The BIOV-111 study was a European multicentre phase II non-randomised, open-label study of the novel purine nucleoside analogue, clofarabine (Evoltra ®). The study recruited patients ≤ 21 years old at initial diagnosis with primary refractory or relapsed/refractory acute lymphoblastic leukemia (ALL). The dose of clofarabine was 52mg/m2 daily x 5 days, every 28–42 days. Patients were evaluable after one complete course. The primary endpoint was overall response rate (OR) defined as either a complete response (CR) or CR without platelet recovery (CRp). Pharmacokinetic parameters and molecular responses were assessed in a sub-group of cases. The study enrolled a total of 74 patients. 65 were evaluable for response. We report the final efficacy and safety data on these evaluable patients. In total 120 courses of clofarabine were administered to 65 patients from 25 centres. The median age was 10 yrs (range 0.5–23 yrs). The median number of prior treatments was 2 (range 1–5) and 22 patients (34%) had been previously transplanted. The OR was 26% (6 CR, 11 CRp). In addition 1 PR was observed. 11/18 (61%) responders had a prior transplant and 3 of these patients received a further transplant post clofarabine. Of the 7 patients proceeding to transplant post-clofarabine; 3 patients had achieved a CR and 4 achieved a CRp. The updated median duration of response and survival will be presented. The pharamockinetic analyses showed plasma clofarabine concentration did not correlate with treatment outcome, however the ratio of day2/day 1 end of infusion intracellular clofarabine triphosphate (cloTP) levels were higher in responding pts. Serious adverse events included febrile neutropenia 50.8%, hepatic events (raised bilirubin, raised ALT/AST) 6.2%, renal failure 6.2%, palmar-plantar erythrodysaesthesia 4.6% and bone pain 4.6%, seizures 7.7% and cardiac failure 1%. In conclusion, this study demonstrated that clofarabine can achieve significant, durable response rates in heavily pre-treated paediatric patients with relapsed/refractory ALL and intracellular cloTP accumulation may be predictive of response. The response rates in this study are consistent with a previous clofarabine study (CLO-212) in relapsed/refractory pediatric ALL, however in BIOV-111 a lower incidence of adverse events was observed, including hepatic and renal adverse events, possibly attributable to fewer prior treatments compared to CLO-212 (median 2 vs 3 respectively). The reported episodes of seizure and cardiac failure were associated with pre-existing co-morbidities and/or sepsis in the majority of cases. The safety profile of clofarabine was manageable and acceptable and does not preclude subsequent HSCT.
Disclosure: Consultancy: Pamela Kearns, Andre Baruchel and Vaskar Saha have provided Consultancy services to Bioenvision in the past 2 years. Research Funding: Research funding has been received from Bioenvision by Simon Joel and Vaskar Saha. Honoraria Information: Honoraria directly recieved from Bioenvision by Andre Baruchel, Pamela Kearns, Gunte Henze and Vaskar Saha.