Clinical Trials /

RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome

NCT02991807

Description:

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.

Related Conditions:
  • Bannayan Syndrome
  • Cowden Syndrome
  • Proteus Syndrome
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome
  • Official Title: A Randomized Double-Blind Controlled Trial of Everolimus in Individuals With PTEN Mutations (RAD001XUS257T)

Clinical Trial IDs

  • ORG STUDY ID: IRB-P00020332
  • SECONDARY ID: 1U54NS092090
  • NCT ID: NCT02991807

Conditions

  • PTEN Gene Mutation
  • PTEN Hamartoma Tumor Syndrome

Interventions

DrugSynonymsArms
RAD001Everolimus, AfinitorRAD001
PlaceboPlacebo

Purpose

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
RAD001ExperimentalRAD001 is formulated as tablets of 5.0 mg or 2.5mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis.
  • RAD001
PlaceboPlacebo ComparatorMatching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10.
  • Placebo

Eligibility Criteria

        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.
      
Maximum Eligible Age:45 Years
Minimum Eligible Age:5 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame:Through study completion, an average of 6 months
Safety Issue:
Description:The primary endpoint will be safety as measured by study drop-out rate due to side effects, comparing everolimus vs. placebo. We will also determine the frequency of adverse events by type and severity.

Secondary Outcome Measures

Measure:Change in Working Memory at 6 Months
Time Frame:6 months
Safety Issue:
Description:Working memory will be evaluated using the Stanford Binet 5 or Mullen Scales of Early Learning at 6 months
Measure:Change in Processing Speed at 6 Months
Time Frame:6 months
Safety Issue:
Description:Processing speed will be evaluated using mean reaction time on the Conner's Continuous Performance Test (CPT)-3.
Measure:Change in Fine Motor Skills at 6 Months
Time Frame:6 months
Safety Issue:
Description:Fine motor skills will be evaluated using the Purdue Pegboard sub-tests average of both hands
Measure:Change in Attention at 6 Months
Time Frame:6 months
Safety Issue:
Description:Attention will be measured by Conners' Continuous Performance Test - 3 - Discriminability index (d') and Omissions
Measure:Change in Impulsivity at 6 Months
Time Frame:6 months
Safety Issue:
Description:Impulsivity will be measured by Conners' Continuous Performance Test-3- Commissions and Bias (B').
Measure:Change in Global Cognitive Ability at 6 Months
Time Frame:6 months
Safety Issue:
Description:Change in global cognitive ability will be measured by Stanford-Binet 5 or Mullen; Full scale, verbal and nonverbal ability (IQ)
Measure:Change in Motor Functioning at 6 Months
Time Frame:6 months
Safety Issue:
Description:Motor functioning will be measured by the Purdue Pegboard (Pegs): Dominant and non-dominant hand combined standard scores and Developmental Coordination Disorder Questionnaire (DCDQ): Total score.
Measure:Change in Communication Ability at 6 Months
Time Frame:6 months
Safety Issue:
Description:Communication ability will be measured by using standard scores of the Peabody Picture Vocabulary Test (PPVT-4), Expressive Vocabulary Test (EVT-2)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Boston Children’s Hospital

Trial Keywords

  • PTEN
  • PTEN Gene Mutation
  • PTEN Hamartoma Tumor Syndrome
  • Autism
  • Intellectual Disability
  • Neurocognition
  • Afinitor
  • Everolimus
  • RAD001

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