Phase I study of vemurafenib in children with recurrent or progressive BRAF^V600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002)

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 Mueller^{14

15

16

17}, Michael Prados^{13

14

17}

Affiliations

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.
¹⁷ Co-Senior authors.

PMID: 32523649
PMCID: PMC7260122
DOI: 10.18632/oncotarget.27600

Phase I study of vemurafenib in children with recurrent or progressive BRAF^V600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002)

Theodore Nicolaides et al. Oncotarget. 2020.

. 2020 May 26;11(21):1942-1952.

doi: 10.18632/oncotarget.27600.

Authors

Affiliations

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.
¹⁷ Co-Senior authors.

PMID: 32523649
PMCID: PMC7260122
DOI: 10.18632/oncotarget.27600

Abstract

Background: BRAF^V600E mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAF^V600E 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 BRAF^V600E 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 (AUC_0-∞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).

Keywords: BRAFV600E; clinical trial; pediatric glioma; vemurafenib.

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Conflict of interest statement

CONFLICTS OF INTEREST There are no conflicts of interest for any authors.

Figures

**Figure 1. Depicted is the centrally reviewed “best response” per patient, based on the maximum change compared to on study MRI.**
Each bar represents a patient. Grey bars depict patients treated on dose level 0 and red bars show subjects treated on dose level-1.

**Figure 2. Depicted are representative images of subjects treated on PNOC-002 demonstrating.**
(A) regression of a contrast enhancing cystic lesion on a contrast, T1 weighted MR image over time; (B) regression of a solid/cystic lesion on a T2 weighted MR image over time; (C) regression of a contrast enhancing solid lesion on a contrast, T1 weighted MR image over time.

See this image and copyright information in PMC

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Phase I study of vemurafenib in children with recurrent or progressive BRAF^V600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002)

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Phase I study of vemurafenib in children with recurrent or progressive BRAF^V600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002)

Authors

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Abstract

Conflict of interest statement

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