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.
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.
;
Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Enrolling by invitation |
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N/A |