PMID- 29196412
OWN - NLM
STAT- MEDLINE
DCOM- 20190513
LR  - 20230202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 131
IP  - 4
DP  - 2018 Jan 25
TI  - A phase 1 trial of vadastuximab talirine as monotherapy in patients with 
      CD33-positive acute myeloid leukemia.
PG  - 387-396
LID - 10.1182/blood-2017-06-789800 [doi]
AB  - 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 microg/kg) or on days 1 and 4 (20 microg/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 microg/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/microL) and 
      10.6 weeks for platelets (>/=100 x 10(9)/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 microg/kg. This trial 
      was registered at www.clinicaltrials.gov as # NCT01902329.
CI  - (c) 2018 by The American Society of Hematology.
FAU - Stein, Eytan M
AU  - Stein EM
AD  - Memorial Sloan-Kettering Cancer Center, New York, NY.
FAU - Walter, Roland B
AU  - Walter RB
AD  - Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Erba, Harry P
AU  - Erba HP
AD  - University of Alabama Birmingham, Birmingham, AL.
FAU - Fathi, Amir T
AU  - Fathi AT
AD  - Massachusetts General Hospital Cancer Center, Boston, MA.
FAU - Advani, Anjali S
AU  - Advani AS
AD  - Cleveland Clinic, Cleveland, OH.
FAU - Lancet, Jeffrey E
AU  - Lancet JE
AD  - H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
FAU - Ravandi, Farhad
AU  - Ravandi F
AD  - University of Texas MD Anderson Cancer Center, Houston, TX.
FAU - Kovacsovics, Tibor
AU  - Kovacsovics T
AD  - Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
FAU - DeAngelo, Daniel J
AU  - DeAngelo DJ
AD  - Dana-Farber Cancer Institute, Boston, MA.
FAU - Bixby, Dale
AU  - Bixby D
AD  - University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
FAU - Faderl, Stefan
AU  - Faderl S
AD  - Hackensack University Medical Center, Hackensack, NJ.
FAU - Jillella, Anand P
AU  - Jillella AP
AD  - Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA.
FAU - Ho, Phoenix A
AU  - Ho PA
AUID- ORCID: 0000-0003-3786-7583
AD  - Seattle Genetics, Inc., Bothell, WA; and.
FAU - O'Meara, Megan M
AU  - O'Meara MM
AD  - Seattle Genetics, Inc., Bothell, WA; and.
FAU - Zhao, Baiteng
AU  - Zhao B
AD  - Seattle Genetics, Inc., Bothell, WA; and.
FAU - Biddle-Snead, Charles
AU  - Biddle-Snead C
AD  - Seattle Genetics, Inc., Bothell, WA; and.
FAU - Stein, Anthony S
AU  - Stein AS
AD  - City of Hope, Gehr Family Center for Leukemia Research, Duarte, CA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01902329
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171201
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Immunoconjugates)
RN  - 0 (Pyrroles)
RN  - 0 (Sialic Acid Binding Ig-like Lectin 3)
RN  - 12794-10-4 (Benzodiazepines)
RN  - T13V17U431 (vadastuximab talirine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal, Humanized/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Antineoplastic Agents, Immunological/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Benzodiazepines/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Female
MH  - Humans
MH  - Immunoconjugates/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Leukemia, Myeloid, Acute/*drug therapy
MH  - Liver/drug effects
MH  - Male
MH  - Middle Aged
MH  - Pyrroles/administration & dosage/adverse effects/pharmacokinetics/*therapeutic 
      use
MH  - Sialic Acid Binding Ig-like Lectin 3/*analysis
PMC - PMC5813721
COIS- 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.
EDAT- 2017/12/03 06:00
MHDA- 2019/05/14 06:00
PMCR- 2018/01/25
CRDT- 2017/12/03 06:00
PHST- 2017/06/12 00:00 [received]
PHST- 2017/11/16 00:00 [accepted]
PHST- 2017/12/03 06:00 [pubmed]
PHST- 2019/05/14 06:00 [medline]
PHST- 2017/12/03 06:00 [entrez]
PHST- 2018/01/25 00:00 [pmc-release]
AID - S0006-4971(20)32524-6 [pii]
AID - 2017/789800 [pii]
AID - 10.1182/blood-2017-06-789800 [doi]
PST - ppublish
SO  - Blood. 2018 Jan 25;131(4):387-396. doi: 10.1182/blood-2017-06-789800. Epub 2017 
      Dec 1.