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

• Published in: Investigational new drugs Vol. 31; no. 1; pp. 136 - 144
• Main Authors: Weiss, Glen J., Donehower, Ross C., Iyengar, Tara, Ramanathan, Ramesh K., Lewandowski, Karen, Westin, Eric, Hurt, Karla, Hynes, Scott M., Anthony, Stephen P., McKane, Scott
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.02.2013; Springer
• Subjects: Biological and medical sciences; General pharmacology; Medical sciences; Medicine; Medicine & Public Health; Oncology; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase I Studies; LY2603618; Pemetrexed; Checkpoint kinase inhibitor; Cancer; Antineoplastic agent; Human; Pharmaceutical technology; Dose escalation; Enzyme; Toxicity; Transferases; Malignant tumor; Antifolate; Kinase; Inhibitor; Safety
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-012-9815-9

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/m 2 ) were combined with 500 mg/m 2 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/m 2 , 70 mg/m 2 , and 195 mg/m 2 ; 13 at 105 mg/m 2 ; six at 150 mg/m 2 ). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m 2 ); reversible infusion-related reaction (150 mg/m 2 ); thrombocytopenia (195 mg/m 2 ); and fatigue (195 mg/m 2 ). The maximum tolerated dose was defined as 150 mg/m 2 . 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/m 2 . Conclusion LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.