Pilot Study of mTOR Inhibitor Therapy in Peutz-Jeghers Syndrome
Condition: Peutz-Jeghers Syndrome
MeSH terms: Peutz-Jeghers Syndrome; Syndrome
Intervention: Everolimus
Intervention description: Everolimus is a novel derivative of rapamycin. Everolimus has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation. Since 2003, RAD001 is approved in Europe (trade name: Certican) via the Mutual Recognition Procedure (MRP) for the prevention of organ rejection in patients with renal and cardiac transplantation. Certican is also approved in Australia, South Africa, the Middle East, Central and South America, the Caribbean and some Asian countries.
Everolimus is being investigated as an anticancer agent based on its potential to act
directly on the tumor cells by inhibiting tumor cell growth and proliferation
indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent inhibition of tumor cell VEGF production and VEGF-induced proliferation of endothelial cells.
Intervention MeSH terms: Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cancer; Polyps

Summary:

      Pilot study, Open-label, Phase II study of Everolimus.

      Objective:

      To determine if Everolimus can diminish large gastrointestinal polyps in patients with
      Peutz-Jeghers Syndrome.

      Methodology:

      Polyp size and number will be compared to baseline by FDG-PET and CT and 12 months after
      treatment with Everolimus. Since this is a pilot study, the polyps prior to treatment will
      serve as the controls.
    

Eligibility criteria:

        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
                  C)

               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
                  resection)

               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.