Research Papers:

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

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Oncotarget. 2020; 11:1942-1952. https://doi.org/10.18632/oncotarget.27600

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Theodore Nicolaides1, Kellie J. Nazemi2, John Crawford3, Lindsay Kilburn4, Jane Minturn5, Amar Gajjar6, Karen Gauvain7, Sarah Leary8, Girish Dhall9, Mariam Aboian10, Giles Robinson6, Janel Long-Boyle11, Hechuan Wang12, Annette M. Molinaro13, Sabine Mueller14,15,16,* and Michael Prados13,14,*

1 Department of Pediatrics, NYU Langone Health, New York, NY, USA

2 Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, OR, USA

3 Rady Children’s Hospital, San Diego, CA, USA

4 Center for Cancer and Blood Disorders, Brain Tumor Institute, Children’s National Health System, Washington, D.C., USA

5 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

6 St. Jude Children’s Research Hospital, Memphis, TN, USA

7 Washington University, St Louis, MO, USA

8 Fred Hutchinson Cancer Research Center, Seattle, WA, USA

9 University of Alabama Division of Hematology and Oncology, Birmingham, AL, USA

10 Department of Radiology, Yale University, New Haven, CT, USA

11 Department of Pharmacology, University of California San Francisco, San Francisco, CA, USA

12 Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA

13 Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA

14 Department of Neurology, University of California San Francisco, San Francisco, CA, USA

15 Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA

16 University Children’s Hospital Zürich, Zürich, Switzerland

* Co-Senior authors

Correspondence to:

Theodore Nicolaides,email: [email protected]
Michael Prados,email: [email protected]

Keywords: BRAFV600E; pediatric glioma; vemurafenib; clinical trial

Received: March 03, 2020     Accepted: April 27, 2020     Published: May 26, 2020


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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