Targeted Approach to Langerhans Cell Histiocytosis (LCH) Using MEK Inhibitor, Trametinib

Summary

The purpose of this Phase II clinical trial is to establish the safety and effectiveness of trametinib, a targeted therapy, for the treatment of newly or recently diagnosed Langerhans Cell Histiocytosis (LCH) among pediatric patients.

Timeline

Start

2024-06-24

Primary completion

2039-06

Completion

2039-12

Publications

• Background Stalemark H, Laurencikas E, Karis J, Gavhed D, Fadeel B, Henter JI. Incidence of Langerhans cell histiocytosis in children: a population-based study. Pediatr Blood Cancer. 2008 Jul;51(1):76-81. doi: 10.1002/pbc.21504.
• Background Badalian-Very G, Vergilio JA, Fleming M, Rollins BJ. Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol. 2013 Jan 24;8:1-20. doi: 10.1146/annurev-pathol-020712-163959. Epub 2012 Aug 6.
• Background Allen CE, Ladisch S, McClain KL. How I treat Langerhans cell histiocytosis. Blood. 2015 Jul 2;126(1):26-35. doi: 10.1182/blood-2014-12-569301. Epub 2015 Mar 31.
• Background Jouenne F, Chevret S, Bugnet E, Clappier E, Lorillon G, Meignin V, Sadoux A, Cohen S, Haziot A, How-Kit A, Kannengiesser C, Lebbe C, Gossot D, Mourah S, Tazi A. Genetic landscape of adult Langerhans cell histiocytosis with lung involvement. Eur Respir J. 2020 Feb 27;55(2):1901190. doi: 10.1183/13993003.01190-2019. Print 2020 Feb.
• Background Chakraborty R, Hampton OA, Shen X, Simko SJ, Shih A, Abhyankar H, Lim KP, Covington KR, Trevino L, Dewal N, Muzny DM, Doddapaneni H, Hu J, Wang L, Lupo PJ, Hicks MJ, Bonilla DL, Dwyer KC, Berres ML, Poulikakos PI, Merad M, McClain KL, Wheeler DA, Allen CE, Parsons DW. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood. 2014 Nov 6;124(19):3007-15. doi: 10.1182/blood-2014-05-577825. Epub 2014 Sep 8.
• Background Vicenzi P, Ray A. Comment on: Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib. Pediatr Blood Cancer. 2021 Apr;68(4):e28776. doi: 10.1002/pbc.28776. Epub 2020 Oct 21. No abstract available.
• Background Gadner H, Minkov M, Grois N, Potschger U, Thiem E, Arico M, Astigarraga I, Braier J, Donadieu J, Henter JI, Janka-Schaub G, McClain KL, Weitzman S, Windebank K, Ladisch S; Histiocyte Society. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013 Jun 20;121(25):5006-14. doi: 10.1182/blood-2012-09-455774. Epub 2013 Apr 15.
• Background Morimoto A, Ikushima S, Kinugawa N, Ishii E, Kohdera U, Sako M, Fujimoto J, Bessho F, Horibe K, Tsunematsu Y, Imashuku S; Japan Langerhans Cell Histiocytosis Study Group. Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer. 2006 Aug 1;107(3):613-9. doi: 10.1002/cncr.21985.
• Background Sieni E, Barba C, Mortilla M, Savelli S, Grisotto L, Di Giacomo G, Romano K, Fonda C, Biggeri A, Guerrini R, Arico M. Early Diagnosis and Monitoring of Neurodegenerative Langerhans Cell Histiocytosis. PLoS One. 2015 Jul 15;10(7):e0131635. doi: 10.1371/journal.pone.0131635. eCollection 2015.
• Background Chohan G, Barnett Y, Gibson J, Reddel SW, Barnett MH. Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg Psychiatry. 2012 May;83(5):573-5. doi: 10.1136/jnnp-2011-300575. Epub 2011 Aug 19. No abstract available.
• Background Titgemeyer C, Grois N, Minkov M, Flucher-Wolfram B, Gatterer-Menz I, Gadner H. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001 Aug;37(2):108-14. doi: 10.1002/mpo.1178.
• Background Diamond EL, Durham BH, Ulaner GA, Drill E, Buthorn J, Ki M, Bitner L, Cho H, Young RJ, Francis JH, Rampal R, Lacouture M, Brody LA, Ozkaya N, Dogan A, Rosen N, Iasonos A, Abdel-Wahab O, Hyman DM. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature. 2019 Mar;567(7749):521-524. doi: 10.1038/s41586-019-1012-y. Epub 2019 Mar 13.
• Background Haroche J, Cohen-Aubart F, Emile JF, Maksud P, Drier A, Toledano D, Barete S, Charlotte F, Cluzel P, Donadieu J, Benameur N, Grenier PA, Besnard S, Ory JP, Lifermann F, Idbaih A, Granel B, Graffin B, Hervier B, Arnaud L, Amoura Z. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease. J Clin Oncol. 2015 Feb 10;33(5):411-8. doi: 10.1200/JCO.2014.57.1950. Epub 2014 Nov 24.
• Background Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4.
• Background Selt F, van Tilburg CM, Bison B, Sievers P, Harting I, Ecker J, Pajtler KW, Sahm F, Bahr A, Simon M, Jones DTW, Well L, Mautner VF, Capper D, Hernaiz Driever P, Gnekow A, Pfister SM, Witt O, Milde T. Response to trametinib treatment in progressive pediatric low-grade glioma patients. J Neurooncol. 2020 Sep;149(3):499-510. doi: 10.1007/s11060-020-03640-3. Epub 2020 Oct 7.
• Background Bouffet E, Hansford JR, Garre ML, Hara J, Plant-Fox A, Aerts I, Locatelli F, van der Lugt J, Papusha L, Sahm F, Tabori U, Cohen KJ, Packer RJ, Witt O, Sandalic L, Bento Pereira da Silva A, Russo M, Hargrave DR. Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. N Engl J Med. 2023 Sep 21;389(12):1108-1120. doi: 10.1056/NEJMoa2303815.
• Background Eckstein OS, Visser J, Rodriguez-Galindo C, Allen CE; NACHO-LIBRE Study Group. Clinical responses and persistent BRAF V600E+ blood cells in children with LCH treated with MAPK pathway inhibition. Blood. 2019 Apr 11;133(15):1691-1694. doi: 10.1182/blood-2018-10-878363. Epub 2019 Feb 4. No abstract available.
• Background Schwartz LH, Litiere S, de Vries E, Ford R, Gwyther S, Mandrekar S, Shankar L, Bogaerts J, Chen A, Dancey J, Hayes W, Hodi FS, Hoekstra OS, Huang EP, Lin N, Liu Y, Therasse P, Wolchok JD, Seymour L. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016 Jul;62:132-7. doi: 10.1016/j.ejca.2016.03.081. Epub 2016 May 14.
• Background Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.

Drugs

Indications