A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia
Autor: | Stefan Faderl, Amir T. Fathi, Megan M. O'Meara, Daniel J. DeAngelo, Charles Biddle-Snead, Dale L. Bixby, Eytan M. Stein, Roland B. Walter, Phoenix A. Ho, Jeffrey E. Lancet, Anjali S. Advani, Anthony S. Stein, Anand Jillella, Farhad Ravandi, Harry P. Erba, Tibor Kovacsovics, Baiteng Zhao |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Myeloid Immunoconjugates Nausea Clinical Trials and Observations Immunology CD33 Sialic Acid Binding Ig-like Lectin 3 Antibodies Monoclonal Humanized Biochemistry Gastroenterology 03 medical and health sciences Benzodiazepines 0302 clinical medicine Antineoplastic Agents Immunological Refractory Internal medicine Medicine Humans Pyrroles Adverse effect Aged Aged 80 and over business.industry Vadastuximab Talirine Myeloid leukemia Cell Biology Hematology Middle Aged medicine.disease Leukemia Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Female medicine.symptom business |
Popis: | 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. |
Databáze: | OpenAIRE |
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