Clinical trial NCT00499486
Conditions: Pancreatic Cancer
Keywords: recurrent pancreatic cancer stage III pancreatic cancer stage IV pancreatic cancer adenocarcinoma of the pancreas
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2005-01-01; Completion date: 2009-06-01
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

Detailed description:
OBJECTIVES:

Primary

* 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.

Secondary

* 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.

Arms: arm 1: Sirolimus 5mg. po QD continously (28 days=cycle)
Interventions: intervention 1: sirolimus
Intervention descriptions: intervention 1: 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.

Protocol documents: