at surgery. (Cisplatin eligible cohort) II. Event-free survival (EFS) will be evaluated for the cisplatin ineligible cohort as a secondary endpoint. (Cisplatin ineligible cohort) III. Overall survival in all, and by post chemotherapy response (ypt0N0, yp =\< T1N0, yp \>= T2Nany). (All patients) IV. To evaluate disease-free survival (DFS) in each arm of the trial separately. (All patients) V. To evaluate cancer-specific survival of patients in each arm of the trial separately. (All patients) VI. To evaluate renal function outcomes following systemic treatment and following surgery (\[RNU) in each arm of the trial separately. (All patients) VII. To evaluate safety and tolerability of neoadjuvant aMVAC alone or in combination with durvalumab prior to RNU. (All patients) OUTLINE: Patients eligible for cisplatin are randomized to Arms A or B. Patients ineligible for cisplatin are assigned to Arm C. ARM A: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1 of chemotherapy cycles 1 and 3. Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. ARM B: Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. ARM C: Patients receive durvalumab IV over 60 minutes on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. Patients also undergo tissue biopsy and blood sample collection on study, and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. After completion of study treatment, patients are followed up within 30 days and then every 3-6 months for up to 5 years from study entry.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
249
Undergo tissue biopsy
Undergo blood sample collection
Given IV
Undergo CT
Given Iv
Given IV
Given IV
Undergo MRI
Given IV
Given via injection
Undergo surgery
Given Iv
Kingman Regional Medical Center
Kingman, Arizona, United States
RECRUITINGMercy Hospital Fort Smith
Fort Smith, Arkansas, United States
SUSPENDEDUniversity of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
ACTIVE_NOT_RECRUITINGSutter Auburn Faith Hospital
Auburn, California, United States
Event-free survival (EFS) (Cisplatin eligible cohort: Arms A and B)
Disease progression prior to surgery or omission of surgery due to unresectable tumors, muscle-invasive cancer or disease recurring outside of the bladder, urethra, or contralateral upper tract are considered as events for EFS.
Time frame: From registration/randomization to the earliest of systemic recurrence outside urinary tract, cancer progression, or death from any cause, assessed up to 5 years
Pathologic complete response (pCR) (Cisplatin ineligible cohort: Arm C)
Will assess pathologic complete response at surgery (pCR, pT0N0/Nx) by local pathology review. Patients who drop out prior to surgery or who have unknown response status will be considered as non-responders.
Time frame: At surgery
pCR (Cisplatin-eligible cohort: Arms A and B)
Time frame: Up to 5 years
EFS (cisplatin-ineligible cohort: Arm C)
Will be characterized using the Kaplan-Meier method.
Time frame: From registration/randomization to the earliest of systemic recurrence outside urinary tract, cancer progression, or death from any cause, assessed up to 5 years
Overall survival (OS) (All Patients)
OS will be evaluated by arm, post chemotherapy response (ypCR, stage yp =\< T1N0, yp \>= T2N0), as well as stage (ypCR and \> ypCR) within and across treatment arms. Will be estimated using Kaplan-Meier method.
Time frame: From registration/randomization to death from any cause, assessed up to 5 years
Urothelial cancer-free survival or disease-free survival (All Patients)
A return of UTUC includes non-muscle invasive recurrences, pathologic T2 or higher muscle-invasive recurrences specifically in the urinary tract, metastatic disease outside the urinary tract, or death. Patients alive without documented UTUC will be censored at the date of last disease assessment.
Time frame: From the date of surgery to the earlier of a return of upper tract urothelial cancer (UTUC) or death from any cause, assessed up to 5 years
Cancer-specific survival (All Patients)
Will be analyzed using Gray's method and cumulative incidence estimates will be reported.
Time frame: From registration/randomization to death due to cancer; deaths due to other causes will be counted as competing events, assessed up to 5 years
Renal function outcomes following systemic treatment and following radical nephroureterectomy (All Patients)
The proportion of patients with renal insufficiency (creatinine \[CrCl\] \< 60 ml/min) post chemotherapy and post nephroureterectomy as well as the proportion of patients with renal function improvement (CrCl \< 60 ml/min at baseline and CrCl \>= 60 ml/min on study) will be reported along with exact binomial confidence intervals. The distribution of changes in renal function post chemotherapy as well as post surgery from baseline will also be reported. The analysis of renal function outcomes will be performed among patients who receive at least one dose of study therapy.
Time frame: Post chemotherapy and post surgery
Incidence of adverse events (All Patients)
Toxicity will be evaluated in all treated patients.
Time frame: Up to 30 days post surgery
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Alta Bates Summit Medical Center-Herrick Campus
Berkeley, California, United States
ACTIVE_NOT_RECRUITINGCity of Hope Comprehensive Cancer Center
Duarte, California, United States
RECRUITINGPalo Alto Medical Foundation-Fremont
Fremont, California, United States
ACTIVE_NOT_RECRUITINGUC San Diego Moores Cancer Center
La Jolla, California, United States
RECRUITINGMemorial Medical Center
Modesto, California, United States
ACTIVE_NOT_RECRUITINGPalo Alto Medical Foundation-Camino Division
Mountain View, California, United States
ACTIVE_NOT_RECRUITING...and 247 more locations