Hamartoma Syndrome, Multiple Clinical Trial
Official title:
A Pilot Study of Sirolimus (Rapamycin, Rapamune[Registered Trademark]) in Subjects With Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN
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.
| Status | Completed |
| Enrollment | 18 |
| Est. completion date | October 2012 |
| Est. primary completion date | October 2012 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years and older |
| Eligibility |
-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. |
Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| United States | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland |
| Lead Sponsor | Collaborator |
|---|---|
| National Cancer Institute (NCI) |
United States,
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. — View Citation
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. — View Citation
Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, Peltomäki 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. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | No |
| Primary | Number of Participants With Adverse Events | Here is the number of participants with adverse events | 47 months | Yes |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Enrolling by invitation |
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N/A |