Reference Detail

Ref Type

Abstract

PMID

Authors

Rachel E. Sanborn, Nashat Y. Gabrail, Nina Bhardwaj, Michael S. Gordon, Mark O'Hara, Danny Khalil, Thomas Hawthorne, Richard Gedrich, Laura Vitale, Mark Rogalski, Tianshu Li, Tracey Rawls, Tibor Keler, Michael Yellin

Title

First-in-human Phase I study of the CD40 agonist mAb CDX-1140 and in combination with CDX-301 (rhFLT3L) in patients with advanced cancers: Interim results

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Res	79	13 Suppl	2019

URL

https://aacrjournals.org/cancerres/article/79/13_Supplement/LB-194/638014/Abstract-LB-194-First-in-human-Phase-I-study-of

Abstract Text

CDX-1140 is an agonist CD40 mAb intended to promote priming of CD8+ effector T cells through activation of dendritic cells (DC), enhance macrophage tumoricidal activity, and mediate direct killing of CD40-expressing tumor cells. CDX-1140 is a human IgG2 mAb with Fc receptor independent activity and is synergistic with sCD40L, suggesting a potential to enhance CD40L-mediated immune activation. CDX-1140 has a broad dose-dependent activity that may achieve maximal agonist activity at doses that provide significant tumor penetration with minimal toxicities from systemic CD40 activation. CDX-301 (rhFLT3L) is a DC growth factor that markedly increases CD141+ DCs, including in the tumor microenvironment (TME). CD141+ DCs are critical for initiating anti-tumor immune responses and are often depleted within the TME. Preclinical studies have shown that treatment with CDX-301 synergizes with CD40 signaling to enhance anti-tumor immune responses, suggesting that combining CDX-1140 and CDX-301 could result in enhanced clinical benefit. CDX1140-01(NCT03329950) is a Phase I dose-escalation study of CDX-1140 as monotherapy or in combination with CDX-301 evaluating safety, PK, PD, and preliminary clinical activity in patients (pts) with refractory solid tumors and non-Hodgkin lymphoma. CDX-1140 is given iv q 4 weeks at doses from 0.01 to 3 mg/kg utilizing a 3+3 design (first 2 cohorts are single-pts). In combination cohorts (solid tumors only), CDX-301 at 75 μg/kg daily x 5 is administered sc prior to cycles 1 and 2 of escalating doses of CDX-1140 starting at 0.09 mg/kg. Tumor-specific expansion cohorts are planned to further explore the activity of monotherapy or combination treatment To date, 18 pts across 10 tumor types have been dosed in CDX-1140 monotherapy cohorts with doses ranging from 0.01 to 0.72 mg/kg and without identification of an MTD. There has been one DLT (0.18 mg/kg): grade 3 pneumonitis and hypoxia. One pt (0.72 mg/kg) experienced grade 3 fatigue requiring hospitalization 48 hrs after the first infusion. There have been 3 additional grade 3 treatment-related adverse events: dyspnea (0.18 mg/kg), nausea (0.36 mg/kg), and vomiting (0.36 mg/kg). The first combination cohort (n=5) has been completed. In monotherapy and combination cohorts there have been no significant drug-related changes in liver function tests to date. CDX-1140 PK is quantifiable at doses ≥ 0.09 mg/kg and exposure appears dose proportional. Expected dose-dependent PD effects have shown activation of peripheral blood lymphocytes and increases in pro-inflammatory cytokines and chemokines. Combination with CDX-301 has shown enhanced cytokine responses. The data suggest that CDX-1140 has the expected biologic and safety profile predicted from preclinical studies and may achieve dose levels optimal for systemic exposure. The addition of CDX-301 may enhance the activity of CDX-1140.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References