Sirolimus to Treat Cowden Syndrome and Other PTEN Hamartomatous Tumor Syndromes
Condition: Cowden's Disease; Hamartoma Syndrome, Multiple
MeSH terms: Hamartoma; Hamartoma Syndrome, Multiple; Syndrome
Intervention: fludeoxyglucose F 18; sirolimus; Clinical Videography
Intervention description: Fludeoxyglucose is the radioactive material/compound used as an injection to have a PET scan performed.; sirolimus 6 mg by mouth loading dose and 2 mg by mouth daily in a 28 day treatment cycle. 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; This examination involves testing of cerebellar function that controls movement, balance, and coordination.
Intervention MeSH terms: Sirolimus; Fluorodeoxyglucose F18
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Sirolimus; Cowden Syndrome; PTEN Mutation; Hamartoma Syndrome

Summary:

      Background:

      People with phosphatase and tensin homolog deleted on chromosome 10 (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 protein kinase B
      (AKT) and mammalian target of rapamycin (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:

        -  Positron emission tomography (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 computerized tomography (CT), ultrasound or magnetic resonance
           imaging (MRI) in patients with cancer before starting treatment and again every two
           cycles to monitor the tumor size and location.
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Patients must have documented germline phosphatase and tensin homolog deleted on
             chromosome 10 (PTEN) mutation performed in a Clinical Laboratory Improvement
             Amendments (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
             gastrointestinal (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 positron emission tomography (PET)/computerized
             tomography (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. Eastern Cooperative Oncology Group (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.

               -  Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase(SGOT)
                  less than or equal to 2.5 times upper limit of institutional normal.

               -  Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(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 low
             density lipoprotein (LDL) and triglyceride levels as defined by National Cholesterol
             Education Program Adult Treatment Panel III (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 principal investigators (PI's) discretion by
             re-signing consent and being re-registered through the Central Registration Office
             (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 enrollment.

        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 cytochrome P450 3A4 (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.