Sirolimus in Treating Patients With Advanced Pancreatic Cancer

This study has been completed.
National Cancer Institute (NCI)
Information provided by:
Sidney Kimmel Comprehensive Cancer Center Identifier:
First received: July 10, 2007
Last updated: August 5, 2010
Last verified: August 2010

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.

Condition Intervention Phase
Pancreatic Cancer
Drug: sirolimus
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
Procedure: biopsy
Phase 2

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Phase II Clinical, Biological and Pharmacological Study of Rapamycin (Rapamune®, Sirolimus) in Patients With Advanced Pancreatic Cancer

Resource links provided by NLM:

Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • Pharmacokinetics [ Designated as safety issue: No ]

Estimated Enrollment: 50
Study Start Date: January 2005
Detailed Description:



  • 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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No


Inclusion criteria:

  • Histologically proven adenocarcinoma of the pancreas

    • Locally-advanced or advanced disease which has progressed after one prior gemcitabine-containing regimen
  • Unidimensionally measurable disease (defined as at least one unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan) OR evaluable disease
  • Tumor tissue available for IHC assessment OR willingness to undergo a safe biopsy of tumor tissue

Exclusion criteria:

  • Histologic or cytologic diagnosis that is not consistent with adenocarcinoma, including adenosquamous, islet cell, cystadenoma or cystadenocarcinoma, carcinoid, or small or large cell carcinoma or lymphoma
  • Adenocarcinoma arising from a site other than the pancreas (e.g., distal common bile duct, ampulla of vater or periampullary duodenum)
  • Known brain metastases


Inclusion criteria:

  • ECOG performance status 0-1
  • WBC > 3,500 cells/mm³
  • ANC > 1,500 cells/mm³
  • Hemoglobin > 9 g/dL
  • Serum creatinine ≤ 2.0 mg/dL
  • Bilirubin ≤ 2 mg/dL
  • ALT, AST, and alkaline phosphatase ≤ 5 times upper limit of normal
  • Triglycerides and total cholesterol < 2 times upper limit of normal
  • Not pregnant or nursing

Exclusion criteria:

  • Uncontrolled medical conditions that could potentially increase the risk of toxicities or complications of this therapy, including immunodeficiency and chronic treatment with immunosuppressors
  • Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease
  • Active infections
  • History of concurrent malignancy or history of a second malignancy within the past 5 years
  • Clinically significant cardiovascular disease, including myocardial infarction (within 12 months prior to randomization), unstable angina, grade II or greater peripheral vascular disease, uncontrolled congestive heart failure, or uncontrolled hypertension (i.e., systolic blood pressure (BP) > 170 mm Hg, diastolic BP > 95 mm Hg)


Exclusion criteria:

  • Any unresolved chronic toxicity greater than CTCAE grade 2 from previous anticancer therapy
  • Any previous surgery, excluding minor procedures (e.g., dental work or skin biopsy) within 4 weeks of enrollment
  • Participation in an investigational new drug trial within 1 month of starting trial
  • Treatment with chemotherapy within 30 days of day 1 treatment
  • At least 10 days since prior and no concurrent:

    • Cyclosporine
    • Diltiazem
    • Ketoconazole
    • Rifampin
    • St. Johns wort
    • Grapefruit juice
  • Concurrent phenytoin, carbamazepine, barbiturates, or phenobarbital
  • No other concurrent investigational or commercial agents
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00499486

United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
National Cancer Institute (NCI)
Principal Investigator: Manuel Hidalgo, MD, PhD Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided Identifier: NCT00499486     History of Changes
Other Study ID Numbers: JHOC-J0415, CDR0000549899  P30CA006973  JHOC-J0415  JHOC-04-06-16-01 
Study First Received: July 10, 2007
Last Updated: August 5, 2010
Health Authority: United States: Food and Drug Administration

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
recurrent pancreatic cancer
stage III pancreatic cancer
stage IV pancreatic cancer
adenocarcinoma of the pancreas

Additional relevant MeSH terms:
Pancreatic Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Neoplasms by Site
Pancreatic Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses processed this record on February 04, 2016