Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia

Abstract

Purpose To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL). Patients and Methods Eligible patients had relapsed/refractory HCL after ≥ two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 μg/kg every other day for three doses (QOD ×3), with up to 16 cycles repeating at ≥ 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies. Results Twenty-eight patients were enrolled, including three patients each at 5, 10, 20, and 30 μg/kg, four patients at 40 μg/kg, and 12 patients at 50 μg/kg QOD ×3 for one to 16 cycles each (median, four cycles). Dose-limiting toxicity was not observed. Two patients had transient laboratory abnormalities consistent with grade 2 hemolytic uremic syndrome with peak creatinine of 1.53 to 1.66 mg/dL and platelet nadir of 106,000 to 120,000/μL. Drug-related toxicities in 25% to 64% of the 28 patients included (in decreasing frequency) grade 1 to 2 hypoalbuminemia, aminotransferase elevations, edema, headache, hypotension, nausea, and fatigue. Of 26 patients evaluable for immunogenicity, 10 patients (38%) made antibodies neutralizing more than 75% of the cytotoxicity of 1,000 ng/mL of immunotoxin, but this immunogenicity was rare (5%) after cycle 1. The overall response rate was 86%, with responses observed at all dose levels, and 13 patients (46%) achieved complete remission (CR). Only 1 CR lasted less than 1 year, with the median disease-free survival time not yet reached at 26 months. Conclusion Moxetumomab pasudotox at doses up to 50 μg/kg QOD ×3 has activity in relapsed/refractory HCL and has a safety profile that supports further clinical development for treatment of this disease.

Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes

“…Treatment was begun on day 8, when the tumors reached about 150 mm 3 . RITs were injected intravenously, every other day × 3, mimicking the schedule used to treat patients (4,7). In mice that received 1.0 mg/kg HA22-LR (with no mutations in domain III), the tumors became smaller, reaching a nadir on day 16, and then began to regrow (Fig.…”

“…One RIT under clinical evaluation is Moxetumomab pasudotox [also known as HA22 or anti-CD22 (Fv)-PE38], which targets CD22 expressed on B-cell malignancies (3). In a phase I trial it produced complete remissions in over 50% of patients with drug-resistant hairy cell leukemia (4) and has produced complete remissions in several patients with acute lymphoblastic leukemia (5). Another RIT undergoing clinical trials, LMB2 or anti-Tac(Fv)-PE38, has shown antitumor activity in patients with adult T-cell leukemia and other hematologic malignancies (6).…”

In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

“…PE-based immunotoxins with truncated 40 kDa or 38 kDa domains have been previously used in preclinical and clinical trials against various tumors (27)(28)(29) (31). The application of immunotoxins against solid tumors is much more complex than against hematological malignancies.…”

A Modified Form of Diphthamide Causes Immunotoxin Resistance in a Lymphoma Cell Line with a Deletion of the WDR85 Gene

“…CD22 is a B-lineage differentiation antigen that is an excellent target for the therapy of hairy cell leukemia, B-lineage ALL, and non-Hodgkin lymphoma (5,6). We have developed a recombinant immunotoxin (HA22/moxetumomab pasudotox) that targets and kills CD22-expressing cells.…”