Evaluation of the safety and efficacy of ALMB-0168, a novel monoclonal antibody activating Cx43 hemichannel, for osteosarcoma after standard therapy failure: A multicenter, open-label, single agent, phase 1/2 study (ACE study).

Abstract

11509 Background: There was limited therapeutic advancement for decades for patients (pts) with relapsed and refractory (R/R) osteosarcoma. Pts with R/R osteosarcoma urgently need effective and safe treatment options after standard therapy failure. ALMB-0168, a first-in-class humanized IgG4 monoclonal antibody targeted to hemichannel protein Cx43, activates hemichannels to release key substances including ATP into the extracellular environment, to inhibit the growth and migration of osteosarcoma and other cancers bone metastases. Here reported the phase 2 study result based on ASCO 2023 Poster (11530). Methods: Pts ≥ 12 years (yrs) with pathologically confirmed osteosarcoma who had failed standard therapy were enrolled. In the phase I dose escalation with an accelerated titration followed by 3+3 design, pts were dosed with 7 planned ALMB-0168 dose levels (1, 3, 6, 12, 18, 24, and 30mg/kg), Q3W, until their disease progressed or intolerable toxicity occurred. Then the cohort at effective dose 6mg/kg was expanded. This trial used RECIST1.1 for efficacy evaluation. Primary endpoints were safety and tolerability. Key secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). The CD73/CD39 expressions evaluated by IHC in osteosarcoma FFPE tissue with the efficacy were retrospectively analyzed. Results: As of Aug 19, 2024, total 27 pts with median age 29 yrs (range 16–69 yrs) were enrolled, of which 17 pts for dose escalation and 10 for dose expansion at 6mg/kg. No dose-limiting toxicity was observed. Treatment related adverse events (TRAEs) of any grade occurred in 18 (66.7%) pts, most of them were grade 1-2. Grade 3 TRAEs occurred in 1 (3.7%) patient (infectious pneumonia); no events were Grade 4 or 5. Common TRAEs observed in ≥ 10% pts were anemia (22.2%), proteinuria (14.8%) and alpha hydroxybutyrate dehydrogenase increased (11.1%). The DCR of whole evaluable pts was 68.2% (15/22), including 3 PR and 12 SD. At the 6mg/kg dose level which was expanded, among 10 evaluable pts, 2 pts achieved partial response (ORR: 20%), of which 1 patient achieved durable PR for 17 months (mo), PFS for 23 mo and OS for 36 mo (not reached). In 6mg/kg group, the DCR was 90% (9/10, 95% CI: 55.5, 99.7%) with 2 PR and 7 SD. And the PFS rate of 6mg/kg group at 4th mo was 70% (95% CI: 22.48, 91.83%). The relationship between the efficacy and the CD73/CD39 expression and other exploratory results will be presented in the future. Conclusion: The maximum tolerated dose of ALMB-0168 was not reached. The recommended phase 2 dose is 6mg/kg. In this study, ALMB-0168 showed encouraging anti-tumor activity, safe profile and durable benefit for pts with R/R osteosarcoma, which might be one of the potential treatment options for R/R osteosarcoma in the future. Clinical trial information: NCT04886765 .