Ixazomib with chemotherapy for childhood relapsed acute lymphoblastic leukemia: a TACL consortium report

Ixazomib (MLN 9708) is an oral proteasome inhibitor, pre-clinically more potent than bortezomib, that is currently FDA approved for the treatment of multiple myeloma. We conducted a phase 1/2 study to estimate the maximum tolerated dose, recommended phase 2 dose (RP2D) and early efficacy of ixazomib when combined with chemotherapy in pediatric patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Patients ≤ 21 years of age with R/R ALL/LL ( including Down Syndrome (DS)) were eligible. Ixazomib was combined with up to three different 28-day blocks of well-established, relapsed ALL chemotherapy. Ixazomib was tested at two dose levels (DL) (DL1: 1.6 mg/m2/dose; DL2: 2 mg/m2/dose) using a 3+3 design. Dose limiting toxicities (DLTs) during Block 1 were utilized to make DL escalation decisions. Twenty-four patients enrolled – all with ALL (10 in phase 1, 14 in phase 2). The most common categories of ≥ grade 3 attributable adverse events (AE) were gastrointestinal disorders (n=12) and febrile neutropenia (n=9). Two patients experienced a DLT (both treated at DL2 in phase 2), however, DL2 was determined to be the R2PD. The complete response (CR) rate for evaluable patients was 67%; 64% (9/14) of whom were also flow minimal residual disease (MRD) negative. The half-life was consistent across DLs and was comparable with that previously reported in adults. Oral capsule and liquid formulations were determined to be palatable. Ixazomib can be combined with chemotherapy with an acceptable safety profile and an encouraging early efficacy signal in pediatric R/R ALL. NCT03817320