Clinical Activity of Lucatumumab (HCD122) In Patients (pts) with Relapsed/Refractory Hodgkin or Non-Hodgkin Lymphoma Treated In a Phase Ia/II Clinical Trial (NCT00670592)

Lucatumumab (LUC) is a pure antagonistic CD40 monoclonal antibody to the transmembrane receptor CD40. In preclinical testing, micromolar concentrations of LUC decrease proliferation of B cells in vitro and LUC shows anti-lymphoma activity in in vivo models. LUC has been clinically evaluated in chronic lymphocytic leukemia and multiple myeloma, and now is under evaluation in pts with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma/mucosal associated lymphoid tissue (MZL/MALT), or Hodgkin's lymphoma (HL) who had progressed after at least two prior therapies.

LUC was given IV once weekly for 4 weeks, followed by a 4 week rest period. Pts with stable disease or whose disease responded are eligible for additional cycles of LUC. Objectives were: (1) determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) dose (dose escalation, phase Ia), (2) assess the clinical response rate at the MTD (dose expansion, phase II), (3) exploratory: pharmacodynamics and correlative humoral biomarkers. Bayesian logistic regression modeling was used to escalate LUC. To estimate the response rate to LUC of each of the subtypes under study, a hierarchical Bayesian model has been used.

During phase Ia, 32 pts received LUC at dose levels of 3.0 mg/kg (15 pts), 4.0 mg/kg (12 pts), or 6.0 mg/kg (5 pts). The MTD and DLT dose were identified as 4.0 mg/kg and 6.0 mg/kg, respectively. DLTs were limited to clinically asymptomatic and reversible grade 3/4 elevations of amylase and/or lipase and grade 3/4 elevations of ALT and/or AST. As of June 14, 2010, 99 patients had received at least 1 infusion of LUC (32 from phase Ia, 67 from phase II). Of these patients, preliminary efficacy data is available for 79 patients (30 from phase Ia, 49 from phase II).

A 40% response rate to LUC was observed in patients who were refractory to rituximab. Peripheral blood CD40 receptor occupancy analyses demonstrated greater than 90% occupancy of circulating B-cells at 4 mg/kg (MTD). The half-life of LUC at 4 mg/kg was calculated as 13 ± 11 days. No immunogenicity was observed in any samples.

Preliminary results for LUC show anti-lymphoma activity on patients who failed at least two lines of therapy at an acceptable safety profile. Enrollment is continuing to further evaluate efficacy in all subtypes. The data warrants further development at least in the refractory setting of FL.

Freedman:Novartis Pharmaceuticals, Inc: Consultancy. Kuruvilla:Hoffman LaRoche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Genzyme: Honoraria; Otsuka: Honoraria. Engert:Novartis Pharmaceuticals, Inc: Honoraria, Research Funding. Corradini:Novartis Pharmaceuticals, Inc: Consultancy; Genezyme: Consultancy; Roche: Speakers Bureau; Celegene: Speakers Bureau. Fanale:Novartis Pharmaceuticals, Inc: Honoraria, Research Funding. Bendiske:Novartis Pharmaceuticals, Inc: Employment. Ewald:Novartis Pharmaceuticals, Inc: Employment. Dey:Novartis Pharmaceuticals, Inc: Employment. Baeck:Novartis Pharmaceuticals, Inc: Employment. Younes:Novartis Pharmaceuticals, Inc: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding; SBIO: Consultancy, Research Funding.