Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors.

Abstract

CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.

• Authors: F E Stuurman, E E Voest, A Awada, P O Witteveen, T Bergeland, P-A Hals, W Rasch, J H M Schellens, A Hendlisz
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 4 Pg. 959-66 (Aug 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 23345000 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antineoplastic Agents
• CP 4126
• Deoxycytidine
• Gemcitabine

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Demography
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Female
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Gemcitabine