EPCT-01. Pediatric Brain Tumor Consortium (PBTC)-055: A phase I study of trametinib and hydroxychloroquine (HCQ) for BRAF-fusion or Neurofibromatosis type-1 (NF1)-associated pediatric gliomas
| العنوان: | EPCT-01. Pediatric Brain Tumor Consortium (PBTC)-055: A phase I study of trametinib and hydroxychloroquine (HCQ) for BRAF-fusion or Neurofibromatosis type-1 (NF1)-associated pediatric gliomas |
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| المؤلفون: | Lindsey M Hoffman, Jean Mulcahy Levy, Lindsay Kilburn, Catherine Billups, Vanetria Stokes, Emily McCourt, Tina Young Poussaint, Olivia Campagne, Sonia Partap, Kathleen Dorris, Sameer Farouk Sait, Giles Robinson, Patricia Baxter, Clinton F Stewart, Jason Fangusaro, Arzu Onar-Thomas, Ira Dunkel |
| المصدر: | Neuro-Oncology. 24:i35-i35 |
| بيانات النشر: | Oxford University Press (OUP), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cancer Research, Oncology, Neurology (clinical) |
| الوصف: | INTRODUCTION: Autophagy is a highly conserved process by which intracellular components are degraded and recycled promoting cell survival. Preclinically, autophagy has been implicated as a resistance mechanism in BRAF-mutant glioma cells treated with MAPK-pathway inhibitors. HCQ, an oral autophagy inhibitor, has been evaluated preclinically and clinically to overcome resistance. METHODS: PBTC-055 (NCT04201457) is a phase I/II trial of HCQ combined with trametinib (BRAF-fusion or NF1-associated gliomas) or trametinib and dabrafenib (BRAFV600E gliomas) in patients < 30 years with progressive glioma. Prior treatment with RAF and/or MEK inhibitor with sub-optimal response (no response or response followed by progression on therapy) was required. Here, we present phase I data combining trametinib with HCQ utilizing a rolling-6 design. HCQ was administered at escalating dose levels (8, 15, or 20 mg/kg/day divided BID) in combination with standard pediatric trametinib dosing. All patients received prior MEK inhibitor therapy; 5/18 (28%) exhibited no response and 13/18 (72%) progressed on active therapy. RESULTS: Eighteen eligible/evaluable subjects were enrolled. Median age was 9.6 years (2.5-20.4 years); 10 were male. There were 2 dose-limiting toxicities (both grade 3 rash one each at DL1 and DL3). The highest dose level of HCQ (20 mg/kg/day divided BID) was declared the RP2D. Grade 3 adverse events possibly related to therapy included skin infection, rash, cardiac ejection fraction decrease, weight loss, and anorexia. There were no grade 4 or 5 attributable toxicities. Preliminarily, combination pharmacokinetic assessment revealed similar metabolism of trametinib to that reported as a single agent; HCQ demonstrated more rapid clearance compared to adults. Pharmacodynamic assessments are ongoing. CONCLUSIONS: The combination of trametinib and HCQ is safe with a RP2D of HCQ of 20 mg/kg/day divided BID. Currently, subjects are enrolling on the phase II portion evaluating the efficacy of this novel combination. |
| تدمد: | 1523-5866 1522-8517 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::0f4873d2c64bb85642e7a791d62a0ce7 https://doi.org/10.1093/neuonc/noac079.129 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........0f4873d2c64bb85642e7a791d62a0ce7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15235866 15228517 |
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