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Pilot Study of mTOR Inhibitor Therapy for Treatment of Intestinal Polyps in Peutz-Jeghers Syndrome

Phase 2
18 Years
Not Enrolling
Peutz-Jeghers Syndrome

Thank you

Trial Information

Pilot Study of mTOR Inhibitor Therapy for Treatment of Intestinal Polyps in Peutz-Jeghers Syndrome

Peutz-Jeghers Syndrome is a hereditary polyposis condition in which hamartomatous tumors
develop in many tissues of the body. These tumors are benign but frequently cause
gastrointestinal obstruction and bleeding beginning in the 2nd-3rd decades of life
necessitating surgical intervention. Unfortunately, a recent study showed that the lifetime
risk of cancers that arise in Peutz-Jeghers Syndrome is 85% by age 70 years and is 60% by
age 60 years (Hearle et al., 2006).

A working definition of PJS has been suggested by Giardiello et al ,1987(

- For individuals with a histopathologically confirmed hamartoma, a definite diagnosis of
PJS requires two of the following three findings:

- Family history consistent with autosomal dominant inheritance

- Mucocutaneous hyperpigmentation (although this can fade with age)

- Small-bowel polyposis

- For individuals without histopathologic verification of hamartomatous polyps, a
probable diagnosis of PJS can be made based on the presence of two of the three
clinical criteria above.

- For individuals without a family history of PJS, diagnosis depends upon the presence of
two or more histologically verified Peutz-Jeghers-type hamartomatous polyps (Tomlinson
& Houlston 1997).

- For individuals with a first-degree relative with PJS, presence of mucocutaneous
hyperpigmentation is sufficient for presumptive diagnosis.

Recently, rapamycin (Rapamune, Wyeth), an FDA-approved drug for use in orthotopic transplant
recipients, was successfully used in an off-label study of 5 individuals with a related
condition called tuberous sclerosis in which the patients had subependymal giant cell
astrocytomas that caused significant and insidious neurological problems such as
hydrocephalus and seizures (Franz, et al. 2006). All astrocytoma lesions exhibited
regression with treatment of oral rapamycin and in one case, necrosis. Treatment was well
tolerated and may offer an alternative to operative therapy in tuberous sclerosis. Tuberous
sclerosis is caused by germline mutations in the tuberous sclerosis 1 or 2 genes. These
genes encode proteins that function downstream of STK11, the gene that is mutated in
Peutz-Jeghers Syndrome. Mutations of STK11 or TSC1/2 leads to activation of mTOR (mammalian
target of rapamycin). Dysregulation of mTOR has been demonstrated in several types of
cancers and clinical trials are underway to see if inhibition of mTOR will be of benefit to
a variety of cancer patients. A recent trial showed efficacy of everolimus in advanced
renal cancer (Hudes, et al. 2007).

All of these studies will be performed on an outpatient basis.

Inclusion Criteria:

Yes/No (Response of "no" = patient ineligible)

1. Patients who are 18 years or older with a clinical or genetic diagnosis of
Peutz-Jeghers Syndrome.

2. Patient has one or more intestinal polyps ≥ 5mm in maximum diameter by contrast
enhanced CT scan that is not clinically indicated for removal or is beyond the reach
of a push endoscope.

3. Minimum of two weeks since any major surgery.

4. Patient has had colonoscopy within the past 24 months and did not have high-grade
dysplasia or colorectal cancers.

5. WHO performance status £ 2

6. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x
109/L, Hgb > 9 g/dL

7. Adequate liver function as shown by: serum bilirubin ≤ 1.5 x upper limit of normal
(ULN), and serum transaminases activity ≤ 2.5 x ULN.

8. Patients must be able to provide written informed consent.

Exclusion Criteria:

Yes/No (Response of "yes" = patient ineligible)

1. Prior treatment with any investigational drug within the preceding 4 weeks

2. Chronic treatment with systemic steroids or another immunosuppressive agent

3. Patients should not receive immunization with attenuated live vaccines during study
period or within one week of study entry

4. Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

5. Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin.

6. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

1. Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction ≤ 6 months prior to first study treatment, serious uncontrolled
cardiac arrhythmia

2. Severely impaired lung function

3. Uncontrolled diabetes as defined by fasting serum glucose >1.5x ULN

4. Any active (acute or chronic) or uncontrolled infection/ disorders.

5. Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy

6. Liver disease such as cirrhosis, or severe hepatic impairment (Child-Pugh class

7. A known history of HIV seropositivity

8. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel

9. Patients with an active, bleeding diathesis or on oral anti-vitamin K medication

7. Women who are pregnant or breast feeding, or women/men able to conceive and unwilling
to practice an effective method of birth control throughout the trial and for 8 weeks
after the last dose of study drug. (Women of childbearing potential must have a
negative pregnancy test). Oral, implantable, or injectable contraceptives may be
affected by cytochrome P450 interactions, and are therefore not considered effective
for this study.

8. Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception during the study and for 9 weeks after the end of treatment.

9. Patients who have received treatment with an mTor inhibitor in the past 6 months.

10. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins
(sirolimus, temsirolimus) or to its excipients

Patients who can not undergo FDG-PET are eligible to participate in this study for the
purpose of the primary endpoint. Patient with the following will be excluded from FDG-PET
piece of the study.

1. Patients cannot have a serum glucose level greater than 200 mg/dl for FDG-PET imaging

2. Patients who are too claustrophobic to undergo FDG-PET imaging

3. Patients who will require conscious sedation to undergo FDG-PET imaging.

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The Size of Intestinal Polyps

Outcome Time Frame:

24 months

Safety Issue:


Principal Investigator

Randall W Burt, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Huntsman Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

November 2008

Completion Date:

March 2011

Related Keywords:

  • Peutz-Jeghers Syndrome
  • Cancer
  • Polyps
  • Peutz-Jeghers Syndrome



Huntsman Cancer Institute Salt Lake City, Utah  84112