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7904: A Randomized Double-Blind Controlled Trial of Everolimus in Children and Adolescents with PTEN Mutations (RAD001XUS257T)

Study Summary

Phosphatase and TENsin homolog (PTEN) gene mutations (mistakes in the gene) are associated with neurocognitive deficits, intellectual disability, autism symptoms, skin lesions, macrocephaly (large head size), overgrowth of tissues, and an increased risk of cancers. Investigators are conducting research to evaluate the potential safety and efficacy (effectiveness) of the drug, RAD001 (everolimus), in patients with PTEN Hamartoma Tumor Syndrome, 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.

For Diseases:

  • PTEN
  • PTEN Hamartoma Tumor Syndrome


PTEN Hamartoma Tumor Syndrome is a genetic syndrome that results from mutations in the PTEN gene. Individuals with PTEN Hamartoma Tumor Syndrome often experience a variety of syndrome-specific manifestations such as skin lesions, macrocephaly, overgrowth of tissues, and increased risk for cancers. There is also a high prevalence of autism, intellectual disability, and other neurocognitive deficits.

Everolimus is a drug in the kinase inhibitor family that treats cancers by stopping cancer cells from reproducing and by decreasing blood supply to the cancer cells. The purpose of this study is to see whether or not everolimus prevents transplant rejection by decreasing the activity of the immune system, and subependymal giant cell astrocytomas (SEGA; a type of brain tumor) in adults and children 1 year of age and older who have a different rare neurogenetic disorder called Tuberous Sclerosis Complex (TSC), is safe and can have any neurocognitive benefits in this population.

The research questions are:

  1. Is everolimus safe for use in the population of individuals with PTEN mutations when compared to placebo?
  2. Does treatment with everolimus have an influence on neurocognition and behavior in children and adolescence with PTEN mutations compared to placebo as measured by standardized, direct and indirect neurocognitive tools and behavioral measures (processing speed/working memory)?

About this Study

This is an interventional double-blind study of 40 individuals with PTEN Hamartoma Tumor Syndrome between the ages of 5 and 45. Participating individuals will be screened for eligibility, and then randomly assigned to receive placebo (inactive drug) or everolimus for a six month period. The study requires six onsite visits at approximately monthly intervals. There are three additional visits that will consist solely of a phone call to collect information between onsite visits. If found to be on the inactive (placebo) medication at the end of the six months, the opportunity to enroll into the open label phase where another six-month trial period will be provided, except this time taking the active medication. For this, an additional three on site visits will be performed and three phone visits.

Throughout the study, you will be asked to:

  • Take the study drug every day at the same time
  • Keep a log of when you take the study drug each day

For each study visit, you will be asked to:

  • Report any illness, fever, cold, rash, etc. to the study team
  • Have a physical exam
  • Perform developmental testing (some visits)
  • Give blood
  • Give a urine sample
  • Perform an optional eye tracking assessment
  • Obtain an optional electroencephalogram (EEG)

Sometimes you/your child will perform neuropsychological tests so that we can keep track of your/their neurocognitive development. The neuropsychological test includes exercises, games and quizzes. These help measure your/their intelligence, attention span, language skills, visual organization, memory, and learning abilities. At the initial visit we will also collect information about your/your child’s medical history and family medical and social history.

Targeted Enrollment

To be eligible to participate, you must:

  1. You are between 5 and 45 years of age (inclusive);
  2. Have a pathogenic PTEN mutation confirmed by clinical genetic testing;
  3. Are 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. Perform 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. Have 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. Have 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. Have adequate renal function: serum creatinine < 1.5 x ULN,
  8. Signed the informed consent form prior to any screening procedures;
  9. If taking psychotropic and anti-epileptic medications, maintain a stable dose for at least 2 months prior to the screening visit;
  10. Provide a negative serum pregnancy test if you are female 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 if you are male, you must agree to use adequate contraception prior to study entry and for the duration of the study. Estrogen-containing oral contraceptives are not recommended if you enroll in this study. Abstinence or two effective non-estrogen or barrier methods of contraception (such as condoms + spermicidal foam) must be used;
  11. Have no anticipated changes in the frequency and intensity of existing interventions such as behavioral and developmental treatments, in home services, and speech therapy;
  12. Have no planned changes in school placement;
  13. For individuals under 18 or who are otherwise incapable, you must have an available caregiver who can reliably bring you to clinic visits and provide trustworthy data
  14. You able to communicate fluently in English

You are not eligible to participate if:

  1. You are currently receiving anticancer therapies or have received anticancer therapies within 4 weeks of the start of Everolimus (including chemotherapy, radiation therapy, antibody based therapy, etc.);
  2. Have a known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus);
  3. Have a known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus;
  4. Have 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. Have uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN.
  6. Have any severe and/or uncontrolled medical or psychiatric conditions (see section 4.6 for additional details)
  7. Have undergone chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed;
  8. Have a known history of or seropositivity for Hepatitis B, Hepatitis C, or HIV;
  9. Have received live attenuated vaccines within 1 week of start of Everolimus and during the study. You 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. 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. Have planned changes to concomitant medications;
  12. Have prior or concomitant therapy with known or possible anti-mTOR activity, including rapamycin (sirolimus);
  13. Have concomitant therapy with strong inhibitor (e.g., cyclosporine and ketoconazole) or inducer of CYP3A;
  14. Have an active infection at time of enrollment;
  15. Have a history of non-compliance to medical regimens or are considered potentially unreliable or will not be able to complete the entire study;
  16. Are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing;
  17. Are pregnant or nursing (lactating) women;
  18. If you are a woman 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 combination of any two of the following:
    1. Use of oral, injected or implanted hormonal non-estrogen containing methods of contraception or;
    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS);
    3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;
    4. Total abstinence or;
    5. 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. Are a male 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. Have had major surgery, radiation therapy, or stereotactic radio-surgery within previous 4 weeks at time of screening
  21. Have had neurosurgery within prior 6 months at time of screening.

How to Join:

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information to the right to ask about participation.