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

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 µg/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 × 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 µg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329.

Conflict of interest statement

Conflict-of-interest disclosure: E.M.S., R.B.W., H.P.E., A.T.F., A.S.A., J.E.L., F.R., T.K., D.J.D., D.B., S.F., A.P.J., and A.S.S. were investigators funded by Seattle Genetics, Inc. to do this study. A.T.F., A.S.A., F.R., H.P.E., and J.E.L. served as consultants to Seattle Genetics, Inc. A.T.F. was a member of a steering committee for Seattle Genetics, Inc. F.R. received an honoraria from Seattle Genetics, Inc. P.A.H., M.M.O., B.Z., and C.B.-S. are Seattle Genetics, Inc. employees.

© 2018 by The American Society of Hematology.

Figures

Figure 1.

Mean concentration-time profiles and ADC to TAb ratio. (A) Cycle 1 arithmetic mean vadastuximab talirine ADC plasma concentration-time profiles after administration of the first dose of vadastuximab talirine at doses ranging from 5 to 60 µg/kg. (B) Cycle 1 arithmetic mean vadastuximab talirine ADC plasma concentration-time profiles after administration of the first dose of vadastuximab talirine at doses of 20 and 40 µg/kg. (C) Cycle 1 arithmetic mean vadastuximab talirine ADC plasma concentration-time profile after administration of 2 doses of vadastuximab talirine, both at 20 µg/kg. Each dose represents n = 12. (D) Ratio of ADC over TAb concentration vs time. n = x represents the total number of subjects in each cohort. NPM40, 40 µg/kg-dose level NPMI mutation cohort; PAL20, 20 µg/kg-dose level post-alloHSCT cohort; PAL40, 40-µg/kg-dose level post-alloHSCT cohort; TN40, 40-µg/kg dose level treatment-naive cohort.

Figure 2.

Summary of OS. (A and B) Monotherapy and summary of OS by best MRD status at the 40-µg/kg dose level.

Figure 3.

Summary of count recovery. Time to platelet count ≥100 × 109 units/L and neutrophils ≥1000 units/uL for patients who achieved a CR or CRi.

Figure 4.

Percent change in BM blasts from baseline. Antileukemic activity was observed across all dose cohorts.