Multicentre Phase I Study with an 8-Dose Regimen of Single Agent Anti-CD20 Monoclonal Antibody LFB-R603 in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL)

LFB-R603 is a next generation anti-CD20 monoclonal antibody (mAb) with an optimised glycosylation profile resulting in high antibody-dependent cellular cytotoxicity. A weekly × 4 dose regimen of LFB-R603 has been found to induce rapid, profound and sustained blood lymphocyte depletion in patients (pts) with advanced stage CLL in a multicentre first-in human dose-escalation phase I study*.

A second part of the phase I study designed to evaluate a weekly × 8 dose regimen was initiated in April 2010. Objectives were 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.

Twelve pts were included. A flat dose of LFB-R603 was administered once a week for 8 weeks consisting of an initial dose of 150 mg followed by 7 doses of 450 mg (total dose 3300 mg). Premedication consisted of allopurinol, dexchlorpheniramine and acetaminophen, combined with methylprednisolone 1mg/kg before the first two infusions.

Median age was 69.5 years [62–77], median time from diagnosis to inclusion was 10.4 years [4.0–23.6], number of prior therapies was 3 [1–8]. Seven pts received at least one prior rituximab-containing regimen (median number was 1 [1–3]). Two pts presented with 17p deletion. Bulky (>5cm) lymph node enlargement was observed in 4 pts, splenomegaly in 9 pts, and hepatomegaly in 4 pts. Median WBC count at baseline was 48.5×10⁹/l [9.9–154.2], hemoglobin 11.9 g/dl [7.3–14.0] and platelets 102×10⁹/l [13–193]. Median lymphocyte bone marrow infiltration was 85% [40–94]. Pharmacokinetic (PK) data showed an increase of mean Cmax, AUC¥ and t1/2 term from the first to the eighth infusion from 23.4 to 220.5 mg/L, 732 to 50, 760 mg.h/L, and 13.4 to 147.8 h, respectively whereas mean CL decreased from 424 to 38.6 mL/h.

Median lymphocyte counts and relative circulating lymphocyte depletions from baseline at D8, D29, M2, M 4, and M 6 are presented in the table below.

Response was evaluated at month 4 according to updated NCI-WG guidelines. Among 11 evaluable pts, overall response rate was 45% (5/11) corresponding to 5 pts in durable partial response (PR). Two additional pts were in PR at month 4 not confirmed 2 months later and 4 pts were in stable disease. Pts with 17p deletion and/or bulky tumor were in stable disease.

All pts but one received the planned 8 infusions without any dose reduction. One patient was prematurely withdrawn from the study due to a concomitant secondary leukemia diagnosed after the 2^nd infusion of LFB-R603. Interim safety data indicate that all pts presented with at least one drug-related adverse event (AE). Forty percent of the AEs were related to the first infusion, 18% to the second, and 21% to the subsequent infusions. The most frequent (> 10%) drug-related AEs were infusion related reactions (IRR) (75% of the pts, including 33% of pts with grade 3 (CT-CAE v3.0) IRR), neutropenia (58%; 33% with grade 3 and 25% with grade 4), grade 1–2 pyrexia (42%), grade 1–2 thrombocytopenia (42%), grade 1–2 infections (25%), chills (17%), asthenia (17%), and grade 3 hepatic cytolysis (17%). One pt experienced a grade 4 drug-related pancytopenia. All AEs were reversible spontaneously or with supportive care intervention.

LFB-R603 induces a promising 45% of ORR in pts with advanced stage CLL at a relatively low dose regimen. PK data indicates that the dose and the schedule of administration could be optimized. Toxicity of LFB-R603 is manageable and makes possible a combination with chemotherapy.

Cazin:LFB Biotechnologies: Honoraria. Leprêtre:LFB Biotechnologies: Honoraria. Coiffier:LFB Biotechnologies: Honoraria. Cartron:GSK: Honoraria; Roche: Consultancy, Honoraria; LFB: Honoraria. Sadoun:LFB Biotechnologies: Employment. Segaud:LFB Biotechnologies: subcontractor. Ribrag:LFB Biotechnologies: Honoraria, Research Funding.