Enrollment in an open-label, Phase I study of CDX-1140, an investigational drug being developed by Celldex Therapeutics, in patients with advanced solid tumors has started.
CDX-1140, is a fully human antibody targeted to CD40, a key activator of immune response that is found on dendritic cells, macrophages and B cells. VD40 is also expressed on many cancer cells.
“CD40 has long been an important target for immunotherapy, as it plays a critical role in the activation of innate and adaptive immune responses,” noted Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics.
Image 1.0: Innate and Adaptive immune responses.“However, balancing systemic dosing and safety has proven elusive to date for CD40 targeted activating therapeutics. CDX-1140 is a unique, potent CD40 agonist that we believe has the potential to successfully balance systemic doses for good tissue and tumor penetration with an acceptable safety profile,? Keler added.
?We look forward to characterizing CDX-1140 in this Phase I study and rapidly moving into combination studies with other anti-tumor agents,? he concluded.
Pre-clincal development
Earlier this year, preclinical data, including the IND-enabling toxicology study of CDX-1140, were presented at the SITC Annual Meeting in November 2017. This toxicology study of CDX-1140 clearly demonstrated strong immune activation effects and low systemic toxicity.
The data supported the design of the Phase I study of CDX-1140 to rapidly identify the dose for characterizing single-agent and combination activity.
Study Design
The Phase I study, which is expected to enroll up to approximately 105 patients with recurrent, locally advanced or metastatic cancers, is designed to determine the maximum tolerated dose during a dose-escalation phase and to recommend dose(s) for further study in a subsequent expansion phase.
During the dose-escalation phase, patients will receive CDX-1140 at dose levels ranging from 0.01 mg/kg to 3.0 mg/kg once every four weeks until disease progression or intolerance. The expansion phase is designed to further evaluate the tolerability and biologic effects of selected dose(s) of CDX-1140 in specific tumor types.
Secondary objectives of the study include analyses of safety and tolerability, pharmacodynamics, pharmacokinetics, immunogenicity and assessment of anti-tumor activity across a broad range of endpoints, such as objective response rate, clinical benefit rate, duration of response, progression-free survival and overall survival.
Targeted drugs
CDX-1140 is a fully human antibody targeted to CD40, a key activator of immune response that is found on dendritic cells, macrophages and B cells and is also expressed on many cancer cells. Potent CD40 agonist antibodies have shown encouraging results in early clinical studies.
Systemic toxicity
Systemic toxicity associated with broad CD40 activation has, however, limited their dosing. CDX-1140 has unique properties relative to other CD40 agonist antibodies: potent agonist activity is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation.
CD40L binding is not blocked, leading to potential synergistic effects of agonist activity near activated T cells in lymph nodes and tumors. Furthermore, the antibody does not promote cytokine production in whole blood assays. As a result, CDX-1140 has shown direct anti-tumor activity in preclinical models of lymphoma.
Researchers at Celldex believe that the potential for CDX-1140 will be best defined in combination studies with other immunotherapies or conventional cancer treatments.
Last Editorial Review: November 30, 2017
Featured Image: Blood testing. Courtesy: ? Fotolia. Used with permission.
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