neurofibromatosis1 (NF1) Clinical Trial
Official title:
Phase II Study of Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas
The purpose of this study is to determine if a drug called sorafenib can shrink LGA tumors (low-grade astrocytomas) in children and adults. Previous research has given us a better understanding of this type of tumor by studying the genetic "make-up" of LGAs. From this research, the investigators found that a drug called sorafenib may stop the growth of tumor cells by blocking some of the molecules needed for cell growth and by blocking blood flow to the tumor. This trial is studying how well sorafenib works in treating patients with LGAs, and how the effects relate to the specific genetic "make-up" of your particular tumor. This testing of your tumor's genetic make-up is optional and requires available tumor tissue for testing. In summary, the aims of this study are: To see if sorafenib can shrink LGAs; how well sorafenib is tolerated in patients with LGAs; and, how the effects of sorafenib relate to the genetic make-up of individual LGAs (Optional Study)
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.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment