Phase 1 study of CB-103, a novel first-in-class inhibitor of the CSL-NICD gene transcription factor complex in human cancers.
Authors: Lopez Miranda Elena , Stathis Anastasios , Hess Dagmar , Racca Fabricio , Quon Doris , Rodon Jordi , Saavedra Santa Gadea Omar , Perez Garcia Jose Manuel , Nuciforo Paolo , Vivancos Ana , Cortes Javier , Ferrarotto Renata , Schönborn-Kellenberger Oliver , Vigolo Michele , Bobadilla Maria , Beni Laura , Lehal Rajwinder , Bauer Michael Pascal , Vogl Florian D. , Garralda Elena 
Published: June 2021

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