Reference Detail

Ref Type

Journal Article

PMID

(28050790)

Authors

Forero A, Bendell JC, Kumar P, Janisch L, Rosen M, Wang Q, Copigneaux C, Desai M, Senaldi G, Maitland ML

Title

First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	35	3	2017 06	298-306	Invest New Drugs

URL

Abstract Text

Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid tumors. Methods The study comprised dose escalation and dose expansion cohorts. The dose escalation cohorts intended to determine the safety and to identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and 24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects were treated at the MAD for further evaluation of PK and safety. Results Thirty two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16 in the dose expansion cohort. No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea. Measures of plasma exposure increased dose-proportionally and the mean terminal elimination half-life was 11 days. Blood samples available from a subset of patients treated at 24 mg/kg revealed declines in myeloid derived suppressor cells (MDSC) at 2 weeks. No objective responses were observed in any subjects. Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure. This agent could be studied further in combination with other agents, pending further proof-of-target-engagement.

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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
DS-8273a		DS 8273		DS-8273a is a monoclonal antibody that activates DR5 signaling, which may lead to tumor cell apoptosis (PMID: 28050790).

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