402?DRAGON: Phase 1 trial of SRK-181, a latent TGFβ1 inhibitor in combination with anti-PD-(L)1 inhibitors for patients with solid tumors unresponsive to anti-PD-(L)1 therapy alone

摘要

Background TGFβ1 is a key mediator of primary resistance to PD1 (programmed cell death protein 1) pathway blockade. SRK-181 is a high-affinity, fully humanized antibody that selectively binds to latent TGFβ1 and inhibits its activation on suppressive immune cells as well as within tumor stroma. Preclinical data demonstrated that selective inhibition of latent TGFβ1 with SRK-181 overcomes primary anti-PD-1 resistance and has an improved safety profile compared to broad inhibition of the TGFβ pathway. Methods The DRAGON trial is a multi-center, open-label, Phase 1, first-in-human (FIH), dose-escalation, and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SRK-181 administered by IV infusion every 3 weeks (q3w) alone and in combination with an anti-PD-(L)-1 in adult patients with locally advanced or metastatic solid tumors. The study is divided into 3 parts: Part A1, a single agent dose escalation, will determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of SRK-181 as a single agent. Part A2, a combination dose escalation, will determine the MTD or MAD of SRK-181 in combination with anti-PD-(L)1 therapy and the RP2D of the combination treatment for use in Part B. Part B, the dose expansion, will enroll parallel cohorts of patients with non-small cell lung cancer, urothelial carcinoma, melanoma, or other advanced solid tumors, to confirm the tolerability of the RP2D and to evaluate the anti-tumor activity of SRK-181 in combination with an anti-PD-(L)1 therapy. Patients in Part A2 and Part B will have previously received anti-PD-(L)1 therapy and considered non-responders to anti-PD-(L)1 therapy alone. Patients will receive SRK-181 alone or in combination with anti-PD-(L)1 until disease progression, unacceptable toxicity, or other reasons for study discontinuation. Safety, PK, PD and efficacy data will be collected and monitored throughout the study. PD effects will be assessed by measuring modulation of tumor immune cells and TGFb pathway within the tumor microenvironment.