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Phosphatase and TENsin homolog (PTEN) gene germline mutations are associated with a spectrum of clinical manifestations characterized by neurocognitive deficits, intellectual disability, autism symptomatology, skin lesions, macrocephaly, hamartomatous overgrowth of tissues, and an increased risk of cancers. Investigators are conducting research to evaluate the potential safety and efficacy of RAD001 (everolimus) in this patient population, and the potential neurocognitive benefits from treatment with RAD001 or placebo for a six month period. The investigators hope this trial will lead to a better understanding of PTEN and to new forms of treatment that may benefit children and adults with PTEN in the future.


PTEN Gene Mutation, PTEN Hamartoma Tumor Syndrome

Recruitment Status


Detailed Description

This is a signal seeking Phase I/II 6-month, randomized, double-blind placebo-controlled trial of everolimus in individuals, ages 5 to 45 years with a PTEN mutation, with safety and neurocognition as the primary endpoints. Participant's or a legal guardian will need to sign an informed consent prior to enrollment in the study. To determine eligibility participants will undergo a series of screening tests and safety measures. If determined to be eligible for the blinded phase of the study, participants will be randomly assigned to take either the study drug or a placebo (pill with no medicine). The blinded phase of the study involves about eight visits, five of which will occur at the study site, and three of which will be conducted over the phone. These visits will take place over a six month period. Study visits will vary in length. Baseline, three month and six month visits may last up to 8 hours, if optional measures are done, while all other visits will be less than 2 hours. The study visits include blood draws, general health exams, and neuropsychological assessments. The study will also include optional eye-tracking, EEG and auditory evoked potential (AEP) measures, and the collection of microbiome/mycobiome and biomarker blood sample. There is no fee to participate in this study. The study drug will be provided at no charge during the study. After the 6 month treatment phase, individuals who were randomly assigned to take placebo will be offered inclusion in a 6 month open label phase where the study drug will be provided at no charge. The open label phase assessments will be similar to those done in the blinded phase, but patients/families will only need to return to the study site three times during this phase. Participants will receive a developmental assessments report after completing the study. After all study data has been analyzed, patients and families will also be informed of the overall results. Treatment on this study may or may not improve an individual's learning skills (neurocognition) or behavior. We hope that future patients and families will benefit from what is learned by this study. Specific Aims /Objectives Primary objective -To evaluate the safety of everolimus compared with placebo in patients with PTEN mutations focusing on NCI CTCAE Grade 3 and 4 adverse events, serious adverse events, and Grade 3 and 4 laboratory toxicities. Secondary objectives -To evaluate the efficacy of everolimus on neurocognition and behavior in inividuals with PTEN mutations compared to placebo as measured by standardized, direct and indirect neurocognitive tools and behavioral measures.

Eligibility Criteria

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 < 1.5 x ULN
AST and ALT levels < 2.5 x ULN
INR ≤ 2
Adequate renal function: serum creatinine < 1.5 x ULN,
Signed informed consent obtained prior to any screening procedures;
Individuals on psychotropic and anti-epileptic medications should maintain a stable dose for at least 2 months prior to the screening visit;
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;
No anticipated changes in the frequency and intensity of existing interventions such as behavioral and developmental treatments, in home services, and speech therapy;
No planned changes in school placement;
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
Able to communicate fluently in English

Double-Blind Exclusion Criteria

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.);
Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus);
Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus;
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;
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 by follow up hormone level assessment is she considered not of child-bearing potential.

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
Major surgery, radiation therapy, or stereotactic radio-surgery within previous 4 weeks at time of screening
Neurosurgery within prior 6 months at time of screening.

Open-Label Inclusion Criteria

Patients who completed Double-Blind phase of the study and were assigned to the placebo treatment arm;
Verbal consent (and assent, as appropriate) obtained prior to any open-label phase study procedures.


Intervention Type

Intervention Name






Phase 1, Phase 2



Min Age

5 Years

Max Age

45 Years

Download Date

February 8, 2022

Principal Investigator

Mustafa Sahin

Primary Contact Information

For more information on this trial, visit


For more information and to contact the study team:

RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome NCT02991807