Phase I and pharmacokinetic trial of oral administration of CYC682, a novel 2’ deoxycytidine type anti-metabolite pro-drug, in patients with advanced solid tumors or lymphoma

Abstract

2026 Background: CYC682 is converted by intestinal and plasma amidases to the active agent CNDAC [1-(2-C-cyano-2-deoxy-β -D-arabino-pentafuranosyl)-cytosine] and intracellularly activated by deoxycytidine kinase to CNDAC triphosphate. The mechanism of action includes inhibition of DNA polymerase, cessation of DNA strand elongation and DNA strand breakage. A previous phase I study of a 5 days/week, for 4 weeks every 6 weeks schedule determined a maximum tolerated dose (MTD) of 40 mg/m2/day (d), with neutropenia as the principal toxicity. To maximize plasma exposure we have evaluated twice daily oral administration on days 1–14 of a 21-day cycle (cyc), with the determination of the MTD and the recommended phase II dose (RD) as objectives. Methods: MTD was defined as ≥2/3 or 3/6 patients (pts) with dose limiting toxicity (DLT) in cyc 1 and RD as next lowest dose level (DL). DL of 20, 40, 66, 100 mg/m2/d were explored. Blood samples for pharmacokinetic (PK) analysis of CYC682 and CNDAC were drawn on d 1 and 14 of the 1st cyc and d 14 of the 3rd cyc. Results: 15 pts have received 22 cyc. M/F: 8/7; median age 59 (range 43–72); PS 0/1: 1/14; principal tumor types: breast (2 pts), NSCLC (3), ovarian (2), colon (2). All but one had been pre-treated with numerous chemotherapy regimes (median 4, range 1–6). DLT of febrile neutropenia (FN) and thrombocytopenia (T) occurred in 2/6 pts at DL3, with the MTD due to FN in 3/3 pts reached at DL4. Expanded accrual is ongoing at 66 mg/m2/d as the potential RD. Non-hematologic toxicities including diarrhea have been observed but are manageable. PK data are available for 12 pts, and demonstrate a moderate correlation between CNDAC exposure and CYC682 dose. The inter-patient variability of CYC682 Cmax and AUC0–8hr observed at DL3 is approximately 4-fold. Terminal half-life in DL3 is 2.3 ±0.9 hr. Conclusion: The MTD for this schedule is 100 mg/m2/d with febrile neutropenia as DLT. DL (mg/m2/d) No. pts (cyc) No. pts DLT NCI-CTC toxicity by pt (grade) Cmax (ng/mL) AUC0–8hr (hr*ng/mL) FN N T Diarrhea N/V 20 3 (4) - - - 1 (2) 1 (2) 2 (1) 1.8±2.3 4.7±7.6 40 3 (7) - - 1 (2) - 1 (2) 1 (2) 6.1±2.3 13.7±21.6 66 6 (4) 2 2 (DLT) 1 (3) 1 (4,DLT) 1 (1) - 5.2±2.8 12.0±6.4 100 3 (3) 3 3 (DLT) - - - - - - Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CAC SA, Kremlin-Bicetre, France, Cyclacel Ltd., Dundee, UK CAC SA, Kremlin-Bicetre, France