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Ref Type Journal Article
PMID (32523649)
Authors Nicolaides T, Nazemi KJ, Crawford J, Kilburn L, Minturn J, Gajjar A, Gauvain K, Leary S, Dhall G, Aboian M, Robinson G, Long-Boyle J, Wang H, Molinaro AM, Mueller S, Prados M
Title Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002).
Journal Vol Issue Date Pages Journal Short Title
Oncotarget 11 21 2020 May 26 1942-1952 Oncotarget
URL
Abstract Text Background: BRAFV600E mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAFV600E kinase. The goal of this multi-center study conducted through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) in children < 18 years with recurrent or progressive BRAFV600E mutant brain tumors. Results: Nineteen eligible patients were enrolled. Eleven patients had received three or more prior therapies. Data reported are from the start of treatment for the first patient (April 30 2014) through August 31 2019. The RP2D was defined as 550 mg/m2 twice daily after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events included secondary keratoacanthoma (n = 1); rash (n =16); and fever (n = 5). Subjects received a median of 23 cycles (range 3-63). Four patients remain on treatment. Centrally reviewed best radiographic responses included 1 complete response, 5 partial responses, and 13 stable disease. The steady-state area under the curve (AUC0-∞median) was 604 mg*h/L (range 329-1052). Methods: Vemurafenib was given starting at 550 mg/m2, twice daily which corresponds to the adult RP2D. Adverse events were graded using the NIH Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Central imaging review was performed. Pharmacokinetic sampling was performed. Conclusions: Vemurafenib has promising anti-tumor activity in recurrent BRAF V600E-positive brain tumors with manageable toxicity. A phase 2 study is ongoing (NCT01748149).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E childhood pilocytic astrocytoma sensitive Vemurafenib Phase I Actionable In a Phase I trial (PNOC-002), Zelboraf (vemurafenib) treatment was tolerable and resulted in 1 complete response, 5 partial responses, and 13 stable disease in 19 pediatric patients with recurrent low grade gliomas harboring BRAF V600E, including pilocytic astrocytoma (n=10), ganglioglioma (n=5), pleomorphic xanthroastrocytoma (n=2), fibrillary astrocytoma (n=1), and astrocytoma NOS (n=1) (PMID: 32523649; NCT01748149). 32523649
BRAF V600E childhood low-grade glioma sensitive Vemurafenib Phase I Actionable In a Phase I trial (PNOC-002), Zelboraf (vemurafenib) treatment was tolerable and resulted in 1 complete response, 5 partial responses, and 13 stable disease in 19 pediatric patients with recurrent low grade gliomas harboring BRAF V600E, including pilocytic astrocytoma (n=10), ganglioglioma (n=5), pleomorphic xanthroastrocytoma (n=2), fibrillary astrocytoma (n=1), and astrocytoma not otherwise specified (n=1) (PMID: 32523649; NCT01748149). 32523649
BRAF V600E pleomorphic xanthoastrocytoma predicted - sensitive Vemurafenib Case Reports/Case Series Actionable In a Phase I trial (PNOC-002), Zelboraf (vemurafenib) treatment was tolerable and resulted in 1 complete response, 5 partial responses, and 13 stable disease in 19 pediatric patients with recurrent low grade gliomas harboring BRAF V600E, including 1 complete response and 1 stable disease among 2 patients with pleomorphic xanthroastrocytoma (PMID: 32523649; NCT01748149). 32523649