Date: 2014-04-08
Type of information: Initiation of the trial
phase: 1-2
Announcement: initiation of the trial
Company: Amgen (USA - CA)
Product: AMG 232 in combination with trametinib and dabrafenib
Action
mechanism: MDM2 inhibitor/kinase inhibitor/RAF kinase inhibitor/MEK (MAP kinase) inhibitor. AMG 232 is an orally available, piperidinone inhibitor of MDM2 (murine double minute 2). It binds to MDM2 protein and prevents its binding to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this MDM2-p53 interaction, the transcriptional activity of p53 is restored. This leads to p53-mediated induction of tumor cell apoptosis. Dabrafenib is an investigational, orally bioavailable inhibitor of the BRAF protein. Dabrafenib was discovered and developed at GSK. Tafinlar and Mekinist target different kinases within the serine/threonine kinase family - BRAF and MEK1/2, respectively - in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. In April 2014, Novartis has acquired GSK oncology products including dabrafenib and trametinib. In 2015, as part of its purchase of oncology products from GSK, Novartis obtained the worldwide exclusive rights granted by Japan Tobacco to develop, manufacture, and commercialize trametinib. Japan Tobacco retains co-promotion rights in Japan. In August 2015, the European Commission approved the combination of Tafinlar™ + Mekinist™ for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. In July 2015, the FDA granted priority review for an application to obtain regular approval of the Tafinlar + Mekinist combination in BRAF V600E/K mutation-positive metastatic melanoma. Since January 2014, the combination of Tafinlar + Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was approved through the FDA's Accelerated Approval program and reviewed under a priority review designation. The approval was contingent on the results of the COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation.
Trametinib is an investigational, orally bioavailable inhibitor of the MEK protein discovered by Japan Tobacco, Inc and in-licensed by GSK in 2006.
Disease: melanoma
Therapeutic area: Cancer - Oncology
Country: Australia, USA
Trial
details: This phase 1b/2a, open-label, sequential dose escalation and expansion study is evaluating AMG 232 in combination with trametinib and dabrafenib in subjects with metastatic melanoma followed by a direct comparison of AMG 232 combined with trametinib and dabrafenib versus trametinib combined with dabrafenib alone. (NCT02110355)
Latest
news: * On April 8, 2014, a Phase I trial sponsored by Amgen was published on the NIH website ClinicalTrials.gov for AMG 232 and is currently recruiting participants.
