Phase i dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m² every 21 days in patients with cancer

Summary: Purpose This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. Experimental design This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m²) were combined with 500 mg/m² of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. Results A total of 31 patients were enrolled into six cohorts (three at 40 mg/m ² over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m², 70 mg/m², and 195 mg/m ²; 13 at 105 mg/m²; six at 150 mg/m²). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m²); reversible infusion-related reaction (150 mg/m²); thrombocytopenia (195 mg/m²); and fatigue (195 mg/m²). The maximum tolerated dose was defined as 150 mg/m². The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m². Conclusion LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.