A Phase I study of LFB-R603, a Novel Anti-CD20 Antibody, in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL) (2010)

Abstract Abstract 2447 Background: LFB-R603 is a chimeric anti-CD20 monoclonal antibody with an optimised glycosylation profile leading to a high binding affinity for the FcγRIIIa receptor and a stronger antibody-dependent cellular cytotoxicity (ADCC) than rituximab, particularly against tumor cells that express low CD20 levels. As a result, LFB-R603 represents a drug candidate in patients (pts) with CLL. Aims: An open-label, multicentre, first-in-human study using escalating doses of LFB-R603 was initiated in November 2008 to assess the safety, pharmacokinetics and potential efficacy of LFB-R603 in pts with CLL relapsing after at least one prior course of therapy with fludarabine. Methods: Twenty one patients were included in 5 dose cohorts. Pts received infusions of LFB-R603 as a flat dose once a week for 4 weeks. The dose was escalated based on safety in a 3+3 design. Total dose of LFB-R603 was 75 mg in cohort A (5–10-20–40 mg), 200 mg in cohort B (20–60×3 mg), 510 mg in cohort C (60–150×3 mg), 1050 mg in cohort D (150–300×3 mg) and 1650 mg in cohort E (300–450×3 mg). Premedication consisted in allopurinol, dexchlorpheniramine and paracetamol, combined with methylprednisolone 1mg/kg before the first two infusions. Results: Six pts were included in cohorts A and E and 3 in cohorts B, C and D. Median age was 62 years [43–76], median time from diagnosis was 8.3 years [2.5–14.0], number of prior therapies was 3 [1–6]. Twelve pts (57%) received at least one prior rituximab-containing regimen. Three pts presented with 17p deletion. Median WBC count at baseline was 31.0×109/l [9.3–218.4], hemoglobin 13.0 g/dl [9.1–16.0] and platelets 109×109/l [42–344]. Mean lymphocyte counts and mean relative circulating lymphocyte depletions from baseline at day8, day29, and month2 in the 21 pts are presented in the table below. At month 4, lymphocyte depletions were 80% and 78% in cohorts C and E, respectively. Response was evaluated 3 months after completion of therapy (month 4) according to updated NCI-WG guidelines. Among 18 evaluable pts, overall response rate was 27% (5/18). corresponding to 5 pts in partial response (PR). Seven pts were in stable disease and 6 in progressive disease. Three patients out of 5 were confirmed in PR at month 6. All the patients received the planned 4 infusions without any dose reduction. Preliminary safety data indicate that all the pts reported at least one drug-related adverse event (AE). Most of the AEs (52%) occurred less than 48 hours after LFB-R603 infusion and 35% of the AEs occurred after the first infusion. The most frequent drug-related AEs were pyrexia (62% of the pts), infusion related reactions (IRR)(48%), transient neutropenia (38%), headache (33%), chills (29%), infections (29%), thrombocytopenia (24%) and reversible hepatic cytolysis (19%) Twelve pts experienced grade 3 (CT-CAE v3.0) drug-related AEs (IRR; allergy; infection; neutropenia; hepatic cytolysis; pancytopenia), 5 of them in cohort E, and 5 pts experienced grade 4 drug-related AEs (infection; neutropenia; pancytopenia), 2 of them in cohort E. In contrast with the first dose of 300 mg which was worse tolerated than lower doses, the maximum subsequent dose of 450 mg was well tolerated. Conclusion: LFB-R603 can induce rapid, profound and sustained lymphocyte depletion in pts with advanced stage CLL. Toxicity of LFB-R603 is manageable. Most of the drug-related AEs are related to the first infusion, probably due to cytokines release. LFB-R603 is clinically active in pts with relapsed CLL and induces partial remissions. An ongoing part 2 of this study will examine the clinical efficacy of an escalating 8-dose regimen. Disclosures: Cartron: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria. Cazin: LFB Biotechnologies: Honoraria. Coiffier: LFB Biotechnologies: Honoraria. Feugier: roche: Consultancy, Honoraria. Chartier: LFB Biotechnologies: Employment. Sadoun: LFB Biotechnologies: Employment. Ribrag: LFB Biotechnologies: Honoraria, Research Funding.