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A Pilot Study of Sirolimus (Rapamycin, Rapammune[Registered Trademark]) in Subjects With Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN

This study is currently Recruiting

January 2011 By National Institutes of Health Clinical Center (CC)

First Recieved on September 3, 2009

Last Updated on August 30, 2011

Sponsor: National Cancer Institute (NCI)
Information provided by: National Institutes of Health Clinical Center (CC)
Identifier: NCT00971789


Background: People with PTEN hamartomatous tumor syndromes (PHTS) have a mutation in one of their genes called PTEN that can lead to benign tumors called hamartomas throughout the body. This puts them at increased risk for breast, thyroid and endometrial cancer. People with a PTEN mutation have increased activity of proteins such as AKT and mTOR, which may be responsible for tumor growth and their increased risk of these cancers. Experiments show that a drug called sirolimus, which is used to prevent the immune system from rejecting transplanted organs, can inhibit cancer cell growth by blocking the mTOR protein. Objectives: To test the ability of sirolimus to decrease the activity of proteins that are regulated by mTOR in both benign and cancerous tumor tissue. Eligibility: People 18 years of age and older with Cowden syndrome or other PHTS. Design: Sirolimus treatment. Patients take sirolimus once a day in 28-day treatment cycles. Patients who do not have cancer take the drug for a total of two cycles (56 days) unless they develop unacceptable side effects. Those who have cancer may continue sirolimus beyond cycle 2 until their disease worsens or they develop unacceptable side effects. Evaluations. Patients come to the clinic for a history and physical examination on day 1 of every treatment cycle, then every month for the first two months off therapy, and then at 6 and 12 months. In addition, they have the following procedures: - PET scan and neuropsychological testing before starting treatment. - Clinical photography (photographic documentation of skin lesions) before starting treatment. Patients who do not have cancer have repeat photography at 2 and 8 weeks and then, if the lesions shrink or go away while on therapy, again every month for the first 2 months off sirolimus, then at 6 months and 1 year. Patients who have cancer and continue treatment beyond 8 weeks have repeat photography every 8 weeks while on the study. - Digital dermoscopy (skin lesion examination using a high resolution camera). This is done at the same intervals as clinical photography. - Multiple biopsies of the skin and lower intestine, and possibly the tumor in patients with cancer, before starting treatment, at 2 weeks of treatment and at 8 weeks of treatment. - Blood and urine tests every week while on treatment for the first two cycles, then every 4 weeks for patients who continue treatment beyond two cycles. - Imaging st...

Study Type: Interventional
Study Design: Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment


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

-INCLUSION CRITERIA: 1. Patients must have documented germline PTEN mutation performed in a CLIA approved laboratory. 2. Patients must meet clinical criteria for Cowden Syndrome. 3. Patients must have the capacity to provide informed consent and demonstrate willingness to comply with an oral regimen. 4. Patients must have at least 6 sites amenable to biopsy within the skin and/or GI tract and /or accessible malignant tumor (for patients with malignancy) and agree to the biopsy of these sites prior to and following sirolimus administration. 5. Patients do not need to have malignant tumors, but if they do, they must have relapsed or failed to respond to standard therapy, and the patient's current disease state must be one for which there is no known curative therapy. Patients who are diagnosed with cancer as a consequence of initial PET/CT scan will be managed according to the flow diagram illustration. 6. Patients must have not received chemotherapy in the 28 days prior to enrollment. 7. Age greater than or equal to 18 years of age. 8. ECOG performance score of less than or equal to 2. 9. An expected survival of greater than or equal to 3 months. 10. Patients must consent to the use of effective barrier-based contraception during the course of treatment and for three months following discontinuation of treatment. 11. Patients must have normal organ and marrow function as defined below: - absolute neutrophil count greater than or equal to 1,500/mL. - platelets greater than or equal to 100,000/mL. - total bilirubin less than 1.5 times upper limit of institutional normal. - AST (SGOT) less than or equal to 2.5 times upper limit of institutional normal. - ALT (SGPT) less than or equal to 2.5 times upper limit of institutional normal. - Creatinine less than 1.5 times upper limit of institutional normal. 12. PHTS subjects with benign hamartomatous disease must have controlled fasting LDL and triglyceride levels as defined by NCEP ATP III guidelines. Please see section 3.5 for further details. 13. Patients must have recovered from any acute toxicity related to prior treatments, including surgery. Toxicity should be < grade 1 or returned to baseline. 14. If a patient withdraws consent within two weeks of starting study drug, he/she may request to re-enter study at the PI's discretion by re-signing consent and being re-registered through the CRO using the initial baseline studies. Sirolimus taken during the period on study (prior to withdrawal of consent) will not be considered as prior sirolimus therapy that otherwise would exclude enrolment. EXCLUSION CRITERIA: 1. Pregnant or lactating women, due to potentially harmful effects of sirolimus on the embryo or fetus or nursing child. 2. Any concurrent therapy with chemotherapeutic agents or biologic agents or radiation therapy. 3. Patients taking immuno-suppressive agents other than prescribed corticosteroids, which must not exceed the equivalent of 20 mg/d of prednisone. 4. Patients that are on the following CYP3A4 inhibitors and cannot replace these medications with other equivalent medications for the period of the study: protease inhibitors, cyclosporine, fluconazole, itraconazole, ketoconazole, metoclopramide, felodipine, nifedipine, carbamazepine, Phenobarbital, grapefruit juice, and St. John's Wort. 5. Patients who have received live vaccines in the past 30 days. 6. Patients with human immunodeficiency virus (HIV) seropositivity, due to potential drug interactions between sirolimus and anti-retroviral medications, as well as the unknown effects of single agent sirolimus on the immune system in HIV patients. 7. Patients with interstitial lung disease or pneumonitis. 8. Patients with bleeding diathesis. 9. Patients with prior or active pneumocystis jirovecii (PJP) pneumonia. 10. Patients with prior use of rapamycin, a rapamycin analogue, or other mTOR inhibitor. 11. Patients who do not agree to have multiple repeated biopsies performed.



  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland 20892 United States

Conditions related to this trial:

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