Complete Remissions In 3 of 12 Patients with Pediatric Acute Lymphoblastic Leukemia (ALL) During Phase I Testing of the Anti-CD22 Immunotoxin Moxetumomab Pasudotox
Authors: Wayne Alan , Bhojwani Deepa , Richards Kelly , Stetler-Stevenson Maryalice , Silverman Lewis B. , Jeha Sima , Pui Ching-Hon , McDevitt Jennifer , FitzGerald David J. , Kreitman Robert J. , Lechleider Robert J. , Pastan Ira 
Published: October 2019

Abstract
Abstract 3246
Although most children and adolescents with ALL are cured, treatment-associated side effects are significant and outcome after relapse is poor. New therapies are needed to overcome drug resistance and reduce toxicities of chemotherapy. CD22 is a B-lymphoid differentiation antigen expressed on most B-lineage ALL blasts. We recently conducted a Phase I trial of the anti-CD22 immunotoxin RFB4(dsFv)-PE38 (CAT-3888 or BL22) in children with ALL or non-Hodgkin lymphoma (NHL). The safety profile was acceptable and transient clinical activity was seen; however, no objective responses were observed (Clin Cancer Res 2010;16:1894). We are conducting a Phase I trial of a modified agent with higher CD22 binding affinity (moxetumomab pasudotox, also known as CAT-8015 or HA22).

Methods:
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.

Results:
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.

Conclusions:
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.

Disclosures:
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.