Summary
Background This Phase 1b study aimed to determine the recommended Phase 2 dose of LY2334737, an oral pro-drug of gemcitabine, in combination with capecitabine, an oral pro-drug of 5-fluorouracil, in patients with advanced solid tumors. In addition, pharmacokinetics (PK) and tumor response were evaluated. Patients and methods Patients with advanced/metastatic solid tumors received 650 mg/m2 capecitabine twice daily (BID) and escalating doses of LY2334737 once daily (QD; initial dose 10 mg/day), both for 14 days followed by 7-day drug holiday. Cycles were repeated until progressive disease (PD) or unacceptable toxicity. Results Fifteen patients received a median of 2 (range 1–7) treatment cycles; 14 patients discontinued due to PD, 1 due to toxicity (pyrexia). LY2334737 doses up to 40 mg/day were explored. Three dose-limiting toxicities were reported by 2 patients (fatigue, diarrhea, hyponatremia; all Grade 3). Seven patients achieved stable disease. Enrollment was stopped after unexpected hepatic toxicities were observed with LY2334737 QD in a study of Japanese patients. PK parameters for LY2334737 were consistent with the first-in-human study of LY2334737; PK data after 14 day combination treatment revealed no drug-drug interactions between LY2334737 and capecitabine. Conclusions No drug interactions or unexpected toxicities were observed in US patients when LY2334737 at doses up to 40 mg/day was administered QD in combination with capecitabine BID; the maximum tolerated dose was not reached.
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Acknowledgments
The study has been funded by Eli Lilly and Company. We would like to thank all patients for participating in the study. Karin Helsberg and Michael Riley, Trilogy Writing & Consulting, Frankfurt, Germany, provided medical writing support on behalf of Eli Lilly and Company.
Disclosure of potential conflicts of interest
The study was funded by Eli Lilly and Company. KAB and SC are employees of Eli Lilly and Company. JRI, GKD, GF, WWM, JB, and AAA have no no conflicts of interest to declare.
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Infante, J.R., Benhadji, K.A., Dy, G.K. et al. Phase 1b study of the oral gemcitabine ‘Pro-drug’ LY2334737 in combination with capecitabine in patients with advanced solid tumors. Invest New Drugs 33, 432–439 (2015). https://doi.org/10.1007/s10637-015-0207-9
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DOI: https://doi.org/10.1007/s10637-015-0207-9