A Novel Anti-CD22 Immunotoxin, Moxetumomab Pasudotox: Phase I Study in Pediatric Acute Lymphoblastic Leukemia (ALL)

Most pediatric patients with acute lymphoblastic leukemia (ALL) are cured. For the 10 to 20% of patients with relapsed or refractory ALL, novel therapies are needed to overcome chemotherapy resistance. CD22 is an antigen commonly expressed on B-lineage ALL blasts. Moxetumomab pasudotox (previously known as CAT-8015 or HA22) is a recombinant immunotoxin composed of the variable domain of an anti-CD22 monoclonal antibody fused to a 38 Kda truncated form of Pseudomonas exotoxin A.

We are conducting a multicenter, open-label, Phase I, dose-escalation study to determine the maximum tolerated dose and to assess the safety profile, activity, and immunogenicity of moxetumomab pasudotox in pediatric patients with relapsed/refractory hematologic malignancies. Eligibility criteria include age 6 months to 24 years, CD22+ B-lineage ALL or non-Hodgkin lymphoma, ≥1 prior salvage therapy, and no isolated testicular or central nervous system (CNS) disease. Moxetumomab pasudotox is administered as a 30-minute intravenous (IV) infusion at doses of 5, 10, 20, 30, or 40 mcg/kg, every other day for 6 doses, every 21 days. Patients receive concomitant IV hydration, pre-medication with acetaminophen, ranitidine, and diphenhydramine, and CNS prophylaxis with intrathecal hydrocortisone, cytarabine, and methotrexate. An initial cohort (A) consisting of an accelerated dose-escalation phase (one patient each treated at 5, 10, and 20 mcg/kg dose levels) followed by standard 3+3 dose-escalation at 30 mcg/kg dose has been completed. To reduce the incidence of capillary leak syndrome (CLS), a second ongoing cohort (B) was added to the study in which dexamethasone (2.5 mg/m² every 12 hours) is coadministered during treatment cycle 1 around moxetumomab pasudotox doses. Standard 3+3 dose-escalation is being followed starting at the 20 mcg/kg dose level.

21 patients 4 – 21 years of age (median, 11) with ALL have been treated; 7 in Cohort A and 14 in Cohort B (Table). They had received 2 – 8 prior regimens (median 4) and 17 were refractory to chemotherapy and 10 had undergone stem cell transplant. 1 – 4 treatment cycles (median, 1) of moxetumomab pasudotox were administered. The most common adverse events (regardless of attribution) reported to date are decreased hemoglobin, decreased platelets, increased aspartate aminotransferase (AST), pyrexia, decreased neutrophils, tachycardia, increased alanine aminotransferase (ALT), hypokalemia, increased weight, and decreased white blood cells. The most common treatment-related adverse events were increased weight, increased AST, increased ALT, and hypoalbuminemia. Most (70%) of the treatment-related toxicities have been mild and reversible. CLS that was dose-limiting was observed in 2 of 7 patients in Cohort A (30 mcg/kg dose level) and in none of 14 patients in Cohort B. One patient treated at 40 mcg/kg developed refractory hypercalcemia and died of a cardiac arrhythmia during attempted central venous catheter placement. That dose level (5B) was expanded and is currently accruing. Of the 17 (81%) patients evaluable for response (Table), objective responses were achieved in 5 (29%), including 4 (24%) complete responses (CR) and 1 (6%) partial response (PR). Hematological activity (HA) (>50% reduction in blasts and/or improvement in neutrophil and/or platelet counts) was observed in 7 patients (41%). Anti-moxetumomab pasudotox neutralizing antibodies (titer ≥50% neutralization) developed in 3 of 21 (14%) patients.

Moxetumomab pasudotox is active in pediatric patients with relapsed and chemotherapy-refractory ALL. The current observed anti-leukemic activity and safety profile at doses up to 40 mcg/kg warrant further development of moxetumomab pasudotox in pediatric ALL.

ClinicalTrials.gov Identifier: NCT00659425

This study was sponsored by MedImmune, LLC, and supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Wayne:NCI: Co-inventor on patents assigned to the NIH for the investigational product. Off Label Use: This is a Phase I trial of an investigational agent. Bhojwani:MedImmune, LLC: Research Funding. Silverman:Enzon: Consultancy, Honoraria; EUSA: Consultancy, Honoraria. Jeha:Genzyme: Honoraria, Research Funding. Pui:EUSA: Honoraria; Enzon: Honoraria; Sanofi: Honoraria. Buzoianu:MedImmune, LLC: Employment. FitzGerald:NCI: Co-inventor on patents assigned to the NIH for the investigational product. Kreitman:NCI: Co-inventor on patents assigned to the NIH for the investigational product. Ibrahim:MedImmune, LLC: Employment.