Durable Remissions Observed in a Phase I/II Study of Clofarabine in Combination with Etoposide and Cyclophosphamide in Pediatric Patients with Refractory or Relapsed Acute Leukemia

We have previously reported encouraging overall complete remission (CR) rates and an acceptable safety profile using the combination of clofarabine, cyclophosphamide and etoposide in relapsed or refractory childhood acute leukemia. Here, we report follow-up results of the phase I portion of the study and provide an update on phase II which is currently enrolling patients.

Patients between 1 and 21 years of age with refractory or relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) (Phase I portion only) were enrolled. A standard 3+3 design was followed to determine the maximally tolerated dose combination in phase I. Five dosing cohorts evaluated escalating doses of clofarabine 20–40 mg/m²/day, etoposide 75–100 mg/m²/day and cyclophosphamide 340–440 mg/m²/day. All 3 study drugs were administered via IV infusion daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients received up to 2 induction cycles, followed by consolidation (up to a maximum of 8 cycles in total). Dose-limiting toxicities in the phase I portion have been previously reported. The recommended phase II doses were clofarabine 40 mg/m²/day, cyclophosphamide 440 mg/m²/day, and etoposide 100 mg/m²/day. The phase II portion of the study is a single-arm open-label study with a planned total enrollment of 33 patients. Twenty-five patients (ALL: 20 patients; AML: 5 patients) were enrolled in the 5 phase I dose cohorts. The median number of prior induction regimens was 2, 7 patients (5 ALL, 2 AML) were refractory to their immediately preceding regimen, and 4 patients (1 ALL, 3 AML) had a prior hematopoietic stem cell transplant (HSCT). Based on investigator’s assessment, data showed complete remission (CR) in 10 patients (9 ALL, 1 AML) and complete remission without platelet recovery (CRp) in 6 patients (2 ALL, 4 AML) for an overall response rate of 64% (ALL: 55%; AML: 100%). Of the 16 responders (CR + CRp), 9 patients proceeded to HSCT after treatment. The median duration of remission (censored at the last known date of follow-up regardless of alternative therapy) for the 16 responders was 18.2 weeks (range 6.6 to 61.4 weeks) (ALL: median 31.4 weeks, range 6.6 to 61.4 weeks; AML: median 15.6 weeks, range 7.3 to 48.9+ weeks), including 31.4 weeks for the 10 patients with CR and 15.3 weeks for the 6 patients with CRp. At the last known date of follow-up, 7 of the 16 responders were alive and 4 of these remained in CR (three of these had undergone post-therapy HSCT). One patient with ALL completed 8 cycles of therapy, with a duration of remission of 61.4 weeks. In phase II, 3 of the first 8 ALL patients enrolled achieved a response (1 CR, 2 CRp). However, 4 patients developed severe hepatotoxicity (3 veno-occlusive disease, 1 hyperbilirubinemia). The study was amended to exclude patients with prior HSCT, viral hepatitis and/or cirrhosis, or elevated conjugated bilirubin levels. Four additional patients have since been enrolled in the amended phase II portion of the study and no cases of severe hepatotoxicity have been observed to date.

In summary, the combination of clofarabine, cyclophosphamide and etoposide induced durable remission in children with relapsed or refractory acute leukemia. The recommended phase II doses of clofarabine, cyclophosphamide, and etoposide were 40 mg/m²/day, 440 mg/m²/day, and 100 mg/m²/day, respectively, each given for 5 days in induction. The phase II portion of the study is now actively enrolling patients with ALL without a history of prior HSCT following development of hepatoxicity in 4 patients. An update of all patients enrolled in phase II will be presented at the meeting.