Sirolimus in Treating Patients With Advanced Pancreatic Cancer
Condition: Pancreatic Cancer
MeSH terms: Pancreatic Neoplasms
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): sirolimus
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): rapamycin
Intervention MeSH terms: Sirolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent pancreatic cancer; stage III pancreatic cancer; stage IV pancreatic cancer; adenocarcinoma of the pancreas