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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

Phase 2
18 Years
Not Enrolling
Cowden's Disease, Hamartoma Syndrome, Multiple

Thank you

Trial Information

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


- PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor
gene whose function is frequently lost through genetic and epigenetic mechanisms in
cancer. Loss of PTEN increases activation of the PI3K/Akt/mTOR pathway, which increases
cellular proliferation and survival.

- Germline mutations in PTEN are associated with a number of hamartomatous syndromes, of
which Cowden Syndrome (CS) is the prototype. The set of syndromes that are defined by
germline PTEN mutations has been labeled PTEN Hamartomatous Tumor Syndromes or PHTS.

- Patients with PHTS suffer increased morbidity and mortality. Benign tumors such as
hamartomas occur in virtually every organ, most commonly in the skin and the
gastrointestinal tract, which prompts frequent monitoring and resection and causes
psychological and physical stressors on patients with this condition.

- CS patients develop thyroid, breast, and endometrial cancers at an earlier age than the
general population, and have an overall increased incidence of these cancers compared
to the general population. These patients have increased morbidity from heightened
surveillance and diagnostic procedures.

- No medical therapies exist for PHTS patients.

- Because tumors from PHTS patients show increased activation of the PI3K/Akt/mTOR
pathway, inhibitors of this pathway might have activity in patients with PHTS.

- Sirolimus (rapamycin) is a specific inhibitor of mTOR that is FDA-approved and is
preferentially effective in cells with mutant PTEN.

- We hypothesize that sirolimus will have activity in patients with PHTS, as measured by
biochemical techniques that will assess mTOR inhibition and clinical tests that will
assess the growth and metabolism of benign and malignant tumors.


- The primary endpoint will be inhibition of the mTOR pathway in tissues obtained before
and after therapy, as assessed using immunohistochemistry in benign as well as
malignant tumors.

- Secondary endpoints will include inhibition of the mTOR pathway in PBMCs as assessed by
immunoblotting, changes and duration of change in benign or malignant tumor size as
assessed by CT, serial digital photography, digital dermoscopy, changes in tumor
metabolism as assessed by PET, changes in lymphocyte counts, as well as changes in
neuropsychological testing.


-Adult subjects with documented germline PTEN mutations who meet diagnostic criteria for
Cowden Syndrome by international criteria.


- Subjects will undergo biopsy, imaging, photography, dermoscopy, and neuropsychological
testing prior to and after a course of therapy with sirolimus to assess the efficacy of

- This pilot protocol will test sirolimus at an FDA-approved dose (6 mg PO loading dose/
2mg PO daily) in a group of twenty patients.

- Treatment will last for 56 days (plus 2 - 3 days to allow flexibility for scheduling of
follow-up procedures) for PHTS subjects with benign hamartomatous tumors.

- For PHTS subjects with established malignancy, measurement of disease will be performed
every other cycle and treatment will continue until disease progression or unacceptable

Inclusion Criteria


1. Patients must have documented germline PTEN mutation performed in a CLIA approved

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.


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

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.

Type of Study:


Study Design:

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

Outcome Measure:

Biochemical changes (i.e., inhibition of the PTEN/Akt/mTOR pathway) in benign and malignant tumor tissues as assessed by immunohistochemistry.

Safety Issue:


Principal Investigator

Giuseppe Giaccone, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

July 2008

Completion Date:

October 2012

Related Keywords:

  • Cowden's Disease
  • Hamartoma Syndrome, Multiple
  • Sirolimus
  • Cowden Syndrome
  • PTEN Mutation
  • Hamartoma Syndrome
  • Hamartoma
  • Hamartoma Syndrome, Multiple



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