| General information |
| Database: | DB00534 |
| Objective: | Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. they aimed to assess its safety and tolerability and to establish a recommendedphase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. |
| Authors: | Falchook GS, et al |
| Title: | Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 doseescalation trial. |
| Journal: | Lancet. |
| Year: | 2012 |
| PMID: | 22608338 |
| Trial Design |
| Clinical Trial Id: | NCT00880321 |
| Agent: | dabrafenib
|
| Target: | BRaf protooncogene serine/threonineprotein kinase
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumours |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | Phase II |
| Key Patients Feature: | Eligibility criteria included written informed consent, histologically confirmed diagnosis ofa solid tumour for which there was no curative therapy, age more than and equal to 18 years, Eastern CooperativeOncology Group (ECOG) performance status (PS) less than and equal to 1, and adequate organ function(Supplementary Methods). Presence of a BRAF mutation was initially optional but latermandatory due to absence of activity in BRAF wildtype tumours. Eligibility criteria for the expansion cohort of melanoma patients with brain metastasesincluded brain metastases more than and equal to 3 mm, no symptoms attributable to brain metastases, and noprior surgical resection or stereotactic radiosurgery to target lesions, or wholebrainradiotherapy. |
| Biomarker: | BRAF mutations |
| Biomark Analysis: | BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wildtype BRAF. |
| Control Group Info: | single arm |
| Treatment Info: | They used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21day cycle. Once doses had been established, they expanded the cohorts to include up to 20 patients. On the basis of initial data, they chose a recommendedphase 2 dose. Efficacy at the recommendedphase 2 dose was studied in patients with BRAFmutant tumours, including those with nonVal600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and nonmelanoma solid tumours. |
| Primary End Point: | safety, tolerability and recommended phase II dose (RP2D) |
| Secondary End Point: | tumour response, and pharmacokinetic and pharmacodynamic profiles. |
| Patients Number: | 184 |
| Trial Results |
| DLT_MTD: | Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, they selected a recommendedphase 2 dose of 150 mg twice daily. |
| Objective Response Rate: | At the recommendedphase 2 dose in 36 patients with Val600 BRAFmutant melanoma, responses were reported in 25 (69%, 95% CI 51.983.7) and confirmed responses in 18 (50%, 32.967.1). 21 (78%, 57.791.4) of 27 patients with Val600Glu BRAFmutant melanoma responded and 15 (56%, 35.374.5) had a confirmed response. In Val600 BRAFmutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with nonVal600Glu BRAF mutations. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | a median progression free survival (PFS) of 5.5 months. |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Among patients treated at all dose levels, the most common treatmentrelated adverse events (AEs) grade 2 or higher included cutaneous squamous cell carcinoma (SCC) or keratoacanthoma (11%), fatigue (8%), and pyrexia (6%). Dose reductions were required in 13 patients (7%), primarily for pyrexia (3%, n=5), fatigue (2%, n=3), and neutropenia (1%, n=2). No deaths or discontinuations of treatment resulted from AEs, and 140 patients (76%) experienced no drugrelated toxicity higher than grade 2. |
| Conclusions: | Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. |