First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors
Andres Forero1, Johanna C Bendell2, Prasanna Kumar3
1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-3300, USA.
Abstract:
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.
Insights
This Phase 1 study found that the novel DR5 agonist DS-8273a was safe and well-tolerated in advanced solid tumor patients. DS-8273a showed linear pharmacokinetics and reduced myeloid-derived suppressor cells, suggesting potential for combination therapies.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Death receptor 5 (DR5) is a transmembrane receptor crucial for initiating apoptosis signaling pathways.
- DS-8273a is a novel monoclonal antibody designed as a potent agonist of DR5.
- Targeting DR5 offers a potential therapeutic strategy for various cancers.
Purpose of the Study:
- To evaluate the safety and tolerability of DS-8273a in patients with advanced solid tumors.
- To determine the pharmacokinetics (PK) and pharmacodynamics (PD) of DS-8273a.
- To identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) of DS-8273a.
Main Methods:
- Phase 1 clinical trial with dose escalation and expansion cohorts.
- Utilized a 3+3 design for dose escalation, assessing safety and PK/PD.
- DS-8273a administered intravenously once every 3 weeks at escalating doses (2-24 mg/kg).
Main Results:
- Thirty-two subjects were enrolled; no dose-limiting toxicities were observed.
- Treatment-emergent adverse events were mostly mild (Grade 1-2), primarily fatigue, nausea, vomiting, and diarrhea.
- DS-8273a exhibited dose-proportional plasma exposure and a long half-life (11 days); decreases in myeloid-derived suppressor cells (MDSC) were noted at 24 mg/kg.
Conclusions:
- DS-8273a demonstrated a favorable safety profile and linear PK in patients with advanced solid tumors.
- A temporal association was observed between DS-8273a exposure and reductions in MDSC.
- Further investigation of DS-8273a, particularly in combination regimens, is warranted to explore its therapeutic potential.
