Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002).

Theodore Nicolaides,Janel Long-Boyle,Jane Minturn,Lindsay Kilburn,John Crawford,Girish Dhall,Amar Gajjar,Sabine Mueller,Mariam Aboian,Sarah Leary,Hechuan Wang,Giles Robinson,Michael Prados,Annette M Molinaro,Karen Gauvain,Kellie J Nazemi

doi:10.18632/oncotarget.27600

Abstract

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).

Highlights

BRAFV600E is one of the most common oncogenic mutations in human tumors, found in 50% of metastatic melanomas, 10% of metastatic colon carcinomas, and 30% of papillary thyroid carcinomas [1]
The most common histology was pilocytic astrocytoma (n=10). This trial was open to both low and high-grade tumors, only patients with low-grade tumors enrolled in the safety study. While this trial was open at multiple sites, the relative scarcity of pediatric patients with recurrent BRAFV600E mutant brain tumors led to expected relatively slow accrual
We report that vemurafenib is safe in children with BRAFV600E gliomas and has promising antitumor efficacy

Summary

Introduction

BRAFV600E is one of the most common oncogenic mutations in human tumors, found in 50% of metastatic melanomas, 10% of metastatic colon carcinomas, and 30% of papillary thyroid carcinomas [1]. An unexpected side effect of this class of inhibitors is a high risk of secondary squamous cell carcinoma (keratoacanthoma) These occur in approximately 25% of treated adults and have been demonstrated to contain activating RAS mutations (or less frequently NOTCH or TGF deletions) and show growth stimulation through paradoxical activation of wild type RAF dimers by BRAF inhibitors [4]. 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

Methods

Results

Conclusion