A phase lb, open-label, multicenter, dose-escalation study of the oral pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor GSK1120212 in patients (pts) with selected advanced solid tumors.

Abstract

3003 Background: MAPK and PI3K/AKT signaling pathways regulate proliferation, differentiation and cell death in human cancers. Known interaction between the 2 pathways provides the rationale for combining both inhibitors in a phase I study. Methods: The objective is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for oral, daily administered, BKM120 + GSK1120212, mainly in pts with tumors with RAS/RAF mutations (mt). A Bayesian logistic regression model with overdose control guides the dose escalation of the treatment. Secondary objectives include safety, tolerability, PK and efficacy. Results: As of 22.09.11, 49 pts were treated with BKM120 + GSK1120212 as follows: 30mg + 0.5mg, 60mg + 0.5mg, 60mg + 1.0mg, 60mg + 1.5mg, 60mg + 2.0mg, 70mg + 1.5mg, 80mg + 1.0mg, 80mg + 1.5mg. 6 pts had dose-limiting toxicities (DLTs); all were reversible. Grade 3 DLTs were: 3 x stomatitis, 1 x dysphagia, 1 x LVEF decrease, 1 x CK increase, 1 x nausea, 1 x anorexia, 1 x decreased oral intake. MTD and/or RP2D for the combination have not been reached. Most common adverse events (AEs) (>25%), all grades and causality, were dermatitis acneiform, diarrhea (51% each); nausea (41%); vomiting (37%); rash (33%); asthenia (31%); CK increase, decreased appetite, pyrexia or stomatitis (29% each) and hyperglycemia (27%). There were 4 on-treatment deaths unrelated to treatment. AEs led to treatment discontinuation, 17 pts (35%) and interruptions/dose reductions, 25 pts (51%). Apparent steady-states of BKM120 and GSK1120212 were reached by day 28. Plasma concentrations of BKM120 in combination with GSK1120212 were lower than for monotherapy. Exposure to GSK1120212 with BKM120 was similar to that observed in monotherapy studies. 3 confirmed partial responses have been observed in pts with KRAS mt ovarian cancer; 2 lasting >9 months. 2 patients with BRAF mt melanoma, who had previously progressed on BRAF inhibitors, had stable disease, for 1 of whom treatment is still ongoing in cycle 6. Conclusions: BKM120 and GSK1120212 can be safely combined. Signs of clinical activity have been seen in pts with RAS/RAF mt tumors.

MEK and PI3K inhibition in solid tumors: rationale and evidence to date

“…The most commonly observed AEs were listed as dermatitis, diarrhea, nausea, vomiting, rash, asthenia, increase in CPK, loss of appetite, pyrexia, stomatitis and hyperglycemia. Partial responses were seen in three patients with K-Ras mutant ovarian cancer and stable disease was observed with two patients with B-Raf mutated melanoma [Bedard et al 2012].…”

Bcl-xl and Mcl-1 are the major determinants of the apoptotic response to dual PI3K and MEK blockage

“…Numerous early-phase clinical studies concerning dual PI3K and MEK targeting are ongoing and some results have recently been presented. Generally, combined PI3K and MEK inhibitor therapy seems to be feasible but, unfortunately, the rate of response is low (10)(11)(12). In preclinical models, the vast majority of cancer cell lines do not show apoptosis in response to dual PI3K and MEK targeting, which could be a major factor behind the limited clinical activity of the approach (8,9).…”

Not just gRASping at flaws: Finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers

“…(33) In a separate trial combining the PI3K inhibitor BKM120 (Novartis, Basel, Switzerland) and the MEK inhibitor trametinib (GlaxoSmithKline, Brentford, UK), three patients with KRAS mutant ovarian cancer achieved partial responses among 66 patients in an unselected population. (34) Based on these three responses, this trial is expanding cohorts to specifically include patients with KRAS or BRAF mutant tumors. These results suggest that the combination of PI3K and MEK inhibitors has activity, but the activity appears relatively limited.…”

“…Grade 3 and 4 toxicities were infrequent, with the most common grade 3 event being skin rash in 14% of patients . In a separate trial combining the PI3K inhibitor BKM120 (Novartis, Basel, Switzerland) and the MEK inhibitor trametinib (GlaxoSmithKline, Brentford, UK), three patients with KRAS mutant ovarian cancer achieved partial responses among 66 patients in an unselected population . Based on these three responses, this trial is expanding cohorts to specifically include patients with KRAS or BRAF mutant tumors.…”