一项1/2a期开放标签临床试验，评估VBC101（一种EGFR和cMET靶向双特异性抗体药物偶联物[ADC]）在晚期实体瘤恶性肿瘤受试者中的疗效

Background: EGFR and cMET are two growth factor receptors frequently co-expressed in solid tumors at significantly high levels, while only limited to moderate expression in normal tissues. Bispecific monoclonal antibodies (Ab) targeting EGFR and cMET have demonstrated clinical benefits in NSCLC and CRC patients, and ADCs represent a novel modality for targeting these receptors. MET pathway activation through increased cMET expression is often associated with resistance to EGFR tyrosine kinase inhibitors (TKI). VBC101 is a bispecific EGFR x cMET ADC which delivers cytotoxic payload exatecan with DAR of 4. Through this innovative design, VBC101 has demonstrated promising anti-tumor activity in preclinical CDX and PDX models. Methods: Phase 1/2a VBC101-01-01 study is first-in-human trial of VBC101 monotherapy in participants with locally advanced or metastatic solid tumors for whom there is no standard systemic treatment available or are refractory to or intolerant of standard systemic treatments. The Phase 1 portion adopts an accelerated titration for the first dose level, followed by BOIN design with potential backfill cohorts. Approximately five dose levels of VBC101 will be evaluated to determine the MTD, RP2D, safety, PK, and other endpoints. Subsequently, to further evaluate the safety, tolerability, anti-tumor efficacy, and PK characteristics of VBC101, up to 20 participants (dose escalation + backfill) will be enrolled at approximately 3 selected dose levels. The Phase 2a portion consists of dose optimization followed by cohort expansion. Two dose optimization cohorts will be evaluated: Cohort 1 (EGFRm NSCLC) and Cohort 2 (mCRC) are planned. Approximately 50 participants per cohort will be randomized 1:1 to two pre-selected dose levels based on Phase 1 data. Three cohorts (Cohort 3 HNSCC; Cohort 4 EGFRwt NSCLC and Cohort 5 other solid tumors) will each enroll approximately 30 participants at the recommended dose. The primary endpoints include safety and tolerability, and anti-tumor efficacy per RECIST v1.1 criteria, and the secondary endpoints include pharmacokinetics and immunogenicity. Baseline and on treatment tumor samples will be collected for retrospective analysis of EGFR and cMET expression. Approximately 310 participants are planned for enrollment (70 in Part 1 and 240 in Part 2a). The clinical trial is currently enrolling patients and will open at approximately 19 sites in the United States and China. Clinical trial information: NCT07136779 (Sponsor: VelaVigo (Shanghai) Limited, Shanghai, China).