Protocol Number: 08-C-0151

Title:

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

Number:

08-C-0151

Summary:

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 studies, such as CT, ultrasound or MRI in patients with cancer before starting treatment and again every two cycles to monitor the tumor size and location.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

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. Cowden syndrome diagnostic criteria are listed in appendix 10.7.

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.

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.

Special Instructions:

Currently Not Provided

Keywords:

Sirolimus

Cowden Syndrome

PTEN Mutation

Recruitment Keyword(s):

Cowden Syndrome

Hamartoma Syndrome

Condition(s):

Cowden's Disease

Hamartoma Syndrome, Multiple

Investigational Drug(s):

(FDG-PET)

Investigational Device(s):

None

Intervention(s):

Drug: (FDG-PET)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997 Mar 28;275(5308):1943-7.

Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, PeltomŠki P, de la Chapelle A, Aaltonen LA, Eng C. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am J Pathol. 2002 Aug;161(2):439-47.

Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM, Eng C. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet. 2001 Jul 21;358(9277):210-1.

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