Wednesday 14 February 2018

Dabrafenib and trametinib in BRAFV600E mutated glioma.


I started looking for information about Trametinib and found encouraging information about the treatment of BRAFV600E mutant tumors with a combination of Dabrafenib and trametinib.

2017 http://www.jnccn.org/content/16/1/4
"BRAF V600E mutations have been successfully treated with targeted therapy in melanoma, non–small cell lung cancer, and thyroid cancer. Interestingly, these mutations have also been identified in a subset of pediatric and adult brain tumors, with several cases reportedly responding to targeted therapy. However, these reports have been limited to single-agent BRAF inhibitor therapy and recurrent disease. Herein, we report dramatic clinical and radiographic responses to combination dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in 2 adults with high-grade gliomas (HGGs), with 1 patient treated in the first-line setting. These observations, together with prior case reports, advocate for routine screening of BRAF point mutations in adult HGGs, and suggest that treatment with dual-targeted therapy, even in newly diagnosed cases, is safe and effective."

2017 https://www.ncbi.nlm.nih.gov/pubmed/28984141
"BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib."

2017 https://www.ncbi.nlm.nih.gov/pubmed/28062673
"A phase I/II clinical trial suggests that dabrafenib shrinks or stabilizes low-grade gliomas in children with the BRAF V600E mutation. Objective, durable responses occurred in 38% of patients, and the side effects were less severe than with chemotherapy. The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib."

To determine which dose of Trametinib can be tolerated and effective, for my mother who does not have the BRAF mutation, I began to look for reports on the treatment of patients. I found two such reports. Unfortunately the articles are paid:
https://www.ncbi.nlm.nih.gov/pubmed/28984141
https://www.ncbi.nlm.nih.gov/pubmed/26936308

Have you seen information about the used doses of trametinib in these reports and clinical trial?

I also found a pediatric clinical trial:
https://clinicaltrials.gov/ct2/show/NCT02684058
But here too, unfortunately, no dose is indicated.

In this studies, not related to the brain, such doses are suggested:
https://clinicaltrials.gov/ct2/show/NCT02034110
Dabrafenib is a 150 mg twice daily capsule administered orally on a continuous basis.
Trametinib is a 2 mg once daily tablet administered orally on a continuous basis.

https://clinicaltrials.gov/ct2/show/NCT02124772
Trametinib Dose-Escalation: Trametinib is administered orally once daily (OD) under fasting conditions. The starting dose of trametinib (0.0125 milligram per kilogram per dose [mg/kg/dose]) is 50% of the recommended fixed dose in adults (2 mg OD). The second dose level (0.025 mg/kg) is equivalent to the recommended dose in adults (2 mg PO daily). The third dose level (0.040 mg/kg) is equivalent to the maximum tolerated dose [MTD] in adults (3 mg PO daily).

2 comments:

  1. The approved dosing of trametinib is 2 mg daily (for melanoma), and that is also the dosing used in this case series:

    Dabrafenib and trametinib in BRAFV600E mutated glioma
    http://sci-hub.la/https://www.futuremedicine.com/doi/pdf/10.2217/cns-2017-0006

    (I was able to obtain both of those "for pay" studies at sci-hub)

    ReplyDelete
  2. That's great! Thank you very much, Stephen!

    ReplyDelete