Multi-Trial Safety Evaluation of the Fully Antagonistic Human Anti-CD40 Monoclonal Antibody Lucatumumab (HCD122) in Patients with Relapsed or Refractory B-Cell Malignancies,

Patients with chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) together accounted for 7% of new cancers and 6% of cancer deaths in 2010. Despite therapeutic advances, many of these patients develop relapsed or refractory disease and have poor survival thereafter. CLL, MM, NHL, and HL highly express the CD40 receptor, which is activated by the CD40 ligand (CD40L, CD154) and stimulates downstream proliferation and survival. Lucatumumab is a fully antagonistic human anti-CD40 monoclonal antibody that has demonstrated activity in preclinical and clinical studies and is hypothesized to act through dual mechanisms of action by inhibiting CD40L-CD40 signaling and inducing antibody-dependent cell-mediated cytotoxicity. Here, we present a full safety analysis from 2 phase I trials in patients with relapsed or refractory CLL (NCT00108108) or MM (NCT00231166) and from an ongoing phase I/II study in patients with NHL and HL (NCT00670592). Methods. These early-phase trials of lucatumumab were designed to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and pharmacodynamics of lucatumumab, and to evaluate early signals of clinical efficacy in CLL, MM, NHL, and HL. Patients with relapsed or refractory CLL, MM, NHL, and HL were enrolled and received 4 intravenous infusions of lucatumumab 0.3, 1.0, 3.0, 4.0, 4.5, or 6.0 mg/kg once weekly per treatment cycle. Dose-limiting toxicities (DLTs), MTD, and adverse events (AEs) were assessed. Results. A total of 164 patients with relapsed or refractory CLL (n=26), MM (n=28), or lymphoma (NHL or HL; n=110) were enrolled in 3 trials. Lucatumumab was well tolerated; the most frequent AEs were primarily grade 1/2 events. Infusion-related reactions typically occurred during or within 1 day of the first infusion and decreased in frequency for subsequent infusions. Any-grade AEs included chills (42%), nausea (32%), pyrexia (32%), and fatigue (25%). Non-laboratory grade 3/4 AEs due to any cause included dyspnea (5%), chills (2%), fatigue (2%), and hypotension (2%). Hematologic grade 3/4 abnormalities, regardless of drug relationship, included neutropenia (14%), anemia (14%), and thrombocytopenia (9%). Cytopenia was manageable, was reversible, and led to treatment discontinuation in 3% of patients. The most common grade 3/4 biochemical laboratory abnormalities included asymptomatic elevations of lipase (25%), amylase (10%), ALT (7%), or AST (5%). The most common AE leading to study discontinuation was increased lipase (n=18; 11%). These elevations resolved per investigators after a median of 16 days (range 1–99 days). A total of 14 DLTs were reported during dose escalation phases of the studies; all DLTs occurred at doses ≥3.0 mg/kg and most commonly included grade 3/4 laboratory elevations lasting >7 days. The lucatumumab MTDs for patients with CLL, MM, or NHL/HL were 3.0, 4.5, and 4.0 mg/kg once weekly, respectively. A total of 14 deaths due to any cause occurred on study or within 28 days of discontinuation, 1 of which (due to sepsis) was considered possibly related to the study drug by the investigator. No antibodies to lucatumumab were detected in any patients. Conclusions. The tolerability profile of lucatumumab reported here supports further study in relapsed or refractory CLL, MM, NHL, and HL as a single agent or in combination with other agents that are established for the treatment of these conditions. A combination study of lucatumumab and bendamustine in follicular lymphoma is ongoing.

Fanale:Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Millenium: Research Funding. Bensinger:Novartis Corporation: Research Funding. Ewald:Novartis Pharmaceuticals Corporation: Employment. Carreon:Novartis Pharmaceuticals Corporation: Fellow for Rutgers University Sponsored by Novartis Pharmaceuticals Corporation. Baeck:Novartis Pharmaceuticals Corporation: Employment. Freedman:Pfizer: Data safety monitoring committee member; GlaxoSmithKline: Data safety monitoring committee member; Novartis Pharmaceuticals Corporation: Research Funding.