RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome

NCT02991807 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: IRB-P000203321U54NS092090
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

PTEN Gene Mutation; PTEN Hamartoma Tumor Syndrome

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability], Dropout

  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. This section displays participant dropout rate and for what reason.

  Through study completion, an average of 6 months

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability], Adverse Events (AEs) Overview (% of Participants)

  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. this section displays the number of participants who experienced an AE and the description of such AEs, pertaining to: 1. Seriousness 2. Grade, 3. Relation to treatment 4. Recovery from AE 5. Category

  Through study completion, an average of 6 months

Secondary Outcomes (6)

• Change at 6 Months in Composite Score

  6 months

• Change in Processing Speed at 6 Months, Conner's Continuous Performance Test (CPT)-3

  6 months

• Change in Fine Motor Skills at 6 Months, Purdue Pegboard

  6 months

• Change in Global Cognitive Ability at 6 Months, Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) or Mullen Scales of Early Learning

  6 months

• Change in Motor Functioning at 6 Months, Purdue Pegboard and Developmental Coordination Disorder Questionnaire (DCDQ)

  6 months

Study Arms (2)

RAD001

EXPERIMENTAL

RAD001 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.

Drug: RAD001

Placebo

PLACEBO COMPARATOR

Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10.

Drug: Placebo

Interventions

RAD001 DRUG

RAD001 is formulated as tablets of 5.0 mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis. RAD001 tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive. Patients will be instructed to take 4.5 mg/m2 of RAD001 orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.

Also known as: Everolimus, Afinitor

RAD001

Placebo DRUG

Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10. Matching placebo tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive. Patients will be instructed to take 4.5 mg/m2 of the matching placebo orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.

Placebo

Eligibility Criteria

• Age: 5 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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;

You may not qualify if:

• 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;

Sponsors & Collaborators

• Boston Children's Hospital: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Office of Rare Diseases (ORD): collaborator
• National Center for Advancing Translational Sciences (NCATS): collaborator
• Novartis Pharmaceuticals: collaborator
• PTEN Research: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (3)

Stanford University

Palo Alto, California, 94305, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44104, United States

Location

Related Publications (1)

• Srivastava S, Jo B, Zhang B, Frazier T, Gallagher AS, Peck F, Levin AR, Mondal S, Li Z, Filip-Dhima R, Geisel G, Dies KA, Diplock A, Eng C, Hanna R, Sahin M, Hardan A; Developmental Synaptopathies Consortium. A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome. Hum Mol Genet. 2022 Oct 10;31(20):3393-3404. doi: 10.1093/hmg/ddac111.

  PMID: 35594551 DERIVED

Related Links

• Developmental Synaptopathies Consortium

MeSH Terms

Conditions

Hamartoma Syndrome, Multiple; Autistic Disorder; Intellectual Disability

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

1\) Small sample size, as recruitment is difficult for rare neurogenetic disorders. 2) A subset of participants was unable to complete all assessments, largely due to the COVID-19 pandemic. Amidst COVID-19 pandemic, participants completed instruments remotely when possible. CPT-3 hit reaction time had a sample size n\<10 at the month 6 timepoint, while the other measures had reasonable sample sizes. 3) Enrollment numbers were insufficient to power subgroup analysis, such as participants with ASD.

Results Point of Contact

• Title: Dr. Mustafa Sahin
• Organization: Boston Children's Hospital

Mustafa.Sahin@childrens.harvard.edu

617-355-8994

Study Officials

• Mustafa Sahin, MD, PhD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Translational Neuroscience Center/ Professor of Neurology, Harvard Medical School

Study Record Dates

• First Submitted: December 2, 2016
• First Posted: December 14, 2016
• Study Start: June 12, 2017
• Primary Completion: February 18, 2021
• Study Completion: December 22, 2021
• Last Updated: February 17, 2025
• Results First Posted: February 17, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share

Locations

US (3)