Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Salvage options for children with relapsed ALL remain sub-optimal, particularly for T-cell ALL, with disease refractoriness and further relapse remaining the leading cause of death. Achieving complete remission (CR) after relapse is the first critical step to cure. Combining the proteasome inhibitor (PI) bortezomib with chemotherapy showed promising CR rates in previous studies in pediatric ALL (Messinger 2012, Horton 2019, Bertaina 2017). We report a multicenter phase 1 pediatric trial for relapsed ALL (NCT02303821) investigating the second generation PI carfilzomib plus VXLD (vincristine, dexamethasone, PEG-asparaginase, daunorubicin) induction therapy. Carfilzomib plus UKALLR3 (dexamethasone, mitoxantrone, methotrexate, PEG-asparaginase, vincristine) was also evaluated but considered not tolerable (Burke 2019). Patients (pts) received 4 weeks of VXLD plus carfilzomib administered intravenously on days 1, 2, 8, 9, 15, and 16. Pts were recruited in cohorts of 3 dose-limiting-toxicity (DLT) evaluable pts, with carfilzomib dose escalation based on a Bayesian logistic regression model. Pts achieving ≥ stable disease post-induction, could receive a cycle of modified BFM consolidation therapy (mercaptopurine, cyclophosphamide, cytarabine, pegaspargase, vincristine) plus carfilzomib at the same dose level and schedule given during induction. Pts