Publications (2)16.39 Total impact

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    ABSTRACT: Purpose To determine recommended dose (RD), dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity and exploratory pharmacodynamic of SAR3419, an antibody-drug conjugate targeting CD19, administered alone by intravenous (IV) infusion weekly (qw), in a dose-escalation phase I study in patients with Refractory/Relapsed (R/R) non Hodgkin's lymphoma (NHL). Experimental design Patients with R/R CD19+ B-NHL were treated with escalating doses of SAR3419 repeated qw for 8 to 12 doses. Based on clinical evidence of late or cumulative toxicities, the study-protocol was amended to test an "optimized" administration schedule consisting of 4 qw doses followed by 4 biweekly (q2w) doses (qw/q2w) at the RD with the intent of reducing drug accumulation. Results Forty-four patients were treated on 7 dose levels ranging from 5 to 70 mg/m². SAR3419 RD was determined as 55 mg/m² qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m² which showed an improved safety profile compared to the qw schedule. Anti-lymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/day), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared to the qw schedule. Conclusion While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves anti-lymphoma activity is selected for clinical phase 2 studies.
    Clinical Cancer Research 10/2013; 20(1). DOI:10.1158/1078-0432.CCR-13-0580 · 8.19 Impact Factor
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    ABSTRACT: SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell-specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative.
    Clinical Cancer Research 10/2011; 17(20):6448-58. DOI:10.1158/1078-0432.CCR-11-0485 · 8.19 Impact Factor