Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2012 May 19;379(9829):1893-901.
doi: 10.1016/S0140-6736(12)60398-5.

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial

Gerald S Falchook  1 , Georgina V Long, Razelle Kurzrock, Kevin B Kim, Tobias H Arkenau, Michael P Brown, Omid Hamid, Jeffrey R Infante, Michael Millward, Anna C Pavlick, Steven J O'Day, Samuel C Blackman, C Martin Curtis, Peter Lebowitz, Bo Ma, Daniele Ouellet, Richard F Kefford
Affiliations
Clinical Trial

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial

Gerald S Falchook et al. Lancet. .

Abstract

Background: Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases.

Methods: We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321.

Findings: We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9-83·7) and confirmed responses in 18 (50%, 32·9-67·1). 21 (78%, 57·7-91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3-74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer.

Interpretation: Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours.

Funding: GlaxoSmithKline.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest

Gerald Falchook received support for congress attendance from GlaxoSmithKline. The Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, Texas received research funds from GlaxoSmithKline on behalf of Gerald Falchook and Razelle Kurzrock. Georgina Long received honoraria from GlaxoSmithKline and Roche, support for congress attendance from GlaxoSmithKline, and payment for lectures from Merck, Sharp & Dohme and Pfizer. The Melanoma Institute Australia received educational grants from Roche. Michael Brown received consultancy fees from GlaxoSmithKline. Omid Hamid received payment for lectures from Genentech and BMS, and The Angeles Clinic received grants for clinical trials from Arqule, BMS, Genentech, and Roche. Drug Development Unit, Sarah Cannon Research Institute, Nashville received consulting fees and support for congress attendance on behalf of Jeffrey Infante, who has no additional personal conflicts of interest. Michael Millward received consultancy fees and the Cancer Council Trials and Sir Charles Gairdner Hospital and University of Western Australia received research funding from GlaxoSmithKline. Samuel Blackman, Martin Curtis, Bo Ma and Danielle Ouellet are employees of GlaxoSmithKline and hold stock options. Peter Lebowitz was an employee of GlaxoSmithKline at the time of the study and holds stock options. Richard Kefford received consultancy fees and support for travel from GlaxoSmithKline, and payment for lectures and board membership from Merck, Sharp & Dohme, Pfizer and Roche. The Melanoma Institute Australia, and University of Sydney, and Westmead Institute for Cancer Research received fees for board membership from Merck, Sharp & Dohme and Roche, and support for congress attendance and research grants from Roche. Tobias Arkenau, Kevin Kim and Anna Pavlick have no conflicts of interest.

Figures

Figure 1
Figure 1
Consolidated Standards of Reporting Trials (CONSORT) diagram
Figure 2
Figure 2
Antitumour response in patients treated with dabrafenib A: V600 BRAF-mutant melanoma patients treated at the recommended Phase II dose (n=36) § One V600E patient developed disease progression prior to the first restaging. Tumour size change was not available and is not included in the figure. ▲ Patients with PD as best response. RR, response rate. B: V600 BRAF-mutant melanoma patients with untreated brain metastases (n=10) and representative images from gadolinium-enhanced magnetic resonance imaging treated at the recommended Phase II dose K V600K patient. Panels I–III, V600E brain at baseline (I) Week 6 (II) and Week 10 (III). Best response by RECIST was 71% decrease, and the best intracranial decrease was 68%.
Figure 2
Figure 2
Antitumour response in patients treated with dabrafenib A: V600 BRAF-mutant melanoma patients treated at the recommended Phase II dose (n=36) § One V600E patient developed disease progression prior to the first restaging. Tumour size change was not available and is not included in the figure. ▲ Patients with PD as best response. RR, response rate. B: V600 BRAF-mutant melanoma patients with untreated brain metastases (n=10) and representative images from gadolinium-enhanced magnetic resonance imaging treated at the recommended Phase II dose K V600K patient. Panels I–III, V600E brain at baseline (I) Week 6 (II) and Week 10 (III). Best response by RECIST was 71% decrease, and the best intracranial decrease was 68%.
Figure 2
Figure 2
Antitumour response in patients treated with dabrafenib A: V600 BRAF-mutant melanoma patients treated at the recommended Phase II dose (n=36) § One V600E patient developed disease progression prior to the first restaging. Tumour size change was not available and is not included in the figure. ▲ Patients with PD as best response. RR, response rate. B: V600 BRAF-mutant melanoma patients with untreated brain metastases (n=10) and representative images from gadolinium-enhanced magnetic resonance imaging treated at the recommended Phase II dose K V600K patient. Panels I–III, V600E brain at baseline (I) Week 6 (II) and Week 10 (III). Best response by RECIST was 71% decrease, and the best intracranial decrease was 68%.
Figure 3
Figure 3
V600 BRAF-mutant melanoma patients treated at the recommended Phase II dose A: Duration on treatment for patients with melanoma (n=36)† ►Time of the first PR or CR * Time of disease progression → Patients remaining in study † The first restaging occurred at 9 weeks and 6 weeks in the escalation and expansion cohorts, respectively. Subsequent restaging occurred every 9 weeks. B: Duration on treatment in melanoma patients with untreated brain metastases (n=10) ►Time of the first PR or CR * Time of disease progression → Patients remaining in study † The patient’s best response was SD; however this was determined after the data cut used in this manuscript § The patient depicted as the top bar in the figure received gamma knife radiation at 5·9 months but did not meet criteria for progression by RECIST. C: Kaplan–Meier progression-free survival curve
Figure 3
Figure 3
V600 BRAF-mutant melanoma patients treated at the recommended Phase II dose A: Duration on treatment for patients with melanoma (n=36)† ►Time of the first PR or CR * Time of disease progression → Patients remaining in study † The first restaging occurred at 9 weeks and 6 weeks in the escalation and expansion cohorts, respectively. Subsequent restaging occurred every 9 weeks. B: Duration on treatment in melanoma patients with untreated brain metastases (n=10) ►Time of the first PR or CR * Time of disease progression → Patients remaining in study † The patient’s best response was SD; however this was determined after the data cut used in this manuscript § The patient depicted as the top bar in the figure received gamma knife radiation at 5·9 months but did not meet criteria for progression by RECIST. C: Kaplan–Meier progression-free survival curve
Figure 3
Figure 3
V600 BRAF-mutant melanoma patients treated at the recommended Phase II dose A: Duration on treatment for patients with melanoma (n=36)† ►Time of the first PR or CR * Time of disease progression → Patients remaining in study † The first restaging occurred at 9 weeks and 6 weeks in the escalation and expansion cohorts, respectively. Subsequent restaging occurred every 9 weeks. B: Duration on treatment in melanoma patients with untreated brain metastases (n=10) ►Time of the first PR or CR * Time of disease progression → Patients remaining in study † The patient’s best response was SD; however this was determined after the data cut used in this manuscript § The patient depicted as the top bar in the figure received gamma knife radiation at 5·9 months but did not meet criteria for progression by RECIST. C: Kaplan–Meier progression-free survival curve
See this image and copyright information in PMC

Comment in

References

    1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954. - PubMed
    1. Catalogue of Somatic Mutations in Cancer (COSMIC) website Wellcome Trust Sanger Institute. [Accessed August 2011];2011 at http://www.sanger.ac.uk/genetics/CGP/cosmic/
    1. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466–474. - PubMed
    1. Elisei R, Ugolini C, Viola D, et al. BRAFV600E Mutation and Outcome of Patients with Papillary Thyroid Carcinoma: A 15-Year Median Follow-Up Study. J Clin Endocrinol Metab. 2008;93:3943–3949. - PubMed
    1. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and Clinicopathologic Associations of Oncogenic BRAF in Metastatic Melanoma. J Clin Oncol. 2011;29:1239–1246. - PubMed

Publication types

MeSH terms

Associated data