Background: Novel therapies are needed to overcome chemotherapy resistance and reduce toxicities of treatment for childhood ALL. CD22 is an antigen expressed on B-lineage ALL blasts. Moxetumomab pasudotox (MP) is a recombinant immunoconjugate composed of an anti-CD22 immunoglobulin variable domain genetically fused to a truncated form of Pseudomonas exotoxin.

Methods: This is a multicenter, open-label, phase 1, dose-escalation study of MP in pediatric patients (pts) with relapsed/refractory ALL and NHL with CD22 expression. MP is administered as a 30-min IV infusion at doses 5-50 µg/kg every other day for 6-10 doses every 21 days. Cohort A (n=7) consisted of an accelerated dose-escalation phase followed by standard 3+3 dose-escalation. To reduce the incidence of capillary leak syndrome (CLS), subsequent cohorts (B, n=23; C, n=14) received dexamethasone (2.5 mg/m2 every 12 hours) around the first 6 doses of MP in cycle 1. In Cohort C, doses were increased to 10/cycle and an expansion phase at 50 µg/kg was added.

Results: 44 pts with ALL 1-23 years of age have been treated. 35/44 had treatment-refractory disease; 20/44 had relapsed after stem cell transplant (SCT). Pts received a median of 1 treatment cycle (range 1-4). The majority (55%) of treatment-related adverse events (AEs) were mild and reversible. The most common treatment-related AEs were increased AST and ALT and weight gain. There were 2 treatment-related deaths and 7 pts discontinued therapy due to a treatment-related AE. Four DLTs included CLS in 2/7 pts in Cohort A (30 µg/kg; 1 reported as pleural effusion); hypercalcemia in 1 pt treated at 40 µg/kg (Cohort B) who died of a cardiac arrhythmia during attempted venous catheter placement; and grade 4 hemolytic uremic syndrome (HUS) in 1 pt at 50 µg/kg (Cohort B). HUS was noted in 6 pts, 5 treated at the 50 µg/kg dose. Two events were grade 4 with remaining cases ≤grade 2. All but 1 patient recovered from HUS. Based on HUS, the 50 µg/kg dose was determined to exceed the maximum tolerated dose and accrual at a lower dose is ongoing. Of the 37 (84%) pts evaluable for response, objective responses were achieved in 11 (30%), including 9 (24%) complete responses (CR). Per investigator report, 4/9 CRs were minimal residual disease negative, and 3 of these pts underwent a second SCT. Hematological activity (≥50% reduction in blasts and/or improvement in neutrophil and/or platelet counts) was observed in 11 (30%) pts. Anti-drug neutralizing antibodies (≥50% neutralization) developed in 7/44 (16%) pts.

Conclusions: MP is active in pediatric pts with relapsed/refractory ALL. The observed antileukemic activity and safety profile warrant further investigation; phase 2 trials are in development. Study sponsored by MedImmune, and supported in part by the Intramural Research Program of the NIH, NCI, CCR. ClinicalTrials.gov NCT00659425.

Citation Format: Alan S. Wayne, Nirali N. Shah, Deepa Bhojwani, Lewis B. Silverman, James A. Whitlock, Maryalice Stetler-Stevenson, Robert J. Kreitman, Trishna Goswami, Ramy Ibrahim, Ira Pastan. Pediatric phase 1 trial of moxetumomab pasudotox: Activity in chemotherapy refractory acute lymphoblastic leukemia (ALL). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT230. doi:10.1158/1538-7445.AM2014-CT230