Mps1 is a serine threonine kinase and a core component of the spindle assembly checkpoint. Two potent, selective, and orally active Mps1 inhibitors -- BAY 1161909 (BAY; lead compound) and BAY 1217389 -- have shown improved efficacy in combination with paclitaxel (Pac) in xenograft models, including Pac-insensitive and acquired resistance models. We report here on the safety, tolerability, and maximum tolerated dose (MTD) of the lead compound BAY in combination with Pac.
Subjects with advanced malignancies (solid tumors) and refractory to standard therapy were eligible. BAY was administered twice daily (BID) in a 2-days on/5-days off dosing schedule in combination with weekly IV Pac starting at 75 mg/m2 (Pac-75), and then at 90 mg/m2 (Pac-90). The dose of BAY was doubled in sequential cohorts until the MTD was reached. Pharmacokinetic analyses were done to determine exposure of BAY and Pac.
A total of 37 patients were enrolled and treated in the Pac-75 cohort and 32 in the Pac-90 cohort, with median age 60 in both groups. Breast, NSCLC, and ovarian adenocarcinomas were the most common cancers. The majority of patients (53.6%) had >3 prior lines of anticancer therapy. BAY exposure generally increased in a dose proportional manner and did not affect Pac exposure. In BAY plus Pac-75 cohorts, 16% of patients had grade (G) 3 BAY-related adverse events (AEs), with no G4/G5 events. In the Pac-90 cohorts, 28% of patients had G3 events, one G4 and no G5 BAY-related events. The most common treatment emergent AEs were fatigue (44.9%), anemia (39.1%), alopecia (37.7%), diarrhea (34.8%) and nausea (33.3%). In 35 evaluable patients from the BAY plus Pac-75 group, there were 5 (14%) PRs, 11 SD,17 PD, and 2 patients not determined. In 28 evaluable patients in the BAY plus Pac-90 group, there were 4 (14%) PRs, 13 SD, and 11 PD. Six of 9 patients with a PR had prior Pac. One dose limiting toxicity (ALT increased) was reported in the BAY 180 mg BID plus Pac-90 dose cohort. The MTD was determined as BAY 90 mg BID plus Pac-90.
BAY in combination with Pac demonstrated good tolerability with manageable AEs and preliminary evidence of efficacy. Study with the follow-up compound BAY 1217389 is ongoing.
Clinical trial identification
Legal entity responsible for the study
P. Rajagopalan, C. Cyris, I. Bruns, J. Mei, F. Souza: Employment: Bayer. All other authors have declared no conflicts of interest.