Sirolimus in Treating Patients With Advanced Pancreatic Cancer
RATIONALE: Sirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase II trial is studying how well sirolimus works in treating patients with advanced pancreatic cancer.
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Clinical, Biological and Pharmacological Study of Rapamycin (Rapamune®, Sirolimus) in Patients With Advanced Pancreatic Cancer|
- Percentage of Patients With Overall Survival at 6 Months [ Time Frame: 6- month survival rate (6mSR) ] [ Designated as safety issue: No ]
- Response Rate (Complete, Partial Response and Stable Disease) as Assessed by RECIST [ Time Frame: response at 2 and 6 months ] [ Designated as safety issue: No ]Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression, a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Response for Stable disease was assessed at 2 months and for complete and partial response at 6 months.
- Severity of Adverse Events as Assessed by NCI CTCAE v3.0 [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
|Study Start Date:||January 2005|
|Study Completion Date:||June 2009|
|Primary Completion Date:||September 2008 (Final data collection date for primary outcome measure)|
Sirolimus 5mg. po QD continously (28 days=cycle)
Treatment with rapamycin will begin on Day 1 at a single flat dose level of 5 mg/day. Rapamycin will be administered continuously without interruption through all cycles in an outpatient setting. Each cycle will last 28 days.
Other Name: rapamycin
- To determine the proportion of patients with previously treated advanced pancreatic cancer surviving at 6 months after treatment with single agent rapamycin.
- To evaluate the relationship between activation of the PI3/Akt/mTOR/S6K signaling pathway in tumor tissues and rapamycin activity in this patient population.
- To characterize toxicity of rapamycin in this patient population.
- To determine the response rate, median time to treatment failure, and median survival of patients with previously treated advanced pancreatic cancer who are treated with single agent rapamycin.
- To characterize the pharmacokinetics of rapamycin in this patient population.
- To explore pharmacogenomic variables that affect rapamycin pharmacokinetics and clinical activity in this patient population.
- To determine the pharmacodynamic effects of rapamycin on S6 kinase activation in PBMC, normal skin, and normal oral mucosa obtained from patients treated with the drug and its relationship with rapamycin pharmacokinetics and clinical effects.
- To explore biomarkers in tumor tissues that might be associated with rapamycin clinical effects.
OUTLINE: Patients receive oral sirolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients undergo blood, normal skin, and tumor tissue collection at baseline and periodically during study for pharmacological, biological, and genotyping studies. Blood samples are analyzed by LC/MS/MS assay to assess rapamycin pharmacokinetics (PKs) during courses 1 and 2 and to determine baseline CYP3A4 activity. Samples are also analyzed by genotyping studies to assess CYP3A4 polymorphisms. Pharmacodynamic activity of rapamycin is assessed in peripheral blood mononuclear cells isolated from PK blood samples using a kinase assay to measure S6K activity. Tumor tissue is collected from pretreatment tumor samples obtained at the time of diagnosis or surgery or by biopsy from patients for whom pre-study tumor specimens are not available. Patients undergo skin biopsies at baseline and on day 1 of course 2 to obtain samples of normal skin. Patients also undergo oral mucosa smears at baseline and weekly during course 1. Tumor tissue, normal skin, and oral mucosa samples are assessed by IHC staining of S6K and p-S6K and by RT-PCR for cyclin D1 and p27.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00499486
|United States, Maryland|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins|
|Baltimore, Maryland, United States, 21231-2410|
|Principal Investigator:||Manuel Hidalgo, MD, PhD||Sidney Kimmel Comprehensive Cancer Center|