A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of an oral antimicrotubular agent, DJ-927 (D), and capecitabine (C) in patients (Pts) with advanced solid tumors

Abstract

2037 Background: DJ-927 (D), an oral, microtubule stabilizer that causes growth arrest in a wide variety of human tumor cell lines, has impressive cytotoxic activity in taxane-sensitive, -resistant, and -refractory tumors and is associated with an acceptable incidence of hematologic toxicity. Taxane and Capecitabine (C) combinations are active in treating solid tumors such as breast cancer. Non-overlapping mechanisms of action and toxicity profiles and the convenience of an all orally administered combination therapy have prompted a phase I evaluation of the safety and tolerability of the combination. D was administered orally once on day 1 and C for 14-days (D1–14), every three weeks. Methods: Eligible pts had advanced, evaluable cancer, minimal prior therapy and performance status ≤ 2. Pts received D starting at 18 mg/m2 once on day 1and concurrent C 1,250 mg/m2 orally twice daily during wks 1 and 2, of a 3-weekly schedule. Incremental doses of both drugs are being explored until the maximum tolerated dose (MTD) is reached. Results: To date, 19 pts [12 Male/ 7 Female; median age (range)- 58 yrs (33–70); PS 0–2pts; PS 1- 17pts] have received 53 cycles of treatment [median (range)- 3 (1–6)] in 4 cohorts, with D and C 18/ 1250 mg/m2 (n = 3), 27/ 1250 mg/m2 (n = 7), 27/ 1900 mg/m2 (n = 6), and 27/ 2500 mg/m2 (n = 3). Dose-limiting toxicity (DLT) was observed in 1 of 6 pts at 27/ 1900 mg/m2 dose [grade (gr) 4 neutropenia & gr 4 thrombocytopenia]. Delayed toxicities observed include neutropenic fever (1), 2), gr 3 hand-foot syndrome (2) and gr 3 diarrhea (1). One pt with hepatocellular carcinoma had partial response at cycle 2 and 5 pts experienced disease stabilization lasting ≥ 16 weeks. Preliminary PK analysis suggests that C does not significantly alter the disposition of D. Conclusions: The combination of D and C appears safe and is well tolerated. Preliminary data suggest that this regimen may be active in pts with advanced cancers. Dose escalation continues at 35/ 1900 mg/m2 of D and C respectively. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Daiichi Medical Research Daiichi Medical Research