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Phase 1b study of the oral gemcitabine ‘Pro-drug’ LY2334737 in combination with capecitabine in patients with advanced solid tumors
Ist Teil von
Investigational new drugs, 2015-04, Vol.33 (2), p.432-439
Ort / Verlag
Boston: Springer US
Erscheinungsjahr
2015
Link zum Volltext
Quelle
SpringerLink
Beschreibungen/Notizen
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/m
2
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.