Neurofibroma/Neurofibromatosis
A Phase II Study of Everolimus (RAD001) for Children With Neurofibromatosis Type-1 and Chemotherapy-Refractory Radiographic Progressive Low-Grade Gliomas
NCI-12-C-0058, NCT00901849
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Investigator(s): |
Katherine E. Warren, M.D.
Principal Investigator
Phone: 301-496-4256
Fax: 301-480-2308
warrenk@mail.nih.gov
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Linda Ellison, R.N.
Research Nurse
Phone: 301-496-8009
Fax: 301-480-8871
ellisonl@mail.nih.gov
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Pediatric Oncology
Phone: 301-496-4256
1-877-624-4878 (Toll free)
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Background:
- Approximately 25 percent of children with NF1 have evidence of low-grade gliomas, a subset of who are at high risk for significant visual loss and blindness
- The only recognized chemotherapy option for unresectable low-grade gliomas is vincristine and carboplatin, and new non-genotoxic approaches are needed
- Recent observations indicate that the NF1 tumor suppressor regulates the mTOR pathway, and that the mTOR inhibitors rapamycin (sirolimus) and everolimus (RAD001) abrogate growth and anti-apoptotic signaling through this pathway and sensitize tumor cells to DNA-damage-induced apoptosis through inhibition of p21 translation, providing the foundation for clinical development of combination therapies
Objectives:
- Primary Objective:
- Determine the response of children with neurofibromatosis type-1 and chemotherapy-refractory radiographic progressive low-grade gliomas to everolimus (RAD001)
- Secondary Objectives:
- Evaluate pharmacogenetic polymorphisms of cytochrome P450 3A4 and 3A5 alleles and P-glycoprotein/MDR for their influence on everolimus metabolism
- Evaluate the role of apolipoprotein E genotypes as predictors for development of hyperlipidemia during therapy with everolimus
- Assess preliminary correlations of response with changes in pharmacodynamic parameters including p70s6 kinase activity in PBMCs
- Describe the toxicity and pharmacokinetic profile of everolimus in this patient population
Key Eligibility Criteria:
- Patients ≥ 1 year to ≤ 21 years of age diagnosed with NF1
- Radiographically measurable progressive low-grade glioma
- Have previously progressed on a carboplatin-based regimen
- Meets performance status and laboratory criteria for adequate organ function, without uncontrolled brain or leptomeningeal metastases, recent prior surgery, or other severe or uncontrolled medical conditions that might affect participation
- Females of reproductive potential may not be pregnant, and all patients of reproductive potential must agree to effective contraceptive methods
- Recovered from acute toxic effects of prior therapies, which may not have been administered within the specified time frames
- Not receiving any prohibited medications including CYP3A4 inhibitors or inducers, enzyme inducing anticonvulsants, or steroids at higher that physiologic doses
Study Outline:
- In this Phase II study, everolimus will be administered orally in a fasting state, once a day, preferably in the morning, at 5.0 mg/m2/day from Day 1 until completion of protocol therapy (48 weeks), progression of disease, unacceptable toxicity, or patient meets the criteria for removal from therapy
- Each course is 28 days
- Disease evaluations will be performed after the first two courses and then after every third course
- Dose adjustments are permitted for specified toxicities
- Pneumocystis pneumonia (PCP) prophylaxis will be required during everolimus administration
- Mandatory pharmacokinetic evaluations will be performed during Course 2, and optional pharmacogenetic and pharmacodynamic studies will be requested
- A total of 23 patients will be enrolled to achieve 20 evaluable patients; five patients will be enrolled at NCI
Additional Information:
- This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
- There is no charge for medical care received at NIH Clinical Center.
Reviewed: 12/14/12
Updated: 8/1/12
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