Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas
Recurrent or Progressive Optic Pathway Gliomas (OPG)
Recurrent or Progressive Low-grade Glioma
Drug: Sorafenib (Nexavar)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Study of Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas|
- Response Rate to Sorafenib [ Time Frame: one year ] [ Designated as safety issue: No ]To estimate the objective response rates to sorafenib in children and young adults with low-grade astrocytomas, including optic pathway gliomas.
- Objective Response Rates [ Time Frame: MRIs performed after every 3rd 28-day cycle and off-study ] [ Designated as safety issue: No ]Determination of tumor response (CR, PR, SD) will be defined based on the comparison of the baseline MRI performed at study entry to the subsequent MRI which demonstrated best response. PR will be defined by a >15% decrease in tumor volume, as measured by 3D volumetric analysis.
|Study Start Date:||April 2011|
|Study Completion Date:||March 2013|
|Primary Completion Date:||March 2013 (Final data collection date for primary outcome measure)|
Experimental: Sorafenib (Nexavar)
Sorafenib will be administered orally BID (approximately every 12 hours). Grapefruit juice is not allowed while taking sorafenib. A cycle of therapy is considered to be 28 days and there is no interruption between cycles. Patients may receive up to a total of 12 cycles provided that no off-protocol or off-study criteria are met.
Drug: Sorafenib (Nexavar)
Sorafenib (in tablet form) will be administered orally BID (approximately every 12 hours). Grapefruit juice is not allowed while taking sorafenib. A cycle of therapy is considered to be 28 days and there is no interruption between cycles. Patients may receive up to a total of 12 cycles provided that no off-protocol or off-study criteria are met.
Children/adolescents (< 18 years of age, non-NF1): 200 mg/m2/dose PO twice daily (rounded to the nearest 50 mg increment as per Section 4.1) to a maximum of 400 mg PO twice daily
Adults (greater than or equal to 18 years of age, non-NF1): 400 mg PO twice daily
NF1 patients (regardless of age): 80 mg/m2/dose PO twice daily (rounded to the nearest 50 mg increment as per Section 4.1) to a maximum of 150 mg PO twice daily
Novel therapies are urgently needed for children with relapsed LGA who are not surgical candidates and/or have exhausted standard chemotherapy approaches. Although a vast number of "molecular targeted" agents have been developed over the past decade for the treatment of cancer, none have been evaluated for the treatment of LGAs. Recently, genetic alterations resulting in oncogenic BRAF have been identified to be highly prevalent in LGAs, providing a rational target for therapeutic intervention.
The aims of this clinical trial are to estimate the efficacy, as well as safety and tolerability of sorafenib, a RAF and tyrosine kinase receptor inhibitor, in the treatment of pediatric patients with recurrent LGA. Sorafenib targets several pathways that, based on preliminary data from us and others, are likely contributing to the growth of LGAs: oncogenic BRAF, which is present in the majority of grade I LGAs and VEGFR2 and PDGFR, which are well-described mediators of tumor angiogenesis. Since sorafenib inhibits a number of additional kinases whose role in LGA growth has not yet been explored, it is possible that inhibition of pathways other than the primary targets may result in additional anti-tumor effects of sorafenib in LGA. Although the investigators hypothesize that LGAs with oncogenic BRAF should be most sensitive to sorafenib, the additional targets of sorafenib may also result in significant anti-tumor effects in LGAs with wild-type BRAF. Therefore, the investigators propose to evaluate the efficacy of sorafenib in children with LGAs in a translational clinical trial, stratified by BRAF status and tumor grade.
The investigators expect to learn the following from this clinical translational trial:
- The anti-tumor activity of sorafenib in pediatric LGAs
- The safety and tolerability of sorafenib in pediatric patients with LGAs
- The association of molecular target expression, e.g. oncogenic BRAF, with response rates
The investigators will use the results of the clinical translational trial to determine if sorafenib warrants further clinical study in pediatric LGAs. If the investigators find associations between molecular target expression and response, further studies may be limited to or focus on patients whose tumors have specific molecular features, such as oncogenic BRAF. Sorafenib has also shown promise in combination with classic chemotherapy and can be given together with carboplatin, which is one of the most active agents in LGAs. Therefore, possible synergy between sorafenib and traditional chemotherapy used in the treatment of LGAs, such as carboplatin, could be explored in future clinical trials.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01338857
|United States, New York|
|New York University Stephen D. Hassenfeld Children's Center for Cancer & Blood Disorders|
|New York, New York, United States, 10016|
|Principal Investigator:||Matthias A Karajannis, MD||NYU|