Background: BI 847325 is an orally bioavailable, potent and selective dual inhibitor of MEK and aurora kinase B. Preclinical studies showed efficacy in a range of xenograft models including tumors with BRAF and KRAS mutation.

Materials and Methods: Patients with advanced, unresectable or metastatic solid malignancies were enrolled into two treatment schedules in a Phase I, first-in-human, dose-escalation study: once a day, D1-14 of a 21-day cycle (Arm A); once a day, D1-5, repeated every week (Arm B; 1 cycle=3 weeks). All patients underwent pharmacokinetic sampling. The following pre- and post-treatment samples were collected: skin biopsies to measure phosphorylated histone H3 (pHH3) by Western blot analysis and immunohistochemistry (IHC) as a marker of Aurora kinase inhibition; and peripheral blood mononuclear cells (PBMC) to measure phosphorylated ERK level (by ELISA) as a marker of MEK inhibition. KRAS, BRAF, and NRAS mutation status was determined from patients’ archival tumor material.

Results: A total of 69 patients (47 in Arm A, 22 in Arm B) were treated at two centers (male/female = 33/36, median age: 57 [range: 26-78]; ECOG performance status: 0/1: 18/51). Median number of courses administered was two (range: 1-12). Patients were treated at 11 dose levels in Arm A (6-160 mg/d) and 8 dose levels in Arm B (6-180 mg/d). The maximum tolerated dose (MTD) was exceeded at 160 mg in Arm A and at 180 mg in Arm B. MTD was defined as 120 mg and 150 mg in Arms A and B, respectively. The most frequent (≥10%) treatment-related adverse events (AEs) were: fatigue (36%), diarrhea (35%), nausea (20%), vomiting (17%), neutropenia (16%), anemia (16%), and decreased appetite (15%). Dose-limiting toxicities in the first cycle, observed in 9 patients, included: neutropenia/febrile neutropenia (n=6), diarrhea (n=2), vomiting (n=2), thrombocytopenia (n=1), troponin I elevation (n=1), increased fatigue (n=1), decreased appetite (n=1), and hypokalaemia (n=1). Dose-limiting neutropenia and diarrhea were seen at higher dose levels and were the main DLTs observed. Among 56 evaluable patients, 1 patient (esophageal SCC, received 160 mg in Arm A) had a partial response, and 7 patients had stable disease which lasted >4 cycles. Nine tumors harbored a KRAS mutation and one had a BRAF V600 mutation: 1 patient with KRAS-mutated thymus cancer was on treatment for 12 cycles, 1 patient with KRAS-mutated rectal carcinoma was on treatment for 6 cycles. Cmax and AUC increased with dose in a greater than linear fashion particularly at the higher dose levels. Mean terminal half life ranged from 4–17 hours with high interpatient variability. Analyses of skin biopsies for pHH3 and PBMC for pERK will be presented.

Conclusions: BI 847325 showed an acceptable safety profile; dose-limiting neutropenia was the most common high grade AE observed; 120 mg and 150 mg were defined as the MTD for Arms A and B, respectively. One patient experienced a PR, and 7 had stable disease lasting >4 cycles.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B281.

Citation Format: Philippe Aftimos, Herlinde Dumez, Ahmad Awada, Maureen Billiet, Amélie Deleporte, Katrien De Block, Jo Costermans, Marie-Anne Meeus, Rainer-Georg Goeldner, David Schnell, Chooi Lee, Patrick Schöffski. Phase I study of two dosing schedules of BI 847325, an orally administered dual inhibitor of MEK and aurora kinase B, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B281.