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.
Genetic: polymorphism analysis
Genetic: reverse transcriptase-polymerase chain reaction
Other: immunohistochemistry staining method
Other: laboratory biomarker analysis
Other: liquid chromatography
Other: mass spectrometry
Other: pharmacological study
|Study Design:||Primary Purpose: Treatment|
|Official Title:||Phase II Clinical, Biological and Pharmacological Study of Rapamycin (Rapamune®, Sirolimus) in Patients With Advanced Pancreatic Cancer|
- Proportion of patients surviving after 6 months [ Designated as safety issue: No ]
- Response rate (complete and partial response, stable and progressive disease) as assessed by RECIST [ Designated as safety issue: No ]
- Overall and progression-free survival at 6 and 12 months [ Designated as safety issue: No ]
- Relationship between activation of PI3K/Akt/mTOR/S6K pathway and survival [ Designated as safety issue: No ]
- Toxicity as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
- Pharmacokinetics [ Designated as safety issue: No ]
|Study Start Date:||January 2005|
- 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|