Phase I Studies of AVE9633, an anti-CD33 Antibody-Maytansinoid Conjugate, in Adult Patients With relapsed/refractory Acute Myeloid Leukemia

Invest New Drugs. 2012 Jun;30(3):1121-31. doi: 10.1007/s10637-011-9670-0. Epub 2011 Apr 26.

Abstract

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/m(2) × 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.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antigens, CD / immunology*
  • Antigens, Differentiation, Myelomonocytic / immunology*
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Bronchial Spasm / chemically induced
  • Drug Hypersensitivity / etiology
  • Female
  • Humans
  • Immunoconjugates / administration & dosage*
  • Immunoconjugates / adverse effects
  • Immunoconjugates / pharmacokinetics
  • Infusions, Intravenous
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / immunology
  • Leukemia, Myeloid, Acute / metabolism
  • Male
  • Maytansine / administration & dosage*
  • Maytansine / adverse effects
  • Maytansine / analogs & derivatives*
  • Maytansine / pharmacokinetics
  • Middle Aged
  • Sialic Acid Binding Ig-like Lectin 3

Substances

  • AVE9633
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Antineoplastic Agents
  • CD33 protein, human
  • Immunoconjugates
  • Sialic Acid Binding Ig-like Lectin 3
  • Maytansine