An Open Label, Dose-Escalation Safety and Pharmacokinetic Study of AVE9633 Administered as a Single Agent by Intravenous Infusion on Day 1, Day 4 and Day 7 of a 4-Week Cycle in Patients With Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia (AML)

The primary objective is to determine the maximum tolerated dose of AVE9633 and to characterize the dose limiting toxicity(ies). Secondary objectives are to determine the anti-leukemia activity, the global safety and the PK profile.

Start Date01 Sep 2007

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with AVE-9633

100 Translational Medicine associated with AVE-9633

100 Patents (Medical) associated with AVE-9633

Literatures (Medical) associated with AVE-9633

01 Jun 2012·Investigational New DrugsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

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

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.

01 Dec 2009·BMC CancerQ2 · MEDICINE

P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients

Q2 · MEDICINE

ArticleOA

Author: Ollivier Legrand ; Hamid Morjani ; Jean-Pierre Marie ; Anne-Marie Faussat ; Ruoping Tang ; Jean-Yves Perrot ; Simy Cohen ; Elise Corre ; Claudia Zuany-Amorim ; Fanny Fava ; Zora Marjanovic

BACKGROUNDAVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML).METHODSThis study used AML cell lines expressing different levels of P-gp, MRP1 or BCRP proteins and twenty-five samples from AML patients. Expression and functionality of the transporter protein were analyzed by flow cytometry. The cytotoxicity of the drug was evaluated by MTT and apoptosis assays.RESULTSP-gp activity, but not MRP1 and BCRP, attenuated AVE9633 and DM4 cytotoxicity in myeloid cell lines. Zosuquidar, a potent specific P-gp inhibitor, restored the sensitivity of cells expressing P-gp to both AVE9633 and DM4. However, the data from AML patients show that 10/25 samples of AML cells (40%) were resistant to AVE9633 or DM4 (IC(50) > 500 nM), and this was not related to P-gp activity (p-Value: 0.7). Zosuquidar also failed to re-establish drug sensitivity. Furthermore, this resistance was not correlated with CD33 expression (p-Value: 0.6) in those cells.CONCLUSIONP-gp activity is not a crucial mechanism of chemoresistance to AVE9633. For patients whose resistance to conventional anthracycline AML regimens is related to ABC protein expression, a combination with AVE9633 could be beneficial. Other mechanisms such as microtubule alteration could play an important role in chemoresistance to AVE9633.

100 Deals associated with AVE-9633

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Indication	Highest Phase	Country/Location	Organization	Date
CD33-positive Acute Myeloid Leukemia	Phase 1	US	Sanofi	01 Sep 2007
CD33-positive Acute Myeloid Leukemia	Phase 1	FR	Sanofi	01 Sep 2007
CD33-positive Acute Myeloid Leukemia	Phase 1	ES	Sanofi	01 Sep 2007
Acute Myeloid Leukemia	Phase 1	US	ImmunoGen, Inc.	-

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