2530 Background: PI3K/mTOR and MAPK signaling pathways are often deregulated in tumors. Simultaneous inhibition of these pathways with the MEK1/2 inhibitor, pimasertib, plus the dual PI3K/mTOR inhibitor, SAR245409, (ClinicalTrials.gov NCT01390818) was investigated. Methods: This was a phase Ib, modified 3+3, dose-escalation trial in patients (pts) with advanced solid tumors. Pts received pimasertib and SAR245409 at the following dose levels (DLs): DL1, 15/30; DL2a, 30/30; DL2b, 15/50; DL3, 30/50; DL4a, 60/50; DL4b, 30/70; DL5, 60/70; DL6a, 90/70; DL6b 60/90 and DL7, 90/90 mg (once-daily, qd). After the qd maximum tolerated dose (MTD) was established, twice-daily (bid) dosing was tested: DL1a, 60/30; DL1b, 45/50 and DL2 60/50 mg bid. A recommended phase II dose (RP2D) was determined. Enrollment continued at the RP2D in four expansion cohorts (18 pts each): dual KRAS/PIK3CA mutated (mt) colorectal cancer (CRC), triple-negative breast cancer, KRAS mt non-small cell lung cancer (NSCLC) and BRAFmt melanoma. Results: 53 pts were treated qd and 7 pts bid. The most common tumors were CRC (n=16), NSCLC (n=8), ovarian and pancreatic (n=7, each). At DL6b 2/3 pts had dose-limiting toxicities (DLTs; both grade [Gr] 3 nausea/vomiting). DL6a was confirmed as the MTD for the qd schedule. At bid DL1a 2/4 pts (both Gr 3 skin rash) and at DL1b 2/3 pts (Gr 3 skin rash and Gr 3 asthenia) had DLTs. DL5 was the RP2D based on tolerability after prolonged exposure. The most common adverse events in qd schedule were: rash (62%, 13% Gr 3), diarrhea (56%, 4% Gr 3), fatigue (51%, 2% Gr 3), nausea (49%, 2% Gr 3), vomiting (45%, 2% Gr 3), peripheral edema and pyrexia (34%, each) and visual impairment with underlying serous retinal detachment (21%). Preliminary pharmacokinetic results suggest no drug-drug interaction. There were 4 partial responses: KRAS mt CRC (n=1) and low-grade ovarian cancer (n=3, 1 KRAS mt/PIK3CA mt and 2 wild-type). Enrollment in expansion cohorts at DL5 is ongoing. Conclusions: Continuousqd dosing of pimasertib and SAR245409 is tolerated and has shown signs of activity. Phase II trials are being planned. Clinical trial information: NCT01390818.
A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors