Sirolimus in Treating Patients With Advanced Pancreatic Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00499486
Recruitment Status : Completed
First Posted : July 11, 2007
Results First Posted : October 19, 2016
Last Update Posted : October 19, 2016
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

July 10, 2007
July 11, 2007
March 18, 2013
October 19, 2016
October 19, 2016
January 2005
September 2008   (Final data collection date for primary outcome measure)
  • Percentage of Patients With Overall Survival at 6 Months [ Time Frame: 6- month survival rate (6mSR) ]
  • Response Rate (Complete, Partial Response and Stable Disease) as Assessed by RECIST [ Time Frame: response at 2 and 6 months ]
    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 ]
  • Proportion of patients surviving after 6 months
  • Response rate (complete and partial response, stable and progressive disease) as assessed by RECIST
  • Overall and progression-free survival at 6 and 12 months
  • Relationship between activation of PI3K/Akt/mTOR/S6K pathway and survival
  • Toxicity as assessed by NCI CTCAE v3.0
Complete list of historical versions of study NCT00499486 on Archive Site
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Sirolimus in Treating Patients With Advanced Pancreatic Cancer
Phase II Clinical, Biological and Pharmacological Study of Rapamycin (Rapamune®, Sirolimus) in 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.



  • 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.

Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Pancreatic Cancer
Drug: sirolimus
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
Experimental: Sirolimus
Sirolimus 5mg. po QD continously (28 days=cycle)
Intervention: Drug: sirolimus
Garrido-Laguna I, Tan AC, Uson M, Angenendt M, Ma WW, Villaroel MC, Zhao M, Rajeshkumar NV, Jimeno A, Donehower R, Iacobuzio-Donahue C, Barrett M, Rudek MA, Rubio-Viqueira B, Laheru D, Hidalgo M. Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer. Br J Cancer. 2010 Aug 24;103(5):649-55. doi: 10.1038/sj.bjc.6605819. Epub 2010 Jul 27.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
June 2009
September 2008   (Final data collection date for primary outcome measure)


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
Sexes Eligible for Study: All
18 Years to 120 Years   (Adult, Older Adult)
Contact information is only displayed when the study is recruiting subjects
United States
JHOC-J0415, CDR0000549899
P30CA006973 ( U.S. NIH Grant/Contract )
Not Provided
Plan to Share IPD: Undecided
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Principal Investigator: Manuel Hidalgo, MD, PhD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP