A Phase I Study with CP-4055 In Patients with Hematologic Malignancies.

Background: CP-4055 (ELACYT™, cytarabine 5′-elaidic acid ester) is a novel cytotoxic nucleoside analogue. While CP-4055 has similar mechanisms of action to cytarabine, it is, unlike cytarabine independent of nucleoside transporters for cellular uptake. This is the first study in patients with haematologic malignancies. CP-4055 is currently in Phase II studies in patients with solid tumors. Aims: Determination of the maximum tolerated dose and the preferred infusion time in patients with haematologic malignancies.

Methods: The study was initiated in May 2006. Patients (pts) received IV CP-4055 over 2 hours (2 hr IV, Arm A) or 24 hours (CIV, Arm B) in a day 1–5 q3w schedule. The starting dose in Arm A was 300 mg/m²/day and in Arm B 200 mg/m²/day, with standard definitions of DLT for haematologic malignancies. Dosing increments were by 50% until non-haematologic toxicities, and thereafter increments were by 30%.

Results: In the ongoing study, 40 pts [25 male, median age 60.5 yrs (range 25–77); ECOG PS 0–1: 32 pts, ECOG PS 2: 8 pts; AML 35 pts, BAL 1 pt, MDS 1 pt, ALL 2 pts, CML-BP 1pt, average 2–3 lines prior chemotherapy (range 0–7)] have been treated at 2 US and 1 European centres. Five patients are ongoing. Two treatment-related serious adverse events (SAE) have been observed. One patient experienced fever and one patient had transaminase increase. Both patients recovered from their SAE while still on the study. No DLT has been observed and dose escalation is ongoing at 1950 mg/m²/day in Arm A and at 1500 mg/m²/day in Arm B. Nausea, anemia, diarrhea and thrombocytopenia were the most common possibly related AEs. One patient (875 mg/m²/day Arm B) with CRp received one course of consolidation therapy. Five patients with stable disease/mild myelosuppression received more than 2 cycles of CP-4055: one pt (AML) received 4 cycles and four patients (3 AML, 1 CML-BP) received three cycles. One of these patients was referred to stem cell transplantation. Fifteen patients received 2 cycles of therapy.

Summary/Conclusion: Patients with haematologic malignancies tolerated CP-4055 well up to a dose of 1500 mg/m²/day (2 hr IV) and 1150 mg/m²/day (CIV) in a d1–5 q3w schedule. Myelosuppression has been observed with minimal toxicity. Accrual is ongoing.