1029P Dazostinag (TAK-676) alone and in combination with pembrolizumab (pembro) in patients (pts) with advanced or metastatic solid tumors: Preliminary safety, PK/PD, and anti-tumor activity in a phase I dose escalation study supporting a recommended dose for expansion (RDE)

Dazostinag (TAK-676) is a novel, IV, small molecule synthetic STimulator of INterferon Genes (STING) agonist, which acts as an innate immunity enhancer. In preclinical models, dazostinag induced dose-dependent cytokine production and activation/proliferation of immune cells. We present data from Part 1 of iintune-1 (NCT04420884), a phase 1 study of single agent (SA) dazostinag and combined with pembro in advanced or metastatic solid tumors. Part 1 comprised a single-pt safety lead-in with SA dazostinag 0.1 mg IV, followed by dose escalation using Bayesian Logistic Regression Model design. Dose escalation in the combination arm began after no dose-limiting toxicities (DLTs) were seen with ≥2 SA doses. Pts receive dazostinag IV (Days 1, 8, 15) +/- pembro 200 mg IV (Day 1) in 21-day cycles. As of May 2023, 36 and 43 pts have received SA dazostinag and with pembro, respectively. There have been no DLTs up to 7 mg SA and 5 mg with pembro. The most common adverse events were fatigue (33%), nausea (29%), and pyrexia (22%). Dazostinag had linear PK across the dose range tested and was not affected by combination with pembro; elimination profile was bi-phasic with a terminal half-life of 0.5–1.7 hrs. Exposure-safety analysis indicated increasing incidence of fever or cytokine release syndrome with dazostinag Cmax. PK/PD analysis for all pts indicated dose/concentration-dependent increases in a blood 24-gene STING signature score, and plasma IFN-γ and IP-10. Dazostinag achieved a >3.5-fold induction of STING signature score across multiple dose levels. For dazostinag 5 mg with or without pembro, a >2-fold increase in IFN-γ and other cytokines (including IP-10) and increased peripheral Ki67+CD8+ T cell proliferation were observed. Three pts had objective confirmed clinical responses with dazostinag plus pembro. Preliminary safety, PK/PD data, and anti-tumor activity support the declaration of the RDE of dazostinag 5 mg + pembro 200 mg. Expansion cohorts in colorectal and head and neck cancer are enrolling.