A Phase I Study of SAR3419, an Anti-CD19 Antibody Maytansinoid Conjuguate, Administered One Weekly In Patients WIth Relapsed/refractory B-Cell Non Hodgkin's Lymphoma
Mené sur 44 patients atteints d'un lymphome non hodgkinien récidivant et/ou réfractaire, cet essai français de phase I évalue la doxe maximale recommandée d'un composé appelé SAR3419, un conjugué anticorps-médicament ciblé sur CD19
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.