Sirolimus, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Bladder Cancer
This phase I/II trial studies the side effects and the best dose of sirolimus when given together with cisplatin and gemcitabine hydrochloride and to see how well it works in treating patients with bladder cancer. Biological therapies, such as sirolimus, may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as cisplatin and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sirolimus together with cisplatin and gemcitabine hydrochloride may be an effective treatment for bladder cancer.
Adenocarcinoma of the Bladder
Recurrent Bladder Cancer
Stage II Bladder Cancer
Stage III Bladder Cancer
Stage IV Bladder Cancer
Transitional Cell Carcinoma of the Bladder
Drug: gemcitabine hydrochloride
Other: laboratory biomarker analysis
Procedure: therapeutic conventional surgery
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
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 ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: No ]The study will follow an optimal two-stage Simon design based on pathologic complete response rate.
- DNA microenvironment damage response proteins using immunohistochemistry (IHC) assay [ Time Frame: Up to 28 days after completion of study treatment ] [ Designated as safety issue: No ]IHC will be performed and evaluated using antibodies to interleukin 6 (IL6), Wingless-Type MMTV Integration Site Family, Member 16 (WNT16B) and will assess mammalian target of rapamycin (mTOR) blockade using antibodies to S6.
- DNA microenvironment damage-responsive transcripts by polymerase chain reaction (PCR) [ Time Frame: Up to 28 days after completion of study treatment ] [ Designated as safety issue: No ]Panels of microenvironment transcripts will be quantitated including WNT16B, serine protease inhibitor Kazal-type 1 (SPINK1), IL6, Matrix metalloproteinases (MMPs), and Amphiregulin. Tumor cell transcripts will include Ki67, p16, p27, myelocytomatosis oncogene (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 ] [ Designated as safety issue: Yes ]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:||December 2013|
|Estimated Primary Completion Date:||October 2014 (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: cisplatin
Other Names:Drug: gemcitabine hydrochloride
Other Names:Other: laboratory biomarker analysis
Correlative studiesProcedure: therapeutic conventional surgery
Undergo cystectomy when appropriate
I. To define the maximum-tolerated dose (MTD) of rapamycin (sirolimus) 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|
|Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium||Recruiting|
|Seattle, Washington, United States, 98109|
|Contact: Robert B. Montgomery 206-616-8289|
|Principal Investigator: Robert B. Montgomery|
|Principal Investigator:||Robert Montgomery||Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium|