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

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Summary

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 × 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.

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The authors declare no competing financial interest.

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Authors and Affiliations

  1. Hematology and Oncology Department, Saint-Antoine Hospital, AP-HP, Paris, France

    Simona Lapusan, Anne Vekhoff, Ruoping Tang, Ollivier Legrand & Jean-Pierre Marie

  2. Servicio de Haematologia, Hospital Universitario de Salamanca, Salamanca, Spain

    Maria B. Vidriales & Jesus F. San Miguel

  3. Leukemia Unit Hematology Department, Edouard Herriot Hospital, Lyon, France

    Xavier Thomas & Charles Dumontet

  4. Hematology Department, Institut Gustave Roussy, Villejuif, France

    Stephane de Botton

  5. Oncology, Sanofi-aventis, Paris, France

    Rodica Morariu-Zamfir & Marie-Laure Ozoux

  6. ImmunoGen, Inc, Cambridge, MA, USA

    John M. Lambert

  7. Biocytex, Marseille, France

    Philippe Poncelet

  8. Université Pierre et Marie Curie-Paris 6, Paris, France

    Ollivier Legrand & Jean-Pierre Marie

  9. Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, MA, USA

    Daniel J. DeAngelo

  10. CTRC, San Antonio, TX, USA

    Francis J. Giles

  11. Département d’Hématologie, Hôpital Saint-Antoine, 184, rue du Faubourg Saint Antoine, 75571, Paris cedex 12, France

    Jean-Pierre Marie

Authors
  1. Simona Lapusan
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  2. Maria B. Vidriales
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  3. Xavier Thomas
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  5. Anne Vekhoff
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  6. Ruoping Tang
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  8. Rodica Morariu-Zamfir
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  9. John M. Lambert
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  10. Marie-Laure Ozoux
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  11. Philippe Poncelet
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  12. Jesus F. San Miguel
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  13. Ollivier Legrand
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  14. Daniel J. DeAngelo
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  15. Francis J. Giles
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  16. Jean-Pierre Marie
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Corresponding author

Correspondence to Jean-Pierre Marie.

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Lapusan, S., Vidriales, M.B., Thomas, X. et al. Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia. Invest New Drugs 30, 1121–1131 (2012). https://doi.org/10.1007/s10637-011-9670-0

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  • DOI: https://doi.org/10.1007/s10637-011-9670-0

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