RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome

Double-Blind Inclusion Criteria

• Male and female outpatients between 5 and 45 years of age (inclusive);
• Pathogenic PTEN mutation confirmed by clinical genetic testing;
• Participant must be able to complete one of the following three standardized assessments: Conners' Continuous Performance Tasks (CPT-3-mean reaction time), Stanford Binet (SB-5; working memory), or the Purdue Pegboard Test;
• Performance below the age-adjusted population mean on at least one of the above standardized measure: attention (CPT-3, mean reaction time), working memory (SB5), or fine motor skills (Purdue Pegboard Test; either dominant hand, non-dominant hand, or both hands);
• Adequate bone marrow function as shown by:
• platelets ≥ 80,000/mm3
• absolute neutrophil count ≥ 1,000/mm3
• hemoglobin ≥ 9 g/dL
• Adequate liver function as shown by:
• Total serum bilirubin 8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary;
• Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN.
• Patients who have any severe and/or uncontrolled medical or psychiatric conditions (see section 4.6 for additional details)
• Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed;
• Known history of or seropositivity for Hepatitis B, Hepatitis C, or HIV;
• Patients who have received live attenuated vaccines within 1 week of start of Everolimus and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines;
• Patients who have a history of another primary malignancy, with the exceptions of:
• non-melanoma skin cancer,
• and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for ≥3 years;
• Planned changes to concomitant medications;
• Prior or concomitant therapy with known or possible anti-mTOR activity, including rapamycin (sirolimus);
• Concomitant therapy with strong inhibitor (e.g., cyclosporine and ketoconazole) or inducer of CYP3A;
• Active infection at time of enrollment;
• Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study;
• Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing;
• Pregnant or nursing (lactating) women;
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during the study and 8 weeks after. Highly effective contraception methods include:

a. A combination of any two of the following: i. Use of oral, injected or implanted hormonal non-estrogen containing methods of contraception or; ii. Placement of an intrauterine device (IUD) or intrauterine system (IUS); iii. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; b. Total abstinence or; c. Male/female sterilization. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed