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/m(2) every 21 days in patients with cancer

Purpose

This Phase I study aims to evaluate the safety and tolerability of LY2603618, a selective Checkpoint Kinase 1 inhibitor, in combination with pemetrexed, while determining the maximum tolerable dose and pharmacokinetic parameters.

Experimental Design

This open-label, multicenter, dose-escalation study involved patients with advanced solid tumors. Patients received escalating doses of LY2603618 (ranging from 40 to 195 mg/m²) alongside 500 mg/m² of pemetrexed. LY2603618 was administered on Days 1 and 9, while pemetrexed was given on Day 8 of a 28-day cycle. In subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.

Results

A total of 31 patients were enrolled across six cohorts: three patients at 40 mg/m² (administered over a 4.5-hour infusion), and subsequent cohorts included three each at 40 mg/m², 70 mg/m², and 195 mg/m², with 13 patients at 105 mg/m² and six at 150 mg/m². Four patients experienced dose-limiting toxicities: diarrhea (at 105 mg/m²), a reversible infusion-related reaction (at 150 mg/m²), thrombocytopenia, and fatigue (both at 195 mg/m²). The maximum tolerated dose was established at 150 mg/m². Pharmacokinetic data indicated that LY2603618 exposure increased in a dose-dependent manner, with an appropriate half-life to ensure required human exposures while minimizing intra- and inter-cycle accumulation; this was unaffected by pemetrexed administration. A pharmacokinetically defined biologically efficacious dose was achieved at doses of ≥105 mg/m².

Conclusion

LY2603618, administered approximately 24 hours after pemetrexed, demonstrated an acceptable safety profile and favorable pharmacokinetics.