Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia
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- 作者：Simona Lapusan (1)
Maria B. Vidriales (2)
Xavier Thomas (3)
Stephane de Botton (4)
Anne Vekhoff (1)
Ruoping Tang (1)
Charles Dumontet (3)
Rodica Morariu-Zamfir (5)
John M. Lambert (6)
Marie-Laure Ozoux (5)
Philippe Poncelet (7)
Jesus F. San Miguel (2)
Ollivier Legrand (18)
Daniel J. DeAngelo (9)
Francis J. Giles (10)
Jean-Pierre Marie (1811) jean-pierre.marie@sat.aphp.fr - 关键词：Acute myeloid leukemia – ; Antibody ; drug conjugate – ; Maytansine – ; Pharmacokinetic – ; Pharmacodynamic
- 刊名：Investigational New Drugs
- 出版时间：June 2012
- 出版年：2012
- 期刊代码：34_01676997
- 类别：ch
- 卷：30
- 期：3
- 页码：1121-1131
- 数据来源：sp
摘要
The efficacy of anti-CD33 immunoconjugates had been previously demonstrated for gemtuzumab-ozogamicin. AVE9633 is an anti-CD33-maytansine conjugate created by ImmunoGen Inc. Phase I trials of AVE9633 were performed in patients with AML to evaluate tolerability, pharmacokinetics and pharmacodynamics. Three phase I studies of AVE9633 were performed in 54 patients with refractory/relapsed AML, evaluating drug infusion on day 1 of a 21-day cycle (Day 1 study), day 1 and 8 (Day 1/8 study) and day 1, 4 and 7 (Day 1/4/7 study) of a 28-day cycle. Toxicity was mainly allergic reaction during infusion (3 grade 3 bronchospasms). DLT was reached for the D1–D7 schedule at 150 mg/sqm (1 keratitis, 1 liver toxicity), and the MTD was set at 130 mg/sqm for this schedule. In the two other phases I, the DLT was not reached. In the Day 1/8 study, CD33 on peripheral blasts was saturated and down-modulated for doses of 75 mg/m2 脳 2 or higher, which was correlated with WBC kinetics and plasma levels of AVE9633. Decrease of DM4/CD33 ratio on the blasts surface between day 1 and 8 was the rational for evaluating day 1/4/7 schedule. This induced relatively constant DM4/CD33 levels over the first 8 days, however no activity was noted. One CRp, one PR and biological activity in five other patients were observed in this study. The Day 1 and Day 1/4/7 studies were early discontinued because of drug inactivity at doses significantly higher than CD33 -saturating doses. No myelossuppression was observed at any trial of AVE9633. The pharmacokinetics/pharmacodynamics data obtained in these studies will provide very useful information for the design of the next generation of immunoconjugates.