Phase 1 study of CB-103, a novel first-in-class inhibitor of the CSL-NICD gene transcription factor complex in human cancers.

• DOI: 10.1200/jco.2021.39.15_suppl.3020
• Publication Date: 2021-06-02T14:00:38Z
• Authors: Elena Lopez Miranda; Anastasios Stathis; Dagmar Hess; Fabricio Racca; Doris Quon; Jordi Rodon; Omar Saavedra San...; Jose Manuel Perez...; Paolo Nuciforo; Ana Vivancos; Javier Cortes; Renata Ferrarotto; Oliver Schönborn-...; Michele Vigolo; Maria Bobadilla; Laura Beni; Rajwinder Lehal; Michael Pascal Bauer; Florian D. Vogl; Elena Garralda
• Keywords: Pharmacodynamics; Tolerability

3020 Background: CB-103 selectively inhibits the CSL-NICD interaction leading to down-regulation of mediated oncogenic pathway activation downstream NOTCH receptor/ligand signaling, and has shown potent anti-cancer activity as single agent in combination with targeted/chemotherapies preclinical models. The aim this dose escalation/expansion phase 1/2a study is assess safety, maximum tolerated (MTD) recommended 2 (RP2D), preliminary activity, pharmacokinetics pharmacodynamics CB-103. Methods: Eligible were adult patients (pts) advanced or recurrent selected solid tumors. Tumor tissue, where available, was retrospectively tested for activating mutations surrogate tissues evaluated gene expression related target genes. given orally 28 days cycles at escalating doses until disease progression toxicity. In a confirmatory cohort, will be prospectively assessed determine eligibility. Results: Forty-one pts (19 adenoid cystic carcinoma (ACC), 16 colorectal 4 breast cancer, prostate cancer) assigned increasing levels starting from 15mg once daily (OD). Median age 55 years (range 25-76). number prior lines therapy 0-7). Thirty-two 8 escalation groups completed 28-day DLT window. One (asymptomatic grade (G) 3 GGT increase) observed highest (600mg). Related treatment emergent adverse events (AE) occurring >10% nausea (24%), diarrhea (20%), dyspepsia (15%), fatigue (12%) vision blurred (12%), all G 1/2. No discontinuations occurred due treatment-related AEs. MTD not been reached. Several reported changes that improved over time fully reversible after stopping drug. on 52 5-249). Best response stable (SD). For ACC pts, median PFS 21.7 weeks (95% confidence interval (CI) 13.7-22.4 weeks) control rate (DCR) 79% week 58 % 20. Three harboring alterations had radiologically confirmed (SD) > 6 months. Importantly, positive temporary stop tumor growth observed. pt showed reduction size liver lesion up 25% before new lesions. Mechanistically, strong on-treatment downregulation genes 600mg OD declared RP2D. Conclusions: first drug effectively transcription complex. well tumors and, expected basis mechanistic studies, absence typical toxicities associated Notch targeting GSIs mABs. RP2D established advancing clinical development into 2. Clinical trial information: NCT03422679.