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RESEARCH PRODUCT

PD-0024 Phase I/II Study of Folfiri Plus the MEK1/2 Inhibitor Pimasertib (MSC1936369B) as Second-Line Treatment for KRAS Mutated Metastatic Colorectal Cancer

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ABSTRACT Introduction Pimasertib is a highly selective inhibitor of the MEK1/2 kinases of the MAPK pathway. It demonstrates potent antitumor activity in cell lines and xenograft models with activating (mainly BRAF and KRAS) mutations. A two-part study, comprising a safety run-in part followed by a randomized phase II part, was designed to investigate FOLFIRI plus pimasertib as second-line treatment for patients with KRAS mutated (mt) metastatic colorectal cancer (mCRC). The results of the safety run-in part, conducted primarily to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), are reported here. Methods Patients with KRAS mt mCRC progressing on first-line oxaliplatin plus fluoropyrimidine ± bevacizumab were eligible. A 3 + 3 design, with fixed dose-escalation based on dose-limiting toxicities (DLTs) occurring during the first cycle (28 days) of treatment, was used to investigate FOLFIRI plus daily oral pimasertib (dosed 5 days on 2 days off, starting dose 45 mg/day). The decision to proceed to the next dose level was made by a safety monitoring committee, comprising investigators and representatives of the sponsor. Results Sixteen atients (median age 64 years [range 38-81] and ECOG performance status 0-1) received FOLFIRI plus pimasertib 45 mg/day (n = 10) or 60 mg/day (n = 6) (safety population). Two patients were not evaluable for the dose escalation and DLT analysis (n = 14). No DLTs were observed in the first 3 patients treated at 45 mg/day, allowing dose escalation to 60 mg/day. On pimasertib 60 mg/day, 2/5 patients had DLTs, both grade 3 mucositis/stomatitis. This led to a per-protocol expansion of the 45 mg/day cohort, during which 1/6 patients had a DLT (grade 3 hyponatremia). The median number of pimasertib cycles initiated was 3 (1-11). Over both doses, the most common treatment-emergent adverse events (TEAEs) were asthenia (44%), diarrhea (44%), mucosal inflammation (38%), ocular events (38%, mainly grade 1/2 macular degeneration) and nausea, rash and vomiting (31% each). Seven patients had at least one ≥ grade 3 treatment-related TEAE: diarrhea (2 patients), mucosal inflammation (3 patients) and neutropenia (3 patients). Eight patients had ≥ 1 serious TEAE: 4 on pimasertib 45 mg/day and 4 on pimasertib 60 mg/day. Five patients had ≥ 1 TEAE leading to permanent treatment discontinuation, 3 on pimasertib 45 mg/day and 2 on 60 mg/day. Over both doses, 9 patients had on-treatment electrocardiogram changes compared with baseline readings. Reasons for stopping treatment included AE (3 patients), disease progression (6 patients) and consent withdrawal (3 patients). As of 23 November 2011, 3 patients remained on treatment with FOLFIRI plus pimasertib. Pimasertib dosed once-daily concomitantly with FOLFIRI exhibited a pharmacokinetic profile comparable to pimasertib monotherapy. Conclusion In combination with FOLFIRI, dose escalation of pimasertib from 45 mg/day to 60 mg/day was limited by toxicity. Due to the fact that 45 mg/day is not considered to be an active dose in this setting, progression to the phase II part of the study was not recommended by the sponsor.