title: Phase 1b study of the oral gemcitabine 'Pro-drug' LY2334737 in combination with capecitabine in patients with advanced solid tumors.
abstract: 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.
authors: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors: Jeffrey R
authors: JR
authors: Infante
authors: Karim A
authors: KA
authors: Benhadji
authors: Grace K
authors: GK
authors: Dy
authors: Gerald
authors: G
authors: Fetterly
authors: Wen Wee
authors: WW
authors: Ma
authors: Johanna
authors: J
authors: Bendell
authors: Sophie
authors: S
authors: Callies
authors: Alex A
authors: AA
authors: Adjei
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine / Q000627:therapeutic use; D003857:Deoxyuridine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; C569272:LY2334737; D011355:Prodrugs; D000069287:Capecitabine; D003857:Deoxyuridine
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