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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT flow diagram: disposition of study participants. After cycle 1, patients (except those with progressive disease [PD]) were re-treated with two to 16 additional cycles, limited to two past documentations of complete remission (CR) or earlier at the time immunogenicity was documented. In total, 114 cycles were administered to 28 patients, and re-treated patients achieved CR or partial remission (PR) or had stable disease (SD). QOD, every other day.

Fig 2.

Toxicity of moxetumomab pasudotox. Incidence of toxicity by cycle is shown by grade for all 114 cycles administered to 28 patients. CPK, creatine phosphokinase; effu, effusion; GGT, γ-glutamyltransferase; HCL, hairy cell leukemia; H&N, head and neck; HGB, hemoglobin; HUS, hemolytic uremic syndrome; Hypo-MG, hypomagnesemia; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase.

Fig 3.

Pharmacokinetics of moxetumomab pasudotox. (A) Peak plasma levels on cycle 1 are compared between dose 1 (day 1) and dose 3 (day 5). (B) Peak plasma levels and (C) areas under the curve (AUCs) are shown for cycle 1, day 5 at each of the dose levels.

Fig 4.

Duration of response. Percentage of patients originally achieving (A) complete remission (CR; n = 13) and (B) CR plus partial remission (n = 24) who maintained at least that level of remission. The vertical bars show the response duration of patients who still meet criteria for response.