A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia Journal Article
| Authors: | Stein, E. M.; Walter, R. B.; Erba, H. P.; Fathi, A. T.; Advani, A. S.; Lancet, J. E.; Ravandi, F.; Kovacsovics, T.; DeAngelo, D. J.; Bixby, D.; Faderl, S.; Jillella, A. P.; Ho, P. A.; O'Meara, M. M.; Zhao, B.; Biddle-Snead, C.; Stein, A. S. |
| Article Title: | 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 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. © 2018 by The American Society of Hematology. |
| Keywords: | adult; cancer survival; treatment response; aged; middle aged; major clinical study; overall survival; constipation; drug tolerability; fatigue; neutropenia; diarrhea; disease classification; drug dose comparison; drug safety; gastrointestinal hemorrhage; monotherapy; side effect; cancer patient; cancer immunotherapy; infection; multiple cycle treatment; neutrophil count; anemia; bone marrow suppression; bleeding; nausea; thrombocytopenia; cohort analysis; antineoplastic activity; hematuria; cancer mortality; alanine aminotransferase blood level; aspartate aminotransferase blood level; asthenia; chill; coughing; dizziness; drug dose escalation; dyspnea; febrile neutropenia; fever; lung embolism; alanine aminotransferase; aspartate aminotransferase; bilirubin; acute kidney failure; hypokalemia; liver failure; myelodysplastic syndrome; minimal residual disease; peripheral edema; single drug dose; sepsis; hyperbilirubinemia; bacteremia; phase 1 clinical trial; fractionation; leukemia relapse; lung infection; epistaxis; bilirubin blood level; brain hemorrhage; congestive heart failure; disease exacerbation; plasma concentration-time curve; cd33 antigen; platelet count; leukemia remission; drug elimination; recurrence free survival; carbon monoxide; decreased appetite; nucleophosmin; petechia; septic shock; drug disposition; acute myeloid leukemia; contusion; infusion related reaction; very elderly; human; male; female; priority journal; article; vadastuximab talirine; carbon monoxide blood level; de novo acute myeloid leukemia; refractory acute myeloid leukemia; secondary acute myeloid leukemia |
| Journal Title: | Blood |
| Volume: | 131 |
| Issue: | 4 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2018-01-25 |
| Start Page: | 387 |
| End Page: | 396 |
| Language: | English |
| DOI: | 10.1182/blood-2017-06-789800 |
| PROVIDER: | scopus |
| PMCID: | PMC5813721 |
| PUBMED: | 29196412 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
