Abstract LB-147: Combination of the MEK inhibitor, pimasertib (MSC1936369B), and the PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial.
Authors: Infante Jeffrey R. , Gandi Leena , Shapiro Geoffrey , Rizvi Naiyer , Burris Howard A. , Bendell Johanna C. , Baselga José , Hsu Karl , von Richter Oliver , Locatelli Giuseppe , Asatiani Ekaterine , Heist Rebecca S. 
Published: August 2014

Abstract
Background: The PI3K/mTOR and MAPK signaling pathways are frequently aberrated in tumors and interact to promote growth. This trial investigated simultaneous inhibition of these pathways using a combination of the selective uncompetitive MEK1/2 inhibitor pimasertib and the dual PI3K/mTOR inhibitor SAR245409 (ClinicalTrials.gov NCT01390818).
Materials and Methods: This phase Ib, dose-escalation trial (modified 3+3 design) included patients (pts) with solid tumors with frequent activation of these pathways, no approved therapy, and ECOG performance status ≤1. Expansion in selected indications, based on activity signals, was allowed after determination of the maximum tolerated dose (MTD). Pts received 21-day cycles of pimasertib (once-daily, qd) and SAR245409 (qd) 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 and DL6b 60/90. The MTD of the combination was the highest dose at which ≤1/6 pts had a dose-limiting toxicity (DLT). Safety, pharmacokinetics (PK), pharmacodynamics (PD) and tumor response were investigated.
Results: Of 46 pts treated, 57% were male, the median age was 58.5 years (range 31-82) and 54% had an ECOG PS of 1. The most common primary tumor types were: colorectal (CRC, n=16), pancreatic and non-small cell lung cancer (NSCLC, n=7, each). Dose escalation was stopped at DL6b as 2/3 pts had DLTs; both had grade 3 nausea and/or vomiting, which resolved after supportive care and treatment interruption. The most frequent adverse events (AEs) (all grades) were: diarrhea (54%), fatigue (50%), nausea (41%) and vomiting and dermatitis acneiform (39% each). The median number of initiated cycles was 2 (range 1-16). There were 2 partial responses (KRAS mutated [mt] CRC with neuro-endocrine features and KRAS mt/PIK3CA mt low grade ovarian cancer and another pt with low grade ovarian cancer had 29% tumor shrinkage) and 7 other pts had stable disease lasting &gt;12 weeks (CRC [n=2, 1 KRAS wild-type (wt) and 1 KRAS mt]; KRAS mt NSCLC [n=2]; and BRAF wt melanoma, KIT mt soft palate cancer and PIK3CA mt bladder cancer [n=1, each]). The MTD was DL6a (pimasertib 90 mg / SAR 245409 70 mg). DL5 (60/70) was the recommended phase II dose (RP2D) based on pimasertib tolerability after prolonged exposure in monotherapy program. Four disease-specific expansion cohorts (CRC, triple-negative breast cancer, NSCLC and melanoma, 18 pts each) are being treated at this dose. Dose escalation with twice-daily administration is ongoing. Preliminary PK and PD data showed no apparent drug-drug interaction.
Conclusions: The combination of pimasertib and SAR245409 qd is feasible. The MTD and RP2D for the combination are within the range of the active doses of each drug as monotherapy. Early signals of activity have been observed.
Citation Format: Jeffrey R. Infante, Leena Gandi, Geoffrey Shapiro, Naiyer Rizvi, Howard A. Burris, Johanna C. Bendell, José Baselga, Karl Hsu, Oliver von Richter, Giuseppe Locatelli, Ekaterine Asatiani, Rebecca S. Heist. Combination of the MEK inhibitor, pimasertib (MSC1936369B), and the PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-147. doi:10.1158/1538-7445.AM2013-LB-147