Celldex Presents Positive Interim Results from Phase 1 Study of CD40 Agonist CDX-1140 at American Association for Cancer Research (AACR) Annual Meeting 2019
--CDX-1140 has achieved good systemic exposure without reaching a maximum tolerated dose to date--
--Addition of dendritic cell growth factor CDX-301 enhances cytokine response without additive toxicity at dose levels tested to date--
--Tumor specific expansion cohorts planned--
CDX-1140 is currently in a Phase 1 dose escalation study. The study includes both monotherapy and combination cohorts with CDX-301, Celldex’s dendritic cell growth factor, designed to increase the number of dendritic cells which are critical to initiating antitumor immunity and are a key target for CDX-1140.
“Preclinical data support that CD40 activation could play an extremely important role in cancer immunotherapy by activating anti-tumor immunity and overcoming resistance to PD-1 blockade,” said
CDX-1140 has a unique combination of properties relative to other CD40 agonist antibodies: potent agonist activity resulting in dendritic cell and B cell activation is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation; CD40 ligand (CD154) binding is not blocked, allowing potential synergy with the natural CD40 activation pathway; and the antibody promotes strong immune activation without significant adverse events in preclinical toxicology studies.
Abstract #: LB-194: First in human Phase 1 study of the CD40 agonist monoclonal antibody (mAb) CDX-1140 alone and in combination with CDX-301 (rhFLT3L) in patients with advanced cancers: interim results (Sanborn, et. al)
- Overview: 30 patients were enrolled in the study at the time of data analysis (n=22 monotherapy; n=8 combination. Six monotherapy dosing cohorts in both solid tumors and non-Hodgkin lymphoma (
NHL) (0.01, 0.03, 0.09, 0.18, 0.36 and 0.72 mg/kg) have been completed. The seventh monotherapy cohort at 1.5 mg/kg is currently being enrolled. Two combination cohorts in solid tumors (0.09 and 0.18 mg/kg) with CDX-301 have been completed and the third cohort at 0.36 mg/kg is currently being enrolled. In general, patients have advanced disease and are heavily pretreated (median number of prior therapies: 4 monotherapy arm; 3.5 combination arm).
- Safety: CDX-1140 has been generally well tolerated. A maximum tolerated dose (MTD) has not been reached to date and only three patients have experienced serious treatment related adverse events (pneumonitis and hypoxia; possible cytokine release, fatigue and fever; and, fatigue and nausea). High grade, drug-related (Grade 3 and above) changes in liver function tests or platelet count have not been observed to date, including at CDX-1140 dose levels which exceed the MTDs reported with other CD40 agonists. The addition of CDX-301 has not affected the tolerability of CDX-1140 at dose levels tested to date in the combination cohorts.
- Systemic Dosing and Biomarker Analysis: Higher dose levels have achieved circulating antibody concentrations in the range of 20 to 30 micrograms CDX-1140 per milliliter. Transient dose-dependent pharmacodynamic effects have been observed including activation of dendritic cells and B cells, along with increases in pro-inflammatory cytokines and chemokines in the blood, all of which are consistent with CD40-mediated immune activation and the hypothesis that CDX-1140 is achieving dose levels optimal for systemic exposure. The addition of CDX-301 has further enhanced cytokine responses.
- Early Clinical Activity: While not anticipated at these lower CDX-1140 dose levels, stable disease has been observed in this heavily pretreated population who have received, at a minimum, all standard of care therapies for their tumor type. Recently enrolled dose levels are still under evaluation.
- Future development: Additional patient enrollment (backfill) has been initiated at the 0.72 mg/kg CDX-1140 dose level to characterize the effects of CDX-1140 in the tumor microenvironment and tumor specific expansion cohorts are planned. Future combination opportunities are being considered, including with PD-1 or PD-L1 inhibitors, radiation therapy and Celldex’s potent CD27 agonist monoclonal antibody varlilumab. Several B cell lymphomas (subtypes of
NHL) express both CD40 and CD27 and varlilumab has been shown to synergize with CDX-1140 in NHLmodels.
Celldex is developing targeted therapeutics to address devastating diseases for which available treatments are inadequate. Our pipeline includes immunotherapies and other targeted biologics derived from a broad set of complementary technologies which have the ability to engage the human immune system and/or directly inhibit tumors to treat specific types of cancer or other diseases. Visit www.celldex.com.
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Source: Celldex Therapeutics, Inc.