PACMEL: A phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel. Issue 3 (February 2015)

• Record Type: Journal Article
• Authors: Coupe, Nicholas; Corrie, Pippa; Hategan, Mirela; Larkin, James; Gore, Martin; Gupta, Avinash; Wise, Adelyn; Suter, Sam; Ciria, Cristian; Love, Sharon; Collins, Linda; Middleton, Mark R.
• Is Part Of: European journal of cancer. Volume 51:Issue 3(2015:Feb.)
• Page Start: 359
• Page End: 366
• Publication Date: 2015-02
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2014.11.018
• Languages: English
• ISSNs: 0959-8049

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title id="st110">Abstract</title> <sec> <title id="st080">Background</title> <p id="sp0005">We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel, with a view to exploring the combination's activity in melanoma lacking a <italic>BRAF</italic> V600 mutation.</p> </sec> <sec> <title id="st085">Methods</title> <p id="sp0010">In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m<sup>2</sup> intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of trametinib (to a maximum 2 mg orally (PO) daily), following a 3 + 3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease.</p> </sec> <sec> <title id="st090">Findings</title> <p id="sp0015">15 patients were enrolled, all but one of whose melanoma was wild type for <italic>BRAF</italic> at codon 600. The maximal monotherapy dose of trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with <italic>NRAS</italic> mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8–7.8 months) and overall survival, 14.1 months (95% CI 4.6–not reached).</p> </sec> <sec> <title id="st095">Interpretation</title> <p id="sp0020">Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 <italic>BRAF</italic> mutation.</p> </sec> </abstract>