Phase i studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia

Simona Lapusan, Maria B. Vidriales, Xavier Thomas, Stephane De Botton, Anne Vekhoff, Ruoping Tang, Charles Dumontet, Rodica Morariu-Zamfir, John M. Lambert, Marie Laure Ozoux, Philippe Poncelet, Jesus F. San Miguel, Ollivier Legrand, Daniel J. DeAngelo, Francis J. Giles, Jean Pierre Marie*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

The efficacy of anti-CD33 immunoconjugates had been previously demonstrated for gemtuzumabozogamicin. 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. Toxicitywasmainly 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 × 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.

Original languageEnglish (US)
Pages (from-to)1121-1131
Number of pages11
JournalInvestigational New Drugs
Volume30
Issue number3
DOIs
StatePublished - Jun 2012

Keywords

  • Acute myeloid leukemia
  • Antibody-drug conjugate
  • Maytansine
  • Pharmacodynamic
  • Pharmacokinetic

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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