Sirolimus to Treat Cowden Syndrome and Other PTEN Hamartomatous Tumor Syndromes

NCT00971789 | Completed Phase 2 Results

• 2 other identifiers: 08015108-C-0151
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Cowden's Disease; Hamartoma Syndrome, Multiple

Keywords

Sirolimus; Cowden Syndrome; PTEN Mutation; Hamartoma Syndrome

Outcome Measures

Primary Outcomes (2)

• Biochemical Changes in Benign and Malignant Tumor Tissues as Assessed by Immunohistochemistry.

  A biochemical change is defined as a decrease in certain protein levels (e.g. P-AKT (phosphorylated AKT), total S6, P-S6, and P-4E-BP1) important in cell growth. These are measured by collecting tissue samples which stained and protein levels are measured under the microscope. Scoring will be based on distribution and intensity of staining. Distribution will be scored as 0 (0%), 1 (1% to 50%), and 2 (51% to 100%) to indicate the percentage of positive cells of interest in a single core. The intensity of the signal will be scored as 1 (weak), 2 (moderate), and 3 (strong). The distribution score and intensity score will be summed into a total score (TS).

  Baseline, day 14, and day 56

• Number of Participants With Adverse Events

  Here is the number of participants with adverse events

  47 months

Study Arms (1)

Sirolimus Patients

EXPERIMENTAL

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.

Radiation: fludeoxyglucose F 18; Drug: sirolimus; Other: Clinical Videography

Interventions

fludeoxyglucose F 18 RADIATION

Fludeoxyglucose is the radioactive material/compound used as an injection to have a PET scan performed.

Also known as: FDG-18

Sirolimus Patients

sirolimus DRUG

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

Also known as: Rapamune

Sirolimus Patients

Clinical Videography OTHER

This examination involves testing of cerebellar function that controls movement, balance, and coordination.

Sirolimus Patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Patients must meet clinical criteria for Cowden Syndrome.
• Patients must have the capacity to provide informed consent and demonstrate willingness to comply with an oral regimen.
• 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.
• 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.
• Patients must have not received chemotherapy in the 28 days prior to enrollment.
• Age greater than or equal to 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2.
• An expected survival of greater than or equal to 3 months.
• Patients must consent to the use of effective barrier-based contraception during the course of treatment and for three months following discontinuation of treatment.
• 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.

You may not qualify if:

• Pregnant or lactating women, due to potentially harmful effects of sirolimus on the embryo or fetus or nursing child.
• Any concurrent therapy with chemotherapeutic agents or biologic agents or radiation therapy.
• Patients taking immuno-suppressive agents other than prescribed corticosteroids, which must not exceed the equivalent of 20 mg/d of prednisone.
• 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.
• Patients who have received live vaccines in the past 30 days.
• 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.
• Patients with interstitial lung disease or pneumonitis.
• Patients with bleeding diathesis.
• Patients with prior or active pneumocystis jirovecii (PJP) pneumonia.
• Patients with prior use of rapamycin, a rapamycin analogue, or other mTOR inhibitor.
• Patients who do not agree to have multiple repeated biopsies performed.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• 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. doi: 10.1126/science.275.5308.1943.

  PMID: 9072974 BACKGROUND

• Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, Peltomaki 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. doi: 10.1016/S0002-9440(10)64200-9.

  PMID: 12163369 BACKGROUND

• 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. doi: 10.1016/s0140-6736(01)05412-5.

  PMID: 11476841 BACKGROUND

• Komiya T, Blumenthal GM, DeChowdhury R, Fioravanti S, Ballas MS, Morris J, Hornyak TJ, Wank S, Hewitt SM, Morrow B, Memmott RM, Rajan A, Dennis PA. A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN. Oncologist. 2019 Dec;24(12):1510-e1265. doi: 10.1634/theoncologist.2019-0514. Epub 2019 Jul 26.

  PMID: 31350329 DERIVED

• Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P. Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer. Obstet Gynecol. 2013 Feb;121(2 Pt 2 Suppl 1):461-464.

  PMID: 23344409 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hamartoma Syndrome, Multiple

Interventions

Fluorodeoxyglucose F18; Sirolimus

Condition Hierarchy (Ancestors)

Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Deoxyglucose; Deoxy Sugars; Carbohydrates; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Arun Rajan
• Organization: National Cancer Institute, National Institutes of Health

rajana@mail.nih.gov

301-594-5322

Study Officials

• Arun Rajan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 3, 2009
• First Posted: September 4, 2009
• Study Start: July 1, 2008
• Primary Completion: October 1, 2012
• Study Completion: October 1, 2012
• Last Updated: September 30, 2015
• Results First Posted: July 19, 2013

Record last verified: 2013-07

Locations

US (1)