| Eligibility |
Double-Blind Inclusion Criteria
1. Male and female outpatients between 5 and 45 years of age (inclusive);
2. Pathogenic PTEN mutation confirmed by clinical genetic testing;
3. 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;
4. 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);
5. Adequate bone marrow function as shown by:
1. platelets = 80,000/mm3
2. absolute neutrophil count = 1,000/mm3
3. hemoglobin = 9 g/dL
6. Adequate liver function as shown by:
1. Total serum bilirubin < 1.5 x ULN
2. AST and ALT levels < 2.5 x ULN
3. INR = 2
7. Adequate renal function: serum creatinine < 1.5 x ULN,
8. Signed informed consent obtained prior to any screening procedures;
9. Individuals on psychotropic and anti-epileptic medications should maintain a stable
dose for at least 2 months prior to the screening visit;
10. Negative serum pregnancy test for females at screening and no plans to become pregnant
or conceive a child while participating in the study. The effects of mTOR inhibitors
on the developing fetus at the doses used in this study are unknown. For this reason,
women of child-bearing potential and men must agree to use adequate contraception
prior to study entry and for the duration of the study. Estrogen-containing oral
contraceptives are not recommended in women enrolled in this study. Abstinence or two
effective non-estrogen or barrier methods of contraception (such as condoms +
spermicidal foam) must be used;
11. No anticipated changes in the frequency and intensity of existing interventions such
as behavioral and developmental treatments, in home services, and speech therapy;
12. No planned changes in school placement;
13. For individuals under 18 or who are otherwise incapable, there must be an available
caregiver who can reliably bring subject to clinic visits and provide trustworthy data
14. Able to communicate fluently in English
Double-Blind Exclusion Criteria
1. Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of Everolimus (including chemotherapy, radiation
therapy, antibody based therapy, etc.);
2. Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g.
sirolimus, temsirolimus);
3. Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral Everolimus;
4. Uncontrolled diabetes mellitus as defined by HbA1c >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;
5. Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR
>7.75 mmol/L AND fasting triglycerides > 2.5 x ULN.
6. Patients who have any severe and/or uncontrolled medical or psychiatric conditions
(see section 4.6 for additional details)
7. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or
inhaled corticosteroids are allowed;
8. Known history of or seropositivity for Hepatitis B, Hepatitis C, or HIV;
9. 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;
10. Patients who have a history of another primary malignancy, with the exceptions of:
1. non-melanoma skin cancer,
2. and carcinoma in situ of the cervix, uteri, or breast from which the patient has
been disease free for =3 years;
11. Planned changes to concomitant medications;
12. Prior or concomitant therapy with known or possible anti-mTOR activity, including
rapamycin (sirolimus);
13. Concomitant therapy with strong inhibitor (e.g., cyclosporine and ketoconazole) or
inducer of CYP3A;
14. Active infection at time of enrollment;
15. 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;
16. Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within 1 month prior to dosing;
17. Pregnant or nursing (lactating) women;
18. 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
by follow up hormone level assessment is she considered not of child-bearing
potential.
19. Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment
20. Major surgery, radiation therapy, or stereotactic radio-surgery within previous 4
weeks at time of screening
21. Neurosurgery within prior 6 months at time of screening.
Open-Label Inclusion Criteria
1. Patients who completed Double-Blind phase of the study and were assigned to the
placebo treatment arm;
2. Verbal consent (and assent, as appropriate) obtained prior to any open-label phase
study procedures.
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