Patient case: 68-year-old male with melanoma; genetic feature: PTEN loss of function

Clinical trial: RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome (PTEN)

Summary: 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.

Detailed description: This is a signal seeking Phase I/II 6-month, randomized, double-blind placebo-controlled trial of RAD001 in children and adolescents, ages 6 to 21 years with a PTEN mutation, with safety and neurocognition as the primary endpoints.
  Prior to enrolling in the study and undergoing a series of screening tests to confirm eligibility, the participant or a legal guardian will need to sign an informed consent. If determined to be eligible for the treatment phase of the trial, participants will be randomly assigned to take either the study drug or a placebo (pill with no medicine).
  The study involves about nine visits, six 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, while all other visits will be less than 2 hours. The study visits include blood draws, laboratory tests and neuropsychological assessments. 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 and assessments will continue as they did in the initial 6 month period.
  After all study data has been analyzed, families will be informed of the overall results. Treatment on this study may or may not improve a child's learning skills (neurocognition). Future patients may benefit from what is learned.
  Specific Aims /Objectives Primary objective
  -To evaluate the safety of everolimus (RAD001) 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 (RAD001) 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.

Eligibility: Inclusion Criteria:
  1. Male and female outpatients between 6 and 21 years of age;
  2. Pathogenic PTEN mutation confirmed by clinical genetic testing;
  3. IQ≥50 (either verbal or nonverbal) (IQ necessary to be able to complete the required neurocognitive and developmental assessments)
  4. Performance below the age-adjusted population mean on at least one standardized measure such as the CPT (mean reaction time) or Working memory (SB5) or Purdue Pegboard fine motor assessment (both hands);
  5. Adequate bone marrow function as shown by: platelets ≥ 80,000/mm3, absolute neutrophil count ≥ 1,000/mm3 hemoglobin ≥ 9 g/dL
  6. Adequate liver function as shown by:Total serum bilirubin <1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine transaminase (ALT) levels < 2.5 x ULN;
  7. Adequate renal function: serum creatinine < 1.5 x ULN,
  8. International Normalized Ratio (INR) ≤2 (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight (LMW) heparin for >2 weeks at time of randomization.)
  9. Signed informed consent obtained prior to any screening procedures;
  10. Individuals on psychotropic and anti-epileptic medications should maintain a stable dose for at least 2 months prior to enrollment;
  11. If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment. Sexually active pre-menopausal female patients (and female partners of male patients) must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on study. Abstinence will be considered an adequate contraceptive measure.
  12. Medically stable with no active medical problem such as unstable seizure or cardiovascular disease as evidenced by a history;
  13. No anticipated changes in the frequency and intensity of existing interventions such as behavioral and developmental treatments, in home services, and speech therapy;
  14. No planned changes in school placement;
  15. 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
  16. English as primary language
  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 Glycated hemoglobin (HbA1c) >8% despite adequate therapy.
  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 conditions or active (acute or chronic) or uncontrolled severe infection and active and chronic hepatitis (i.e. quantifiable Hepatitis B Virus (HBV-DNA) and/or positive hepatitis B virus surface antigen (HbsAg), quantifiable hepatitis C virus (HCV-RNA), known severely impaired lung function (spirometry and Diffusing capacity of the lungs for carbon monoxide (DLCO) 50% or less of normal and O2 saturation 88% or less at rest on room air), Active, bleeding diathesis;
  7. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed;
  8. Known history of HIV seropositivity;
  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, bacille Calmette Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines;
  10. 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;
  11. Planned changes to concomitant medications;
  12. Prior or concomitant therapy with known or possible anti- mammilian target of rapamycin (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. 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
  19. Major surgery, radiation therapy or stereotactic radio-surgery within previous 4 weeks at time of enrollment
  20. Neurosurgery within prior 6 months at time of enrollment.

Relevance to patient case: not relevant