A dose-escalation study of SAR3419, an anti-CD19 antibody maytansinoid conjugate, administered by intravenous infusion once weekly in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Abstract

PURPOSE:

To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody-drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL).

EXPERIMENTAL DESIGN:

Patients with R/R CD19(+) B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an "optimized" administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation.

RESULTS:

Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m(2). SAR3419 recommended dose was determined as 55 mg/m(2) qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m(2), which showed an improved safety profile compared with the qw schedule. Antilymphoma 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/d), 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 with 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 antilymphoma activity is selected for clinical phase II studies.

• Authors: Vincent Ribrag, Jehan Dupuis, Herve Tilly, Franck Morschhauser, Fabrice Laine, Roch Houot, Corinne Haioun, Christiane Copie, Andrea Varga, John Lambert, Laurence Hatteville, Samira Ziti-Ljajic, Anne Caron, Sandrine Payrard, Bertrand Coiffier
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 1 Pg. 213-20 (Jan 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24132920 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Maytansine
• coltuximab ravtansine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacokinetics, toxicity)
• Antineoplastic Agents (administration & dosage, pharmacokinetics, toxicity)
• Asthenia (chemically induced)
• Drug Resistance, Neoplasm
• Female
• Humans
• Infusions, Intravenous
• Kidney (drug effects)
• Liver (drug effects)
• Lymphoma, B-Cell (drug therapy)
• Male
• Maximum Tolerated Dose
• Maytansine (administration & dosage, analogs & derivatives, pharmacokinetics, toxicity)
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy)
• Treatment Outcome