A Phase 1 Study of Moxetumomab Pasudotox, An Anti-CD22 Recombinant Immunotoxin, In Relapsed/Refractory Hairy Cell Leukemia (HCL): Updated Results
Authors: Kreitman Robert J. , Tallman Martin S. , Coutre Steven , Robak Tadeusz , Wilson Wyndham H. , Stetler-Stevenson Maryalice , Noel Pierre , FitzGerald David J. , Buzoianu Manuela , Lechleider Robert J. , Pastan Ira 
Published: October 2019

Abstract
Abstract 2516
Currently no adequate therapies exist for patients with refractory hairy cell leukemia (HCL). The CD22 antigen is commonly expressed on the cell surface of B cells and B-cell malignancies. CD22 is highly expressed in HCL, even in chemoresistant disease, and is therefore a potential target for antibody-directed therapy in refractory/resistant HCL. We developed CD22-specific targeted immunotoxins composed of the variable domains of a monoclonal anti-CD22 antibody fused to a truncated form of a Pseudomonas exotoxin. The first anti-CD22 immunotoxin we studied was CAT-3888 (BL22), which demonstrated remarkable activity in patients with relapsed/refractory HCL. Moxetumomab pasudotox (also known as CAT-8015 or HA22) is a derivative of CAT-3888 with a higher affinity to CD22 and an improved cytotoxicity profile ex vivo against HCL and other B-cell malignancies. A phase 1 dose-escalation study is being conducted to determine the maximum tolerated dose (MTD) of moxetumomab pasudotox and to assess its safety and immunogenicity profiles and clinical activity in HCL. Preliminary safety data and antitumor activity from the study were previously reported (Kreitman et al, ASH 2009, ASCO 2010). Eligibility criteria include age ≥18 years, ≥2 previous systemic therapies (including purine analogs), ECOG performance status of 0–2, and the presence of cytopenia or symptomatic splenomegaly. A standard 3+3 dose-escalation design with an expanded cohort at the MTD or highest dose level is being used. Patients receive moxetumomab pasudotox as a 30-min IV infusion administered on days 1, 3, and 5 (QODx3) of a 28-day treatment cycle, up to a total of 10 cycles. Patients receive prophylaxis with low-dose aspirin (if platelets >100,000/μL) and IV hydration to prevent hemolytic uremic syndrome (HUS), the dose-limiting toxicity (DLT) in clinical studies with CAT-3888. Additionally, patients receive hydroxyzine, ranitidine, and acetaminophen to avoid infusion reactions. Response is evaluated before cycle 2 and thereafter before even-numbered cycles. Enrollment and treatment are ongoing. At the time of reporting, a total of 32 patients had received moxetumomab pasudotox at one of five dose levels: 5, 10, 20, and 30 μg/kg (n=3 in each cohort), and 40 μg/kg (n=4), and in an expanded cohort at the 50-μg/kg dose level (n=16). Median age was 59 years (range, 40–77 years). Patients were heavily pretreated; 19 (59%) were previously treated with rituximab. No DLTs have been observed, and an MTD has not been reached. Adverse events have been mostly mild and consistent with those seen in clinical studies with CAT-3888. The most frequently reported drug-related adverse events have been hypoalbuminemia (53%), peripheral edema (44%), pyrexia (34%), elevated ALT (34%) and AST (31%), fatigue (28%), headache (28%), localized edema (22%), and nausea (22%). Capillary leak syndrome (grade 2) has developed in 7 patients (22%); 5 patients were in the 50-μg/kg dose cohort. Reversible grade 2 HUS has been reported in 2 patients (6%; 30 μg/kg, n=1; 50 μg/kg, n=1); both began on day 8 of the treatment cycle. Treatment-related toxicities ≥grade 3 have been observed in 3 patients (30 μg/kg, n=1; 50 μg/kg, n=2) and include decreased haptoglobin levels, elevated gamma-glutamyltransferase, and lymphopenia. Moxetumomab pasudotox has shown clinical activity in 47% of recipients, and responses have been observed in both the dose-escalation and expansion cohorts. Overall response (OR), complete response (CR), and partial response (PR) rates observed to date are listed in the table. The median time to response is currently 2.79 months. Neutralizing antibodies have developed in 14 patients (44%). Moxetumomab pasudotox appears to have a safety profile similar to that of CAT-3888 (BL22), and with a lower incidence of HUS at the highest dose tested (50 μg/kg QODx3). Moxetumomab pasudotox has demonstrated antitumor activity in patients with relapsed/refractory HCL, including 44% of patients in the expansion cohort. Further studies in HCL and other B-cell malignancies expressing CD22 are warranted.
Clinical Activity
5 μg/kg (n=3) 10 μg/kg (n=3) 20 μg/kg (n=3) 30 μg/kg (n=3) 40 μg/kg (n=4) 50 μg/kg (n=16) Total (N=32) OR 33% 67% 67% 33% 50% 44% 47% CR 0% 33% 67% 33% 50% 25% 31% PR 33% 33% 0% 0% 0% 19% 16%
ClinicalTrials.gov Identifier: NCT00462189
This study was sponsored by MedImmune, LLC.

Disclosures:
Kreitman: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Robak: MedImmune, LLC: Research Funding. Noel: NIH: Patents & Royalties. FitzGerald: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Buzoianu: MedImmune, LLC: Employment. Lechleider: MedImmune, LLC: Employment. Pastan: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties.