A phase 1 study of the pan-Notch inhibitor CB-103 for patients with advanced adenoid cystic carcinoma and other tumors

Abstract

Purpose: CB-103 selectively inhibits the CSL-NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose escalation/expansion study aimed to determine safety, pharmacokinetics (PKs), and preliminary anti-tumor activity. Experimental design: Patients ≥18 years of age with selected advanced solid tumors (namely adenoid cystic carcinoma [ACC]) and hematologic malignancies were eligible. CB-103 was dosed orally in cycles of 28-days at escalating doses until disease progression. Notch activating mutations were required in a dose confirmatory cohort. Endpoints included dose-limiting toxicities (DLTs), safety, tumor response, PKs, and pharmacodynamics. Exploratory analyses focused on correlates of Notch and target gene expression. Results: Seventy-nine patients (64, 12 dose escalation cohorts; 15, confirmatory cohort) enrolled with 54% receiving 2 or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed (elevated liver function tests [LFTs], visual changes); RP2D was declared as 500 mg twice daily (5 days on, 2 days off weekly). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 15 patients (19%), including elevated LFTs, anemia, and visual changes. Four (5%) discontinued drug for toxicity; with no drug-related deaths. There were no objective responses, but 37 (49%) had stable disease (SD); including 23/40 (58%) ACC patients. In the ACC cohort, median progression-free survival was 2.5 months (95%CI, 1.5-3.7) and median overall survival was 18.4 months (95%CI, 6.3-not reached). Conclusions: CB-103 had a manageable safety profile and biological activity but limited clinical anti-tumor activity as monotherapy in this first-in-human study.