A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia

Eytan M. Stein, Roland B. Walter, Harry P. Erba, Amir T. Fathi, Anjali S. Advani, Jeffrey E. Lancet, Farhad Ravandi, Tibor Kovacsovics, Daniel J. DeAngelo, Dale Bixby, Stefan Faderl, Anand P. Jillella, Phoenix A. Ho, Megan M. O'Meara, Baiteng Zhao, Charles Biddle-Snead, Anthony S. Stein

Research output: Contribution to journalArticle

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Abstract

Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients. Patients received vadastuximab talirine IV on day 1 (5-60 μg/kg) or on days 1 and 4 (20 μg/kg) of 21-day cycles. A total of 131 patients (median age, 73 years [range, 26-89 years]) had intermediate I-II (48%) or adverse (34%) risk by European LeukemiaNet classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (grade 2 pulmonary embolism and grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AEs) were consistent with myelosuppression; nonhematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 mg/kg, the complete remission + CRi rate was 28% (5 of 18 patients); 50% of patients who responded achieved minimal residual disease negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1000/μL) and 10.6 weeks for platelets (≥100 x 109/L). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose of vadastuximab talirine is 40 mg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329.

Original languageEnglish (US)
Pages (from-to)387-396
Number of pages10
JournalBlood
Volume131
Issue number4
DOIs
StatePublished - Jan 25 2018

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Acute Myeloid Leukemia
Patient treatment
Pharmacokinetics
Platelets
Dimers
Refractory materials
Toxicity
Monoclonal Antibodies
Fatigue of materials
Recovery
Antibodies
Pharmaceutical Preparations
Safety
Residual Neoplasm
Proxy
Pulmonary Embolism
Nausea
Fatigue
Diarrhea
Neutrophils

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Stein, E. M., Walter, R. B., Erba, H. P., Fathi, A. T., Advani, A. S., Lancet, J. E., ... Stein, A. S. (2018). A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood, 131(4), 387-396. https://doi.org/10.1182/blood-2017-06-789800

A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. / Stein, Eytan M.; Walter, Roland B.; Erba, Harry P.; Fathi, Amir T.; Advani, Anjali S.; Lancet, Jeffrey E.; Ravandi, Farhad; Kovacsovics, Tibor; DeAngelo, Daniel J.; Bixby, Dale; Faderl, Stefan; Jillella, Anand P.; Ho, Phoenix A.; O'Meara, Megan M.; Zhao, Baiteng; Biddle-Snead, Charles; Stein, Anthony S.

In: Blood, Vol. 131, No. 4, 25.01.2018, p. 387-396.

Research output: Contribution to journalArticle

Stein, EM, Walter, RB, Erba, HP, Fathi, AT, Advani, AS, Lancet, JE, Ravandi, F, Kovacsovics, T, DeAngelo, DJ, Bixby, D, Faderl, S, Jillella, AP, Ho, PA, O'Meara, MM, Zhao, B, Biddle-Snead, C & Stein, AS 2018, 'A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia', Blood, vol. 131, no. 4, pp. 387-396. https://doi.org/10.1182/blood-2017-06-789800
Stein, Eytan M. ; Walter, Roland B. ; Erba, Harry P. ; Fathi, Amir T. ; Advani, Anjali S. ; Lancet, Jeffrey E. ; Ravandi, Farhad ; Kovacsovics, Tibor ; DeAngelo, Daniel J. ; Bixby, Dale ; Faderl, Stefan ; Jillella, Anand P. ; Ho, Phoenix A. ; O'Meara, Megan M. ; Zhao, Baiteng ; Biddle-Snead, Charles ; Stein, Anthony S. / A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. In: Blood. 2018 ; Vol. 131, No. 4. pp. 387-396.
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AU - Advani, Anjali S.

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