Complete Remissions In 3 of 12 Patients with Pediatric Acute Lymphoblastic Leukemia (ALL) During Phase I Testing of the Anti-CD22 Immunotoxin Moxetumomab Pasudotox

Patients 6 months to 24 years of age with relapsed or refractory CD22+ B-lineage ALL or NHL are eligible for enrollment. Moxetumomab pasudotox is being administered at doses of 5, 10, 20, or 30 μg/kg every other day for 6 doses, every 21 days for up to 6 cycles. All patients receive pre-medication with acetaminophen, ranitidine, and diphenhydramine and prophylaxis for central-nervous-system leukemia with intrathecal hydrocortisone, cytarabine, and methotrexate. An initial completed cohort (A) consisted of one patient each treated at the first 3 dose levels (5, 10, 20 μg/kg) followed by standard 3+3 dose escalation commencing at 30 μg/kg. In attempt to reduce the incidence of vascular leak syndrome (VLS), a second ongoing cohort (B) is also receiving dexamethasone 2.5 mg/m² every 12 hours around doses of moxetumomab pasudotox during cycle 1 with standard 3+3 dose escalation commencing at 20 μg/kg.

At the time of reporting, 14 patients 5 to 22 years of age (median, 11) with ALL (13 precursor-B, 1 mature B-cell) have been treated in the clinical trial. Patients had received a median of 4 prior regimens (range, 2–8), 12 were chemotherapy refractory, and 7 had received prior stem cell transplantation. Thirteen had leukemia-associated baseline cytopenias and thus were not evaluable for hematologic toxicities. The most common adverse events observed to date have been hyperbilirubinemia, transaminase elevations, hypoalbuminemia, elevated creatinine, febrile neutropenia, hypertension, microscopic proteinuria, hemoglobinuria, hypoxia, and pleural effusion. Two of 7 patients in Cohort A treated at 30 μg/kg experienced Grade 3 and Grade 4 VLS. None of 7 patients treated in Cohort B developed VLS. All toxicities attributed to moxetumomab pasudotox were reversible. Twelve patients were evaluable for response: 3 (25%) achieved complete remission by morphology and flow cytometry after 1, 1, and 2 cycles, respectively; 5 (42%) had hematologic activity (blood count improvement, blast reduction); and 3 (25%) had stable disease. One patient treated at the lowest dose level had progressive disease. Two patients developed high-titer neutralizing antibodies.

Moxetumomab pasudotox has shown clinical activity against chemotherapy-refractory pediatric ALL, with complete remissions achieved in 3 of 12 patients. The demonstration of clinical activity and the safety profile exhibited by this agent to date support further study in ALL.

ClinicalTrials.gov Identifier: NCT00659425

This study was sponsored by MedImmune, LLC.

Off Label Use: Moxetumomab pasudotox is an investigational agent. Bhojwani:MedImmune: Research Funding. Silverman:Enzon: Consultancy, Honoraria; EUSA: Consultancy, Honoraria. Jeha:Genzyme: Honoraria, Research Funding. Pui:EUSA Pharma: Honoraria; Enzon: Honoraria; Sanofi-Aventis: Honoraria. McDevitt:MedImmune, LLC: Employment. FitzGerald:NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Kreitman:NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Lechleider:MedImmune, LLC: Employment. Pastan:NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties.