Phase I, multicenter, first-in-human (FIH) global study of SIM0505, an anti-CDH6 (CDH6) antibody-drug conjugate (ADC) in patients with advanced solid tumors.

Abstract

5580 Background: Cadherin 6 is a transmembrane glycoprotein overexpressed in multiple cancers, including ovarian cancer (OC) and uterine serous cancer (USC). SIM0505 is an ADC comprised of an anti-CDH6 humanized IgG1 monoclonal antibody, a stable linker cleaved within tumor cells, and a novel topoisomerase I inhibitor, CPT116. Here, we report initial results from a global FIH study of SIM0505 (NCT06792552). Methods: This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of SIM0505 in patients (pts) with advanced solid tumors. SIM0505 was administered IV every 21 days from 1.6 mg/kg to 9.6 mg/kg. Dose levels from 3.2-8.0 mg/kg were backfilled. Results: As of 26 Dec 2025, 38 pts were enrolled without preselection for CDH6 expression (29 OC, 4 USC, 2 endometrioid endometrial cancer, 3 renal cell cancer) from 1.6 mg/kg to 9.6 mg/kg in the dose-escalation part. The median age was 57.0 years (range 42-78). The median number of prior therapy regimens was 5 (range 1-11). Of the 29 OC pts, 27 (93.1%) were high grade serous and 23 (79.3%) were platinum resistant. 22 (75.9%), 20 (69.0%) and 2 (6.9%) had received bevacizumab, PARPi and mirvetuximab soravtansine (MIRV), respectively. The median treatment duration was 10.6 weeks (range 3.0-33.6). Any-grade and Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 37 (97.4%) and 21 (55.3%) pts, respectively. Any-grade and Grade ≥3 treatment-related adverse events (TRAEs) occurred in 35 (92.1%) and 17 (44.7%) pts, respectively. The most common (≥10%) Grade ≥3 TRAEs were thrombocytopenia (23.7%), neutropenia (21.1%), and white blood cell count decreased (18.4%). One pt at 9.6 mg/kg had dose-limiting toxicity of Grade 4 febrile neutropenia and thrombocytopenia and discontinued treatment. Another patient discontinued treatment due to Grade 2 interstitial lung disease. Serious TRAEs were observed in 6 (15.8%) pts. No TEAEs led to death. MTD was not reached. Among 30 evaluable pts, 11 partial responses (PR, 9 OC and 2 USC) and 13 stable disease were observed. 8 PRs occurred among 14 evaluable OC pts at potential therapeutic dose range of 4.8-8 mg/kg. 9 of 21 Gynecological Cancer Intergroup (GCIG) evaluable pts had CA-125 response. The exposure of SIM0505 was proportional to dose in general, with a half-life of about 8 days. The PK profile was similar to that of total antibody, indicating good stability of the ADC in the circulation. Conclusions: SIM0505, a first in class CDH6 CPT116 payload ADC showed manageable safety and tolerability, including at higher dose levels with encouraging efficacy in OC and USC, with a favorable PK profile. These data support initiating the dose optimization portion of the study in gynecological cancers. Clinical trial information: NCT06792552 .