CompletedNCT00971789Updated Sep 30, 2015Results posted

Sirolimus to Treat Cowden Syndrome and Other PTEN Hamartomatous Tumor Syndromes

A Phase 2 interventional study of fludeoxyglucose F 18 and sirolimus in Cowden's Disease and Hamartoma Syndrome, Multiple, sponsored by National Cancer Institute (NCI). Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2015-09-30.

Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 18
Allocation: Not applicable
Ages: 18 Years and older
Sex: All

Study 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.

Read the detailed description

Background:

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 phosphoinositide 3-kinase (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.
Cowden syndrome (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 Food and Drug Administration (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.

Objectives:

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 peripheral blood mononuclear cells (PBMCs) as assessed by immunoblotting, changes and duration of change in benign or malignant tumor size as assessed by computed tomography (CT), serial digital photography, digital dermoscopy, changes in tumor metabolism as assessed by positron emission tomography (PET), changes in lymphocyte counts, as well as changes in neuropsychological testing.

Eligibility:

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

Design:

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 treatment.
This pilot protocol will test sirolimus at an FDA-approved dose (6 mg by mouth (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 toxicity.

Conditions studied

Cowden's Disease
Hamartoma Syndrome, Multiple

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Keywords

Sirolimus
Cowden Syndrome
PTEN Mutation
Hamartoma Syndrome

In context

Hamartoma Syndrome, Multiple

20 studies on the registry are indexed under Hamartoma Syndrome, Multiple; 9 are open to participants now.

Browse Hamartoma Syndrome, Multiple studies →

Lead sponsor

National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.

Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

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.
- 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.
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.
Patients must have recovered from any acute toxicity related to prior treatments, including surgery. Toxicity should be \< grade 1 or returned to baseline.
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

EXCLUSION CRITERIA:

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.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 18 participants (actual)

Study arms

Experimental
Sirolimus Patients
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

Radiationfludeoxyglucose F 18
Fludeoxyglucose is the radioactive material/compound used as an injection to have a PET scan performed.
Also known as: FDG-18
Drugsirolimus
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
OtherClinical Videography
This examination involves testing of cerebellar function that controls movement, balance, and coordination.

What researchers measure

Primary outcomes

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).
Time frame: Baseline, day 14, and day 56
Number of Participants With Adverse Events
Here is the number of participants with adverse events
Time frame: 47 months

Results

Posted Jul 19, 2013

Participant flow

Participant flow — Overall Study
Milestone	Sirolimus Patients
Started	18
Completed	18
Not completed	0

Outcome measures

PrimaryBiochemical 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).

Time frame:: Baseline, day 14, and day 56

No measurements were reported for this outcome.

PrimaryNumber of Participants With Adverse Events

Here is the number of participants with adverse events

Time frame:: 47 months
Reported as:: Number · Participants

Number of Participants With Adverse Events
Participants	Sirolimus Patients
Number of Participants With Adverse Events	17

Adverse events

Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Sirolimus Patients	—	0/18 (0%)	17/18 (94.4%)

Most frequent other events

Showing 10 of 62

Most frequent other events
Event	Sirolimus Patients
ALT, SGPT (serum glutamic pyruvic transaminase)Metabolism and nutrition disorders	7/18
Albumin, serum-low (hypoalbuminemia)Metabolism and nutrition disorders	7/18
Fatigue (asthenia, lethargy, malaise)General disorders	7/18
HemoglobinMetabolism and nutrition disorders	7/18
DiarrheaGastrointestinal disorders	6/18
Alkaline phosphataseMetabolism and nutrition disorders	5/18
Cholesterol, serum-high (hypercholesteremia)Metabolism and nutrition disorders	5/18
Triglyceride, serum-high (hypertriglyceridemia)Metabolism and nutrition disorders	5/18
ConstipationGastrointestinal disorders	4/18
InsomniaGeneral disorders	4/18

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Sirolimus Patients
<=18 years	0
Between 18 and 65 years	15
>=65 years	3

Age, Continuous
Age, Continuous(years)	Sirolimus Patients
Mean	43.54 ± 15.54

Sex: Female, Male
Sex: Female, Male(Participants)	Sirolimus Patients
Female	9
Male	9

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Sirolimus Patients
Hispanic or Latino	0
Not Hispanic or Latino	18
Unknown or Not Reported	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Sirolimus Patients
American Indian or Alaska Native	0
Asian	1
Native Hawaiian or Other Pacific Islander	0
Black or African American	0
White	17
More than one race	0
Unknown or Not Reported	0

Region of Enrollment
Region of Enrollment(participants)	Sirolimus Patients
United States	18

Study locations

1 site

National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland 20892, United States

References and documents

Publications

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. PubMed 9072974 ↗
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. PubMed 12163369 ↗
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. PubMed 11476841 ↗
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. PubMed 31350329 ↗
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. PubMed 23344409 ↗

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Sep 30, 2015, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT00971789
Lead sponsor: National Cancer Institute (NCI)
Responsible party: Arun Rajan, M.D. (Principal Investigator, National Institutes of Health Clinical Center (CC)) — Principal investigator
First posted: Sep 4, 2009
Start date: Jul 2008
Primary completion: Oct 2012
Completion: Oct 2012
Results posted: Jul 19, 2013
Last update: Sep 30, 2015

Study contacts

Arun Rajan, M.D.

principal investigator · National Cancer Institute (NCI)

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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