title: Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia.
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.
authors.affiliation: Hematology and Oncology Department, Saint-Antoine Hospital, AP-HP, Paris, France.
authors.forename: Simona
authors.initials: S
authors.lastname: Lapusan
authors.forename: Maria B
authors.initials: MB
authors.lastname: Vidriales
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.forename: Stephane
authors.initials: S
authors.lastname: de Botton
authors.forename: Anne
authors.initials: A
authors.lastname: Vekhoff
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.forename: Rodica
authors.initials: R
authors.lastname: Morariu-Zamfir
authors.forename: John M
authors.initials: JM
authors.lastname: Lambert
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Ozoux
authors.forename: Philippe
authors.initials: P
authors.lastname: Poncelet
authors.forename: Jesus F
authors.initials: JF
authors.lastname: San Miguel
authors.forename: Ollivier
authors.initials: O
authors.lastname: Legrand
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marie
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001986:Bronchial Spasm / Q000139:chemically induced; D004342:Drug Hypersensitivity / Q000209:etiology; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008453:Maytansine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008875:Middle Aged; D063268:Sialic Acid Binding Ig-like Lectin 3
chemical_list: C574990:AVE9633; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; C571163:CD33 protein, human; D018796:Immunoconjugates; D063268:Sialic Acid Binding Ig-like Lectin 3; D008453:Maytansine