Bortezomib for children with acute lymphoblastic leukemia (ALL) without other treatment options.

Multicenter, multinational, open label, comparative and randomised phase II study on the antileukemic activity of bortezomib with conventional combination chemotherapy in relapsed/refractory ALL in children and adolescents. The study will include one cohort of patients with relapsed/refractory ALL, with treatment guidelines for all patients for 3 weeks. Thereafter, bortezomib may be repeated in combination with the same conventional chemotherapy for patients with a good initial response to reinduction therapy, while treatment of all other patients will be left at the discretion of the patient, parents and the responsible clinician. Standard reinduction chemotherapy will consist of 2 weeks of dexamethasone plus vincristine given twice, plus intrathecal administration of methotrexate. In addition, all patients will be treated with one cycle of bortezomib, consisting of 4 doses in 2 weeks. However, they will be randomised 1:1 in 2 arms, group A getting 'early' bortezomib, starting at day 1 of therapy, and group B getting 'late' bortezomib, starting at day 8. Randomisation will be stratified for the number of circulating leukemic blasts at diagnosis. This design allows demonstrating an additional antileukemic effect of bortezomib when added to dexamethasone, after 1 week of therapy, measured by a reduction in ALL cells in peripheral blood and bone marrow. In addition, this design allows comparing the toxicity of limited (group A) and more extended (group B) overlap of administrations of bortezomib and vincristine. A total of 24 patients must be randomised and be fully evaluable in order to prove additional antileukemic effect of bortezomib when added to dexamethasone. Bortezomib will be available for further use in case of patients with a favourable early treatment response, i.e. bone marrow M1 or M2 (¡Ü15% blasts) 3 weeks after start of reinduction therapy, in combination with the same combination chemotherapy.

This is a phase II study of bortEzomib in combination with other chemotherapy as re-induction therapy for childhood relapsed/refractory ALL.

The major time point is the steroid response at day 8 and the response rate at day 22.

The patients will be treated with bortezomib (1.3 mg/m2/dose twice weekly (days 1 and 4 of each week) for a total of 2 weeks. Group A will get bortezomib on days 1, 4, 8 and 11, while group B will get it on days 8, 11, 15 and 18. Bortezomib will be administered as i.v. push. In addition, patients will get standard reinduction chemotherapy consisting of dexamethasone and vincristine. Dexamethasone will be given from day 1 onwards for 2 weeks at 10 mg/m2/day in 3 doses, orally. In addition, patients will receive vincristine on days 8 and 15, at 1.5 mg/m2/dose, in a 60 minutes i.v. infusion.
Finally, intrathecal methotrexate will be given on days 1 and 22 with age-adjusted dosing.



Further therapy for good responders (bone marrow (BM) M1 or M2 on day 22) may consist of an additional cycle of bortezomib, but this decision is left to the discretion of the treating physician. A next cycle should start 11 days after the previous administration of bortezomib. Then, bortezomib must again be combined with 2 weeks of dexamethasone (same dose and schedule) and vincristine twice (same dose and schedule). Such cycles may be repeated if justified by efficacy and (lack of) toxicity, which again is left to the discretion of the treating physician.



Patients with a BM M3 on day 22 and/or those with progressive disease will go off study.