Phase 1b study of GS-3583, a novel FLT3 agonist Fc fusion protein, in patients with advanced solid tumors.

Abstract

2566 Background: We have previously shown that systemic administration of GS-3583, a Fms-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein leads to expansion of conventional dendritic cells (cDC), both subtype 1 (cDC1) and subtype 2 (cDC2), in the periphery of healthy volunteers (Rajakumaraswamy N, et al. J Clin Oncol. 2021;39[suppl_15]:2559.). This mechanism may increase cDC in the tumor microenvironment and promote T cell mediated antitumor activity in patients with solid tumors. Methods: This ongoing, Phase 1b, open label study is investigating the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of escalating multiple doses of GS-3583 monotherapy in adult patients with advanced solid tumors using a standard 3 + 3 design. GS-3583 was administered intravenously on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 52 weeks or until progressive disease or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 therapy at each dose level. Results: At the time of the Dec 3, 2021 data cut-off, 9 patients have enrolled in 3 dose escalation cohorts. Median (range) age was 71 (44-79); 4 (44%) patients were male. Tumor types were pancreatic (n=3), ovarian (n=4), and rectal (n=2). To date, no DLTs or discontinuation due to adverse events (AE) have been observed. Three patients had Grade ≥3 AEs which were also recorded as serious AEs, none of which were considered related to GS-3583. Dose dependent increase in GS-3583 exposure was observed in the evaluated dose range 2 to 12 mg with target-mediated drug disposition appearing to be saturated at doses above Dose Level 2. GS-3583 accumulation was observed at higher dose levels. GS-3583 treatment resulted in expansions of cDC1 and cDC2 at all 3 doses (Table); a dose-dependent trend in the magnitude and the durability of cDC expansion was observed. At the highest dose evaluated, GS-3583 produced ≥100-fold expansion of both cDC1 and cDC2 at multiple time points. Dose escalation on the study is still ongoing. Conclusions: GS-3583 was safe and well tolerated and induced dose-dependent expansion of cDCs in the periphery in patients with advanced solid tumors up to doses of 12 mg. These findings support further dose escalation and clinical development of GS-3583 in combination with agents that would stimulate the expanded cDCs to produce anti-tumor responses. Clinical trial information: NCT04747470. [Table: see text]