Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2
|Neurofibromatosis Type II||Drug: Everolimus (RAD001) , Afinitor®||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2|
- Radiographic Response [ Time Frame: 1 Year ]To estimate the objective response rates to RAD001 in patients with NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas. Radiographic response for study purposes = greater than or equal to 15% reduction in tumor volume in any of the target tumors (partial response). Complete disappearance of any of the target tumors = complete response. MRI of the brain and spine will be performed every 3 months. If an objective response (15% reduction in tumor volume compared to baseline) is observed in any target tumor or stable disease, drug will be continued.
- Change in Tumor Size From Baseline [ Time Frame: 1 Year ]
- Audiologic Response [ Time Frame: 1 Year ]
Defined as improvement in speech discrimination score (SDS), defined as an improvement in the score above the 95% critical difference threshold, compared to baseline audiogram at initiation of treatment. Audiologic worsening: decrease in SDS score below the 95% critical difference threshold, compared to baseline audiogram at initiation of treatment.
Patients with vestibular schwannomas will receive baseline audiograms within 28 days before enrollments and subsequent audiograms at the time of each MRI.
|Study Start Date:||October 2011|
|Study Completion Date:||December 2013|
|Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age
Drug: Everolimus (RAD001) , Afinitor®
Everolimus will be provided by Novartis. Everolimus is formulated as tablets for oral administration of 2.5 mg, 5 mg, 10 mg strength. Everolimus will be self-administered (by the patients themselves) or administered by the patient's parent or guardian (for minors). The investigator will instruct the patient to take the study drug exactly as specified in the protocol. Depending the age-based dosing schedule, everolimus should be administered orally once (or twice) daily, preferably in the morning (and evening), at the same time every day with our without food. Everolimus tablets should be swallowed whole with a glass of water. The tablets must not be chewed or crushed. In cases where tablets can not be swallowed, the tablets should be disintegrated in water just prior to being taken. Everolimus will be administered orally as per the age-based dosing schedule continuously from study day 1 until progression of disease or unacceptable toxicity.
Other Name: Afinitor®
Everolimus (RAD001) has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation and has obtained marketing authorization (Certican®) for prophylaxis of rejection in renal and cardiac transplantation in a number of countries, including the majority of the European Union. Everolimus has been in development for patients with various malignancies since 2002. Everolimus 2.5mg, 5mg and 10mg tablets were approved under the trade name Afinitor® for patients with advanced renal cell carcinoma (RCC) after failure of treatment with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US, EU and several other countries and is undergoing registration in other regions worldwide. Afinitor® was also recently approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. Everolimus is being investigated as an anticancer agent based on its potential to act: 1. Directly on the tumor cells by inhibiting tumor cell growth and proliferation; and 2. Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity.
For pediatric cancer patients, safety of RAD001 has been established in a phase 1 trial and the recommended phase II dose is 5 mg/m2 once daily. This existing pediatric data allows for inclusion of children in this phase 2 trial, which is an important consideration since some NF2 patients with the most aggressive clinical course present at school age.
RAD001 was recently approved by the Food and Drug Administration (FDA) for the treatment of children and adults with subependymal giant cell astrocytoma (SEGA), a benign brain tumor associated with tuberous sclerosis (TS). Although surgical resection is effective at tumor reduction, serious complications may follow a radical resection, such as permanent deafness and facial nerve damage. Most importantly, the tumors often recur after surgery. Radiation therapy (RT) has been proposed as an alternative. However, its safety and efficacy in the NF2 population has not been established. A medical therapy option is desperately needed. This study is a single-center, 2-stage, phase II open-label study. All subjects will get RAD001 taken continuously until disease progression or unacceptable toxicity. The primary objective of this study is to look at the objective response rate to RAD001 in patients with NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas. Participation will consist of screening/baseline visit(s), Day 1, Weeks 1, 2, and 4; and up to 12 cycles and will include standard of care procedures such as medical history, vital signs, physical examinations, ECGs, MRIs, audiograms, and laboratory tests. Novartis will provide the RAD001 free of charge to eligible study subjects. The primary efficacy response for study purposes will be a greater than or equal to 15% reduction in tumor volume in any of the target tumors (partial response). Complete disappearance of any of the target tumors will constitute a complete response (CR).
Please refer to this study by its ClinicalTrials.gov identifier: NCT01419639
|United States, New York|
|New York University Medical Center|
|New York, New York, United States, 10016|
|Principal Investigator:||Matthias A Karajannis, MD, MS||New York University|