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Invest New Drugs (2014) 32:955968 DOI 10.1007/s10637-014-0114-5
PHASE I STUDIES
Preclinical analyses and phase I evaluation of LY2603618 administered in combination with Pemetrexed and cisplatin in patients with advanced cancer
Emiliano Calvo & Victor J. Chen & Mark Marshall & Ute Ohnmacht & Scott M. Hynes &
Elizabeth Kumm & H. Bruce Diaz & Darlene Barnard & Farhana F. Merzoug & Lysiane Huber &
Lisa Kays & Philip Iversen & Antonio Calles & Beatrice Voss & Aimee Bence Lin &
Nicolas Dickgreber & Thomas Wehler & Martin Sebastian
Received: 12 March 2014 /Accepted: 12 May 2014 /Published online: 20 June 2014 # Springer Science+Business Media New York 2014
Summary LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m2) and
cisplatin (75 mg/m2) and escalating doses of LY2603618: 130275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses 240 mg. The pharmacokinetics of
LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in
These authors are Thomas Wehler and Martin Sebastian contributed equally to this study.
Research support: The study was sponsored by Eli Lilly and Company. Trial Registration ID: NCT01139775
E. Calvo (*) : A. CallesSTART Madrid, Clara Campal Comprehensive Cancer Center, Medical Oncology Division, Madrid Norte Sanchinarro University...