Table 1.

Inclusion and exclusion criteria for double-blind treatment phase and open-label phase.

Double-blind treatment phase 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: CPT-3 mean reaction time, 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 (SB-5), or fine motor skills (Purdue Pegboard Test; either dominant hand, non-dominant hand, or both hands).

5. Adequate bone marrow function as shown by: a. platelets ≥80,000/mm3, b. absolute neutrophil count ≥1000/mm3, c. hemoglobin ≥9 g/dL.

6. Adequate liver function as shown by: a. Total serum bilirubin <1.5 x ULN, b. AST and ALT levels <2.5 x ULN, c. 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 treatment phase 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 function or gastrointestinal 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.

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. Patients 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: a. non-melanoma skin cancer, and b. 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, 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 either a combination of any two of the following: a. use of oral, injected, or implanted hormonal non-estrogen containing methods of contraception, b. placement of an intrauterine device system, c. barrier methods of contraception such as condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository, d. total abstinence, or e. 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 women of child-bearing potential 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 radiosurgery within previous 4 weeks at time of screening.

21.Neurosurgery within prior 6 months at time of screening.

Open-label phase inclusion criteria

1.Patients who completed the 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,

CPT-3: Conners' Continuous Performance Test, Third Edition; SB-5: Stanford-Binet Intelligence Scales, Fifth Edition.