Sirolimus, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Bladder Cancer
|Recurrent Bladder Carcinoma Stage II Bladder Cancer Stage III Bladder Cancer Stage IV Bladder Cancer||Drug: Cisplatin Drug: Gemcitabine Hydrochloride Other: Laboratory Biomarker Analysis Drug: Sirolimus Procedure: Therapeutic Conventional Surgery||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Phase 1-2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Bladder Cancer|
- MTD of sirolimus based on the incidence of dose-limiting toxicity (DLT) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: Up to 28 days ]Safety will be assessed through summaries of adverse events, vital signs, physical examinations, and clinical laboratory test data (including change from baseline).
- Percent of patients with pathologic complete response (Phase II) [ Time Frame: 12 weeks ]The study will follow an optimal two-stage Simon design based on pathologic complete response rate.
- DNA microenvironment damage-responsive proteins and transcripts using immunohistochemistry (IHC) assay and polymerase chain reaction [ Time Frame: Up to 28 days after completion of study treatment ]IHC will be performed and evaluated using antibodies to IL6, WNT16B and will assess mTOR blockade using antibodies to S6. Panels of microenvironment transcripts will be quantitated including WNT16B, SPINK1, IL6, MMPs, and Amphiregulin. Tumor cell transcripts will include Ki67, p16, p27, Myc and epithelial-mesenchymal transition (EMT) markers including vimentin and Snail.
- Incidence of adverse events including any unfavorable and unintended sign, symptom, diagnosis, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product (Phase I and II) [ Time Frame: Up to 28 days after completion of study treatment ]Graded according to the NCI CTCAE version 4.0. Safety will be assessed through summaries of adverse events, vital signs, physical examinations, and clinical laboratory test data (including change from baseline). All adverse events resulting in discontinuation, dose modification, dosing interruption, and/or treatment delay of study drug will also be listed and tabulated by preferred term.
|Study Start Date:||October 2013|
|Primary Completion Date:||August 18, 2016 (Final data collection date for primary outcome measure)|
Experimental: Treatment (sirolimus, cisplatin, gemcitabine hydrochloride)
Patients receive sirolimus PO two hours before or after grapefruit juice on day -2, cisplatin IV on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy as clinically appropriate after 1-4 courses of treatment.
Other Names:Drug: Gemcitabine Hydrochloride
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Sirolimus
Other Names:Procedure: Therapeutic Conventional Surgery
Undergo cystectomy when appropriate
I. To define the maximum-tolerated dose (MTD) of sirolimus (rapamycin) combined with gemcitabine hydrochloride and cisplatin (GC). (Phase I)
II. To determine the pathologic complete response rate at cystectomy in patients with localized, muscle invasive carcinoma of the bladder (clinical tumor [T]2-4, node [N]0 or N1). (Phase II)
I. To assess the response rate to rapamycin combined with GC. (Phase I)
II. To assess effect of rapamycin with GC on deoxyribonucleic acid (DNA) damage surrogates in cancer associated stroma compared to untreated and GC treated stroma. (Phase I)
III. To assess effect of rapamycin with GC on DNA damage surrogates in cancer associated stroma compared to untreated and GC treated stroma. (Phase II)
IV. To assess toxicity of the MTD dose of rapamycin with GC. (Phase II)
OUTLINE: This is a phase I, dose de-escalation study of sirolimus followed by a phase II study.
Patients receive sirolimus orally (PO) two hours before or after grapefruit juice on day -2, cisplatin intravenously (IV) on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy as clinically appropriate after 1-4 courses of treatment.
After completion of study treatment, patients are followed up for 28 days.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01938573
|United States, Washington|
|VA Puget Sound Health Care System|
|Seattle, Washington, United States, 98101|
|Fred Hutch/University of Washington Cancer Consortium|
|Seattle, Washington, United States, 98109|
|Principal Investigator:||Robert Montgomery||Fred Hutch/University of Washington Cancer Consortium|