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Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors

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Abstract

Purpose

LY2334737 is an oral gemcitabine prodrug. This Phase I study assessed the safety and tolerability of LY2334737 in Japanese patients with solid tumors and evaluated pharmacokinetics (PK), pharmacodynamics, and antitumor activity.

Methods

Patients with advanced/metastatic solid tumors received escalating doses of LY2334737 once daily for 14 days, followed by a 7-day drug-free period. Cycles were repeated until discontinuation criteria were met.

Results

Of 13 patients treated, 3 received 20 mg/day, 6 received 30 mg/day, 4 received 40 mg/day. On the 40 mg dose, 3 patients experienced dose-limiting toxicities (DLTs): hepatic toxicities (e.g., Grade [G]3/4 transaminase and G1–3 bilirubin elevation) and G4 thrombocytopenia; all 3 showed features of disseminated intravascular coagulation. One additional DLT occurred on the 30 mg dose (G3 transaminase elevation). Exploratory pharmacogenetic analyses identified a genetic variation in the CES2 gene potentially associated with these DLTs. PK data showed no clear relationship between the AUC of gemcitabine and its incorporation into leukocyte DNA; 2 of the 3 DLT patients had high incorporation. Two patients (30 mg/day) achieved stable disease with progression-free survival lasting 135 and 155 days.

Conclusions

LY2334737 was tolerated by Japanese patients up to 30 mg/day. The toxicities observed at the 40 mg dose may require the development of alternative dosing schedules.

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Acknowledgments

We would like to thank all patients for participating in the study. Karin Helsberg and Sarah Richardson, Trilogy Writing and Consulting, Frankfurt, Germany, provided medical writing support on behalf of Eli Lilly and Company. This work was supported by Eli Lilly and Company, Indianapolis, IN.

Conflict of interest

K.U., R.S., and T.M. are employees of Eli Lilly Japan, C.S. and K.A.B. are employees of Eli Lilly and Company. N.Y., H.N., Y.Y., K.U., and T.M. have no conflicts of interest to declare. T.T. has received honoraria from Eli Lilly Japan.

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Authors and Affiliations

  1. Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

    Noboru Yamamoto, Hiroshi Nokihara & Tomohide Tamura

  2. Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan

    Yasuhide Yamada

  3. Eli Lilly Japan KK, Kobe, Japan

    Kazunori Uenaka, Risa Sekiguchi & Takeshi Makiuchi

  4. Early Oncology Clinical Investigation, Eli Lilly and Company, Indianapolis, IN, USA

    Christopher A. Slapak

  5. Lilly France, 13 rue Pages, 92158, Suresnes Cedex, France

    Karim A. Benhadji

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  1. Noboru Yamamoto
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Correspondence to Karim A. Benhadji.

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Yamamoto, N., Nokihara, H., Yamada, Y. et al. Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 71, 1645–1655 (2013). https://doi.org/10.1007/s00280-013-2165-2

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  • DOI: https://doi.org/10.1007/s00280-013-2165-2

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