Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Breast Cancer
      • Clinical Trials
      • Immunotherapy: Facts and Hopes
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Clinical Cancer Research
Clinical Cancer Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Breast Cancer
      • Clinical Trials
      • Immunotherapy: Facts and Hopes
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Clinical Trials: Targeted Therapy

Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation–Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study

Darren R. Hargrave, Eric Bouffet, Uri Tabori, Alberto Broniscer, Kenneth J. Cohen, Jordan R. Hansford, Birgit Geoerger, Pooja Hingorani, Ira J. Dunkel, Mark W. Russo, Lillian Tseng, Kohinoor Dasgupta, Eduard Gasal, James A. Whitlock and Mark W. Kieran
Darren R. Hargrave
1Pediatric Oncology Unit, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Darren R. Hargrave
  • For correspondence: darren.hargrave@nhs.net
Eric Bouffet
2Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Uri Tabori
3Arthur and Sonia Labatt Brain Tumor Research Center, Division of Hematology/Oncology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alberto Broniscer
4Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenneth J. Cohen
5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Division of Pediatric Oncology, Baltimore, Maryland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kenneth J. Cohen
Jordan R. Hansford
6Department of Pediatrics, The Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jordan R. Hansford
Birgit Geoerger
7Department of Childhood and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pooja Hingorani
8Phoenix Children's Hospital, Center for Cancer and Blood Disorders, Phoenix, Arizona.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ira J. Dunkel
9Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ira J. Dunkel
Mark W. Russo
10Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lillian Tseng
10Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Lillian Tseng
Kohinoor Dasgupta
11Novartis Healthcare Pvt. Ltd., Hyderabad, India.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eduard Gasal
10Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James A. Whitlock
2Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark W. Kieran
12Harvard Medical School, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1078-0432.CCR-19-2177 Published December 2019
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Additional Files
  • Figure 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 1.

    Dabrafenib treatment duration and best response. A, Duration of exposure to dabrafenib analyzed by best overall response assessed by independent review using the RANO criteria. B, Best reduction in tumor size analyzed by best overall response, assessed by independent review using the RANO criteria, for the subset of patients with measurable disease. Dashed line represents a 50% reduction from baseline, which corresponds to the threshold for partial response per the RANO criteria. aIncludes only patients with measurable disease and ≥1 postbaseline evaluation. Five of these patients had the best overall response as stable disease, with no confirmation from the scan results; 1 patient was not evaluable.

  • Figure 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 2.

    MR images of a partial response (ongoing) achieved after 8 weeks of dabrafenib therapy in an 11-year-old male patient with BRAF V600–mutant ganglioglioma determined using coronal T1 postgadolinium contrast sequence. The arrows indicate the location of the tumor.

  • Figure 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 3.

    Kaplan–Meier progression-free survival. Kaplan–Meier estimates of progression-free survival. Eleven disease progression events occurred; eight were on-treatment and three were off-treatment. Tumor assessments were by independent review using the RANO criteria.

Tables

  • Figures
  • Additional Files
  • Table 1.

    Patient demographics, baseline characteristics, prior treatments, disposition, and dabrafenib exposurea

    Part 1Part 2
    CharacteristicDabrafenib 3.75 mg/kg (n = 3)Dabrafenib 4.5 mg/kg (n = 6)Dabrafenib 5.25 mg/kg (n = 6)Dabrafenib RP2D (n = 17)All patients treated with dabrafenib at RP2D (n = 24)All patients with LGG (N = 32)
    Median age (range), years8 (4–13)8.5 (2–16)7.5 (3–11)11 (2–17)9.5 (2–17)8.5 (2–17)
     <2 years, n000000
     2–<6 years, n1225710
     6–<12 years, n1344812
     12–≤18 years, n1108910
    Sex, n (%)
     Male2 (67)5 (83)3 (50)9 (53)13 (54)19 (59)
     Female1 (33)1 (17)3 (50)8 (47)11 (46)13 (41)
    Race, n (%)
     White3 (100)5 (83)6 (100)13 (76)19 (79)27 (84)
     Black01 (17)02 (12)3 (13)3 (9)
     Asian0002 (12)2 (8)2 (6)
    Performance status, n (%)b
     1002 (67)3 (50)3 (50)9 (53)12 (50)17 (53)
     80–901 (33)1 (17)2 (33)7 (41)10 (42)11 (34)
     <8002 (33)1 (17)1 (6)2 (8)4 (13)
    Histology at initial diagnosis, n (%)
     Pilocytic astrocytoma1 (33)3 (50)1 (17)8 (47)10 (42)13 (41)
     Ganglioglioma01 (17)1 (17)5 (29)6 (25)7 (22)
     Pleomorphic xanthoastrocytoma001 (17)2 (12)3 (13)3 (9)
     Pilomyxoid astrocytoma1 (33)001 (6)1 (4)2 (6)
     Otherc1 (33)2 (33)3 (50)1 (6)4 (17)7 (22)
    Histologic grade at initial diagnosis, n (%)d
     Grade I2 (67)4 (67)4 (67)12 (71)16 (67)22 (69)
     Grade II1 (33)2 (33)2 (33)4 (24)7 (29)9 (28)
    Median time since initial diagnosis (range), months36 (32–39)15 (11–90)39 (18–83)26 (6–190)31 (6–190)32 (6–190)
    Prior treatments, n (%)e
     Chemotherapy3 (100)5 (83)6 (100)14 (82)20 (83)28 (88)
     Radiotherapy1 (33)1 (17)1 (17)3 (18)5 (21)6 (19)
     Small-molecule therapy001 (17)1 (6)2 (8)2 (6)
     Immunotherapy0001 (6)1 (4)1 (3)
     Other0003 (18)3 (13)3 (9)
    Median time from last recurrence to dabrafenib start (range), monthsfNANA0.8 (0.2–1.3)1.1 (0.1–81.5)1.1 (0.1–81.5)1.1 (0.1–81.5)
    Median time from last progression to dabrafenib start (range), monthsg7.6 (0.5–14.7)0.8 (0.5–1.1)1.8 (0.2–26.2)1.6 (0.1–10.3)1.5 (0.1–26.2)1.1 (0.1–26.2)
    Continuing treatment, n (%)2 (67)3 (50)2 (33)8 (47)10 (42)15 (47)
    Discontinued treatment, n (%)1 (33)3 (50)4 (67)9 (53)14 (58)17 (53)
     Reasons for discontinuation
      Investigator discretion1 (33)1 (17)4 (67)5 (29)10 (42)11 (34)
      Disease progression02 (33)02 (12)2 (8)4 (13)
      Adverse event0002 (12)2 (8)2 (6)
    Median duration of exposure to dabrafenib (range), weeks157 (62–159)120 (8–185)96 (25–152)105 (<1–149)104 (<1–152)108 (<1–185)
    Patients with dose reductions and/or interruptions, n (%)1 (33)3 (50)1 (17)5 (29)6 (25)10 (31)
    • Abbreviation: NA, not applicable.

    • ↵aAs of data cutoff (September 12, 2017).

    • ↵bUsing Karnofsky (≥16 years of age; n = 28) or Lansky (<16 years of age; n = 4) performance status, as appropriate.

    • ↵cDesmoplastic neuroepithelial neoplasm, cervicomedullary tumor, glioneuronal brain stem tumor, posterior fossa brain tumor, optic pathway glioma, gliomatosis cerebri, and other low-grade glioma.

    • ↵dOne patient had missing data for disease grade at initial diagnosis but was confirmed to have LGG.

    • ↵ePatients may have had multiple therapies and prior therapy type was undetermined in 2 patients; best response to last therapy received included 5 patients with a partial response, 13 patients with stable disease, and 9 patients with progressive disease (response to last therapy was undetermined in 5 patients).

    • ↵fIn 11 patients with recurrence.

    • ↵gIn 25 patients with disease progression.

  • Table 2.

    Dabrafenib efficacy

    Part 1Part 2
    CharacteristicDabrafenib 3.75 mg/kg (n = 3)Dabrafenib 4.5 mg/kg (n = 6)Dabrafenib 5.25 mg/kg (n = 6)Dabrafenib RP2D (n = 17)All patients treated with dabrafenib at RP2D (n = 24)All patients with LGG (N = 32)
    Independent reviewa
     Best overall response, n (%)
      Complete response01 (17)0001 (3)
      Partial response2 (67)2 (33)2 (33)7 (41)9 (38)13 (41)
      Stable diseaseb1 (33)3 (50)4 (67)8 (47)13 (54)16 (50)
      Progressive disease0002 (12)2 (8)2 (6)
     Objective response, n (%) [95% CI]2 (67) [9–99]3 (50) [12–88]2 (33) [4–78]7 (41) [18–67]9 (38) [19–59]14 (44) [26–62]
     Median duration of response (range), months————11.0 (3.7–14.5)11.0 (7.4–14.5)
     Disease control, n (%) [95% CI]3 (100) [29–100]5 (83) [36–100]5 (83) [36–100]12 (71) [44–90]18 (75) [53–90]25 (78) [60–91]
     Median progression-free survival (95% CI), monthsc35 (15–NE)(NE–NE)13 (13–NE)(NE–NE)14 (13–NE)35 (13–NE)
     1-year progression-free survival rate (95% CI), %c100 (100–100)80 (20–97)100 (100–100)78 (46–92)79 (53–92)85 (64–94)
    • Abbreviation: NE, not estimable.

    • ↵aUsing RANO criteria.

    • ↵bIncludes 5 patients with independent review of stable disease but lacking any confirmation scan results.

    • ↵cKaplan–Meier estimate.

  • Table 3.

    Safety summary and treatment-related AEs

    All patients with LGG (N = 32)
    All gradeGrade 3/4
    Patients with a treatment-related AE, n (%)29 (91)9 (28)
     Treatment-related AEs (in >20% of patients), n (%)
      Fatigue11 (34)0
      Rash10 (31)0
      Dry skin9 (28)0
      Pyrexia9 (28)0
      Rash maculopapular9 (28)3 (9)
      Arthralgia8 (25)1 (3)
      Headache7 (22)0
      Vomiting7 (22)0
    AEs leading to discontinuation, n (%)2 (6)2 (6)
    Treatment-related deaths, n (%)00
    Patients with a treatment-related serious AE, n (%)5 (16)3 (9)
     Treatment-related serious AEs, n (%)
      Arthralgia1 (3)1 (3)
      Disseminated intravascular coagulation1 (3)1 (3)
      Ejection fraction decreased1 (3)0
      Febrile neutropenia1 (3)0
      Hypotension1 (3)1 (3)
      Pyrexia1 (3)0
      Rash maculopapular1 (3)1 (3)

Additional Files

  • Figures
  • Tables
  • Supplementary Data

    • Figure S1 - Trial design
    • Figure S2 - Investigator-assessed percent change at maximum reduction from baseline in tumor measurement per RANO criteria
PreviousNext
Back to top
Clinical Cancer Research: 25 (24)
December 2019
Volume 25, Issue 24
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Clinical Cancer Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation–Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study
(Your Name) has forwarded a page to you from Clinical Cancer Research
(Your Name) thought you would be interested in this article in Clinical Cancer Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation–Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study
Darren R. Hargrave, Eric Bouffet, Uri Tabori, Alberto Broniscer, Kenneth J. Cohen, Jordan R. Hansford, Birgit Geoerger, Pooja Hingorani, Ira J. Dunkel, Mark W. Russo, Lillian Tseng, Kohinoor Dasgupta, Eduard Gasal, James A. Whitlock and Mark W. Kieran
Clin Cancer Res December 15 2019 (25) (24) 7303-7311; DOI: 10.1158/1078-0432.CCR-19-2177

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation–Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study
Darren R. Hargrave, Eric Bouffet, Uri Tabori, Alberto Broniscer, Kenneth J. Cohen, Jordan R. Hansford, Birgit Geoerger, Pooja Hingorani, Ira J. Dunkel, Mark W. Russo, Lillian Tseng, Kohinoor Dasgupta, Eduard Gasal, James A. Whitlock and Mark W. Kieran
Clin Cancer Res December 15 2019 (25) (24) 7303-7311; DOI: 10.1158/1078-0432.CCR-19-2177
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Patients and Methods
    • Results
    • Discussion
    • Disclosure of Potential Conflicts of Interest
    • Authors' Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Adjuvant Sirolimus in Canine Appendicular Osteosarcoma
  • NUC-1031 in Recurrent Ovarian Cancer
  • Phase I Study of Evofosfamide and Ipilimumab in Solid Tumors
Show more Clinical Trials: Targeted Therapy
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • CCR Focus Archive
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Clinical Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Clinical Cancer Research
eISSN: 1557-3265
ISSN: 1078-0432

Advertisement