Phase I dose escalation and pharmacokinetic evaluation of two different schedules of LY2334737, an oral gemcitabine prodrug, in patients with advanced solid tumors.
BACKGROUND
This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated.


METHODS
Patients received escalating doses of LY2334737 either every other day for 21 days (d) followed by 7 days-drug-free period (QoD-arm) or once daily for 7 days every other week (QD-arm). The 28 days-cycles were repeated until disease progression or unacceptable toxicity. Standard 3 + 3 dose-escalation was succeeded by a dose-confirmation phase (12 additional patients to be enrolled on the maximum tolerated dose [MTD]).


RESULTS
Forty-one patients received QoD- (40-100 mg) and 32 QD-dosing (40-90 mg). On QoD, 3/9 patients experienced dose-limiting toxicities (DLTs) on the 100 mg dose (2 × G3 diarrhea, 1 × G3 transaminase increase); 1 additional DLT (G3 diarrhea) occurred during dose confirmation at 90 mg (12 patients). On QD, 1 patient each experienced DLTs on 60 mg (G3 transaminase increase) and 80 mg (G3 prolonged QTcF-interval); 2/7 patients had 3 DLTs on the 90 mg dose (diarrhea, edema, liver-failure; all G3). The MTD was established at 90 mg for the QoD-arm. Seven patients on QoD and 4 on QD achieved SD (no CR + PR). Pharmacokinetics showed a dose-proportional increase in exposure of LY2334737 and dFdC without accumulation after repeated dosing. Significant increases in CK18 levels were observed. Genetic polymorphism of the cytidine deaminase gene (rs818202) could be associated with ≥ G3 hepatotoxicity.


CONCLUSIONS
Both schedules displayed linear pharmacokinetics and acceptable safety profiles. The recommended dose and schedule of LY2334737 for subsequent Phase-II-studies is 90 mg given QoD for 21 day.
['Faivre|Sandrine J|SJ|', 'Olszanski|Anthony J|AJ|', 'Weigang-Köhler|Karin|K|', 'Riess|Hanno|H|', 'Cohen|Roger B|RB|', 'Wang|Xuejing|X|', 'Myrand|Scott P|SP|', 'Wickremsinhe|Enaksha R|ER|', 'Horn|Candice L|CL|', 'Ouyang|Haojun|H|', 'Callies|Sophie|S|', 'Benhadji|Karim A|KA|', 'Raymond|Eric|E|']
D000284:Administration, Oral D000328:Adult D000368:Aged D000971:Antineoplastic Combined Chemotherapy Protocols D003841:Deoxycytidine D003857:Deoxyuridine D018450:Disease Progression D004305:Dose-Response Relationship, Drug D004334:Drug Administration Schedule D005260:Female D006801:Humans D008297:Male D008875:Middle Aged D009369:Neoplasms D011355:Prodrugs
Pharmacokinetics Oral gemcitabine prodrug Solid tumors Pharmacogenomics Phase I study