Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations
Summary
This was a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors. Part A was a repeat dose, dose escalation and expansion phase that identified the recommended phase II dose (RP2D) of trametinib monotherapy. Part B evaluated the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Part C was aimed to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part D evaluated the preliminary activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of subjects. The overall goal of this trial was to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.
Timeline
- Start
- 2015-01-15
- Primary completion
- 2020-12-29
- Completion
- 2020-12-29
Publications
- Whitlock JA, Geoerger B, Dunkel IJ, Roughton M, Choi J, Osterloh L, Russo M, Hargrave D. Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv. 2023 Aug 8;7(15):3806-3815. doi: 10.1182/bloodadvances.2022008414.
- Bouffet E, Geoerger B, Moertel C, Whitlock JA, Aerts I, Hargrave D, Osterloh L, Tan E, Choi J, Russo M, Fox E. Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. J Clin Oncol. 2023 Jan 20;41(3):664-674. doi: 10.1200/JCO.22.01000. Epub 2022 Nov 14.
- Shahid S, Kushner BH, Modak S, Basu EM, Rubin EM, Gundem G, Papaemmanuil E, Roberts SS. Association of BRAF V600E mutations with vasoactive intestinal peptide syndrome in MYCN-amplified neuroblastoma. Pediatr Blood Cancer. 2021 Oct;68(10):e29265. doi: 10.1002/pbc.29265. Epub 2021 Jul 31.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Dabrafenib | Small molecule | 2.25 mg/kg | Oral |
| Subject | Dabrafenib | Small molecule | 2.63 mg/kg | Oral |
| Subject | Dabrafenib | Small molecule | 4.5 mg/kg | Oral |
| Subject | Dabrafenib | Small molecule | 5.25 mg/kg | Oral |
| Subject | Trametinib | Small molecule | 0.0125 mg/kg | Oral |
| Subject | Trametinib | Small molecule | 0.025 mg/kg | Oral |
| Subject | Trametinib | Small molecule | 0.032 mg/kg | Oral |
| Subject | Trametinib | Small molecule | 0.04 mg/kg | Oral |