Phase i study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies

Veronika Bachanova, Arthur E. Frankel, Qing Cao, Dixie Lewis, Bartosz Grzywacz, Michael R. Verneris, Celalettin Ustun, Aleksandr Lazaryan, Brian McClune, Erica D. Warlick, Hagop Kantarjian, Daniel J. Weisdorf, Jeffrey S. Miller, Daniel A. Vallera

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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 x4. A phase II study exploring repetitive courses of DT2219 is planned.

Original languageEnglish (US)
Pages (from-to)1267-1272
Number of pages6
JournalClinical Cancer Research
Volume21
Issue number6
DOIs
StatePublished - Mar 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bachanova, V., Frankel, A. E., Cao, Q., Lewis, D., Grzywacz, B., Verneris, M. R., Ustun, C., Lazaryan, A., McClune, B., Warlick, E. D., Kantarjian, H., Weisdorf, D. J., Miller, J. S., & Vallera, D. A. (2015). Phase i study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies. Clinical Cancer Research, 21(6), 1267-1272. https://doi.org/10.1158/1078-0432.CCR-14-2877