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Preclinical analyses and phase I evaluation of LY2603618 administered in combination with Pemetrexed and cisplatin in patients with advanced cancer

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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: 130–275 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 combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.

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Acknowledgments

The authors acknowledge Justin Meyer, Rita Bowers and Lisa Green at Covance Laboratory for their help with the flow cytometry, Ignacio Garcias-Ribas and Eric Westin for their contributions to the CHK1 clinical program, and Suzanne R.L. Young of Eli Lilly and Company for writing assistance.

Conflict of interest

M.S. reports the following: Advisory Board: Lilly, Boehringer Ingelheim, Pfizer, TEVA Lectures: Novartis, Roche, Pfizer, Abbott, Amgen, Lilly, Boehringer Ingelheim. E.K. is an employee of inVentiv HealthClinical.

M.M., V.C., U.O., S.M.H., H.B.D., D.B., F.F.M., L.H., L.K., P.I., and A.B.L. are all employees and shareholders of Eli Lilly and Company.

This study was conducted in accordance with applicable laws and regulations, GCPs, and the ethical principles that have their origin in the Declaration of Helsinki.

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Authors and Affiliations

  1. START Madrid, Clara Campal Comprehensive Cancer Center, Medical Oncology Division, Madrid Norte Sanchinarro University Hospital, Madrid, Spain, 28050

    Emiliano Calvo & Antonio Calles

  2. Eli Lilly and Company, Indianapolis, IN, USA

    Victor J. Chen, Mark Marshall, Ute Ohnmacht, Scott M. Hynes, H. Bruce Diaz, Darlene Barnard, Farhana F. Merzoug, Lysiane Huber, Lisa Kays, Philip Iversen & Aimee Bence Lin

  3. inVentiv Health Clinical, LLC, 200 Cottontail Ln, Somerset, NJ, USA

    Elizabeth Kumm

  4. Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Antonio Calles

  5. Department of Internal Medicine, Hematology and Oncology, Johannes Gutenberg-University Mainz, Mainz, Germany

    Beatrice Voss & Thomas Wehler

  6. Department of Respiratory Medicine and Thoracic Oncology, Mathias-Spital Rheine, Rheine, Germany

    Nicolas Dickgreber

  7. Department of Hematology/Oncology, Rheumatology, HIV, J.W. Goethe University, Frankfurt, Germany

    Martin Sebastian

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  1. Emiliano Calvo
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Corresponding author

Correspondence to Emiliano Calvo.

Additional information

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

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Calvo, E., Chen, V.J., Marshall, M. et al. Preclinical analyses and phase I evaluation of LY2603618 administered in combination with Pemetrexed and cisplatin in patients with advanced cancer . Invest New Drugs 32, 955–968 (2014). https://doi.org/10.1007/s10637-014-0114-5

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