TY - JOUR
T1 - Efficacy and safety of dabrafenib in pediatric patients with BRAF V600 mutation–positive relapsed or refractory low-grade glioma
T2 - Results from a phase I/IIa study
AU - Hargrave, Darren R.
AU - Bouffet, Eric
AU - Tabori, Uri
AU - Broniscer, Alberto
AU - Cohen, Kenneth J.
AU - Hansford, Jordan R.
AU - Geoerger, Birgit
AU - Hingorani, Pooja
AU - Dunkel, Ira J.
AU - Russo, Mark W.
AU - Tseng, Lillian
AU - Dasgupta, Kohinoor
AU - Gasal, Eduard
AU - Whitlock, James A.
AU - Kieran, Mark W.
N1 - Funding Information:
We thank the patients and their families for their participation in this trial, and we thank the investigators and site staff for their contributions. This trial was sponsored by GlaxoSmithKline and Novartis; dabrafenib is an asset of Novartis AG as of March 2, 2015, after which Novartis took sponsorship of the trial. Medical writing and editorial assistance was provided by Staci Heise, PhD (ArticulateScience LLC), William Fazzone, PhD (ArticulateScience LLC), and Sharol Janice Rodrigues (Novartis Healthcare Pvt. Ltd.), and was funded by Novartis Pharmaceuticals Corporation. Medical review assistance was provided by Mark Russo, MD, of Novartis Pharmaceuticals Corporation. Data were collected by the clinical staff at each study site and monitored by the funder. The funder participated in the data analysis and interpretation as well as in the writing of this report. All authors had full access to the data in the study and accepted responsibility for the decision to publish the report. I.J. Dunkel is supported by the NIH/NCI Support Grant (P30 CA008748). D. Hargrave is supported by the NIH Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. J.A. Whitlock is supported by the Women's Auxiliary Millennium Chair in Hematology/Oncology at The Hospital for Sick Children. E. Bouffet and U. Tabori are supported by the Garron Family Chair in Childhood Cancer Research. M.W. Kieran was supported by the National Cancer Institute of the NIH under award number P50CA165962. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/12/15
Y1 - 2019/12/15
N2 - Purpose: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation–positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. Patients and Methods: Patients ages 1 to <18 years who had BRAF V600–mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/ day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2. Results: Overall, 32 patients with pLGG were enrolled (part 1, n ¼ 15; part 2, n ¼ 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26–62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64–94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). Conclusions: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600–mutant pLGG.
AB - Purpose: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation–positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. Patients and Methods: Patients ages 1 to <18 years who had BRAF V600–mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/ day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2. Results: Overall, 32 patients with pLGG were enrolled (part 1, n ¼ 15; part 2, n ¼ 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26–62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64–94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). Conclusions: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600–mutant pLGG.
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U2 - 10.1158/1078-0432.CCR-19-2177
DO - 10.1158/1078-0432.CCR-19-2177
M3 - Article
C2 - 31811016
AN - SCOPUS:85076506426
SN - 1078-0432
VL - 25
SP - 7303
EP - 7311
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -