(P 431) INVOKE: A PHASE 1 STUDY OF OKN4395, A FIRST-IN-CLASS EP2/EP4/DP1 TRIPLE PROSTANOID RECEPTOR ANTAGONIST, IN PATIENTS WITH ADVANCED SOLID TUMORS, INCLUDING SARCOMAS

Objective: The immunosuppressive pathway of prostaglandin E2 (PGE2), part of the cyclooxygenase (COX) pathway, is upregulated in certain cancers and has been implicated in tumor evasion of immune cells, allowing tumor growth and metastasis (Jin et al., 2023). COX2 inhibitors, aspirin and nonsteroidal anti-inflammatories (NSAIDS) have shown some survival benefit in patients with certain cancers (Cao et al., 2016; Lim et al., 2012; Huang et al., 2014; Takiuchi et al., 2018), however results are inconsistent, highlighting the need for more potent but selective COX pathway inhibitors. OKN4395 is a first-in-class, highly selective, equipotent inhibitor of EP2, EP4 and DP1, downstream receptors for PGE2, and PGD2, respectively. DP1 is described in immunosuppression and apoptosis inhibition, supporting the therapeutic rationale (Luo et al., 2024; Peinhaupt et al., 2017). OKN4395 is hypothesized to modulate the tumor microenvironment to allow an effective immune response, and to potentiate the effect of other immunotherapies, both evaluated in INVOKE.

Methods: INVOKE (OKN-4395-121; NCT06789172) is a Ph1a/1b, first-in-human study of OKN4395 (oral, BID) as monotherapy (mono) or in combination with pembrolizumab 200mg IV 3-weekly (combo), in patients with COX-associated immunosuppressed advanced tumors. Ph1a, a mono Bayesian dose escalation followed by combo dose confirmation, assesses safety and establishes the Ph1b dose. Using artificial intelligence (AI) drug-matching algorithms, Ph1b tumors were selected, and response will be assessed (n=20 each): select sarcomas (mono), pancreatic (mono), non-small cell lung (combo), colorectal (combo), head & neck squamous cell (combo). Key inclusion criteria include COX-active (Ph1a) or above-listed (Ph1b) tumors, performance status 0-1, biopsy-amenable lesions, and adequate organ function. Ph1b mono cohorts will explore the effect of food & gastric pH on OKN4395 pharmacokinetics. Trial data, paired pre- and on-treatment biopsies, and exploratory biomarkers will be used to enhance development using advanced agentic AI systems, including a synthetic digital twin control arm.

Ph1a is currently recruiting in the US, UK, and Australia.

Results: N/A

Conclusion: N/A