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

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 Ho, Megan M. O'Meara, Baiteng Zhao, Charles Biddle-Snead and Anthony S. Stein

Key points

  • Vadastuximab talirine, a novel antibody-drug conjugate, consists of an engineered antiCD33 mAb conjugated to pyrrolobenzodiazepine dimers.

  • In a phase 1 trial, vadastuximab talirine demonstrates single agent activity and minimal non-hematologic toxicity in patients with AML.


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 ( NCT01902329) 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-naïve patients. Patients received vadastuximab talirine intravenously on Day 1 (5-60 µg/kg) or on Days 1 and 4 (20 µg/kg) of 21-day cycles. 131 patients (median age 73 years [range, 26-89]) had intermediate I-II (48%) or adverse (34%) risk by ELN 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 (AE) were consistent with myelosuppression; non-hematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the CR+CRi rate was 28% (5/18); 50% of patients who responded achieved MRD negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1,000/µL) and 10.6 weeks for platelets (≥100,000/µL). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose is 40 µg/kg.

  • Submitted June 12, 2017.
  • Accepted November 16, 2017.