Results from an international phase 2 study of the anti‐CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B‐lineage acute lymphoblastic leukemia

Abstract

Background In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti‐CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy. Procedure This international, multicenter, phase 2 study enrolled children with relapsed/refractory B‐cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21‐day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations. Results Thirty‐two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment‐related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment‐related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS. Conclusions Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.

Fatal capillary leak syndrome in a child with acute lymphoblastic leukemia treated with moxetumomab pasudotox for pre‐transplant minimal residual disease reduction

“…Based on prior moxe studies in hairy‐cell leukemia and ALL, there is a known pharmacodynamics “sink‐effect” with higher disease burden and CD22 expression 2,6 . Thus, we postulate that reduced target antigen binding and internalization of moxe in the setting of MRD could account for the relatively higher drug exposure and observed toxicity in comparison to the rapid receptor‐mediated clearance observed in overt ALL 2,3 . Alternative possibilities include an idiosyncratic reaction or culture negative sepsis.…”

“…2 A follow-up phase 2 trial was recently published in this journal. 3 A parallel phase 2 trial (12-MOXE) tested moxe for pre-transplant MRD reduction in pediatric patients with ALL and MRD (≥0.01% to <5%). Due to the low disease burden on that trial, the study regimen consisted of moxe 32 mcg/kg/dose every other day for six doses, which was equivalent to one dose level below the recommended phase 2 dose in the relapsed/refractory setting.…”

“…2,6 Thus, we postulate that reduced target antigen binding and internalization of moxe in the setting of MRD could account for the relatively higher drug exposure and observed toxicity in comparison to the rapid receptor-mediated clearance observed in overt ALL. 2,3 Alternative possibilities include an idiosyncratic reaction or culture negative sepsis. Low-burden disease generally correlates with decreased toxicity, as seen with chimeric antigen receptor T-cell therapies 7 or bispecific T-cell engagers.…”

“…This case underscores the importance of dose level selection and close clinical F I G U R E 1 First-dose pharmacokinetics demonstrate higher peak plasma concentration (835 ng/mL), lower clearance (22.81 mL/h/kg), and longer elimination half-life (1.53 h) in comparison to pediatric patients with relapsed/refractory ALL (mean peak concentration <500 ng/mL, clearance 24.4-41.8 mL/h/kg, mean half-life approximately 1 h). 2,3 Dotted line represents the lower limit of quantification LETTER TO THE EDITOR and laboratory monitoring of patients treated with novel immunotherapies.…”

“…MRD‐negative complete responses (CR) were observed in pediatric patients with relapsed/refractory ALL treated on a phase 1 trial of the anti‐CD22 immunotoxin, moxetumomab pasudotox (moxe) 2 . A follow‐up phase 2 trial was recently published in this journal 3 . A parallel phase 2 trial (12‐MOXE) tested moxe for pre‐transplant MRD reduction in pediatric patients with ALL and MRD (≥0.01% to <5%).…”