CRD3874-SI（一种全身给药的第三代变构STING激动剂）治疗晚期实体瘤患者的I期试验

Introduction: Identifying novel approaches that harness and augment anti-tumor immune response is an important area of ongoing research and drug development. Based on their performance in pre-clinical models, orthosteric activators of the Stimulator of Interferon Genes (STING) have been investigated in human trials. The activation of STING by its ligand cGAMP leads to both IFN dependent innate immune signaling as well as IFN independent pharmacology associated with STING's proton transport activity that leads to autophagy and pyroptosis. CRD3874 is a first in class small molecule allosteric STING agonist that binds to an allosteric site within STING's proton channel and decouples the IFN and non-IFN consequences of STING activation by blocking STING's non-IFN actions. CRD3874-SI, is a proprietary intravenous formulation of CRD3874, potent activator of all five human STING variants that has demonstrated promising pre-clinical anti-cancer activity in serval mouse tumor models when systemically administered as mono therapy or in combination with checkpoint therapy. Drug administration led to elevated plasma levels of CXCL10 and IFNbeta in mice and monkeys. High IV doses up to 75mg/kg were systemically tolerated in cynomolgus monkeys. Methods: This is a single institution, phase Ia/b study of CRD3874-SI in patients with advanced solid tumors who received at least one line of prior therapy. The dose escalation phase will explore the safety and tolerability of CRD3874-SI following standard 3+3 design. CRD3874-SI is administered by intravenous infusion once per week for two cycles. From cycle 3 onwards, participants will received 3 or 4 consecutive weekly infusions, over a 28-day treatment cycle. The primary objective is to assess the safety and tolerability of CRD3874-SI by determining the maximum tolerated dose, recommended phase 2 dose and schedule of administration. Secondary objectives include further defining the safety profile, examining the pharmacokinetics and pharmacodynamics (CXCL10 analysis) of CRD3874-SI and evaluating the efficacy of CRD3874-SI as determined by the best objective response rate and clinical benefit rate per RECIST v1.1. Treatment will continue until disease progression or unacceptable toxicity. This study is currently open to enrollment. 21 patients have received treatment across 4 dose levels to date. Expansion cohorts are planned after determining the appropriate dose (RP2D). Clinical trial information: NCT 06021626. Research sponsor: Curadev Pharma, Inc.