Phase I Study of a Bispecific Ligand-Directed Toxin Targeting CD22 and CD19 (DT2219) for Refractory B-cell Malignancies

• Published in: Clinical cancer research Vol. 21; no. 6; pp. 1267 - 1272
• Main Authors: Bachanova, Veronika, Frankel, Arthur E., Cao, Qing, Lewis, Dixie, Grzywacz, Bartosz, Verneris, Michael R., Ustun, Celalettin, Lazaryan, Aleksandr, McClune, Brian, Warlick, Erica D., Kantarjian, Hagop, Weisdorf, Daniel J., Miller, Jeffrey S., Vallera, Daniel A.
• Format: Journal Article
• Language: English
• Published: United States 15.03.2015
• Subjects: Adult; Aged; Antibodies - adverse effects; Antibodies - therapeutic use; Antigens, CD19 - metabolism; B-Lymphocytes - pathology; Diphtheria Toxin - adverse effects; Diphtheria Toxin - therapeutic use; Dose-Response Relationship, Drug; Female; Humans; Immunotoxins - therapeutic use; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Lymphoma, Non-Hodgkin - drug therapy; Male; Maximum Tolerated Dose; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cells, B-Lymphoid - pathology; Sialic Acid Binding Ig-like Lectin 2 - antagonists & inhibitors
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-2877

Purpose: The novel bispecific ligand-directed toxin (BLT) DT2219 consists of a recombinant fusion between the catalytic and translocation enhancing domain of diphtheria toxin (DT) and bispecific single-chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. We conducted a phase I dose-escalation study to assess the safety, maximum tolerated dose, and preliminary efficacy of DT2219 in patients with relapsed/refractory B-cell lymphoma or leukemia. Experimental Design: DT2219 was administered intravenously over 2 hours every other day for 4 total doses. Dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in nine dose cohorts until a dose-limiting toxicity (DLT) was observed. Results: Twenty-five patients with mature or precursor B-cell lymphoid malignancies expressing CD19 and/or CD22 enrolled to the study. Patients received median 3 prior lines of chemotherapy and 8 failed hematopoietic transplantation. All patients received a single course of DT2219; one patient was retreated. The most common adverse events, including weight gain, low albumin, transaminitis, and fever were transient grade 1–2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day). Two subjects experienced DLT at dose levels 40 and 60 μg/kg. Durable objective responses occurred in 2 patients; one was complete remission after 2 cycles. Correlative studies showed a surprisingly low incidence of neutralizing antibody (30%). Conclusions: We have determined the safety of a novel immunotoxin DT2219 and established its biologically active dose between 40 and 80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned. Clin Cancer Res; 21(6); 1267–72. ©2015 AACR.