Discussion
ACC-I, fatigue, diarrhea, toxicity, toxicities, anemia, aggressive disease, deaths
DISEASE, ANEMIA, SOLID TUMOR
This phase I/II study of the novel, oral pan-Notch inhibitor CB-103 determined the RP2D as 500 mg twice daily utilizing a 5 day on and 2 day off weekly schedule. Overall, CB-103 was well tolerated with 15 of 79 patients (19%) experiencing grade 3 or 4 AEs which were all reversible, with no deaths related to study drug, and only 5 patients (6%) discontinuing study drug for toxicity. In addition, CB-103 demonstrated favorable pharmacokinetic properties with mean plasma concentrations increasing across dose escalation.Among all 76 evaluable solid tumor patients (most with ACC) there were no objective responses observed, but 58% of ACC patients exhibited SD with a 3- and 6-month CBR of 58% and 28%, respectively. Notably, 68% (27/40) of patients with ACC in our trial had confirmed GSIs can result in diarrhea and fatigue in >60% of patients but grade 3+ AE rates were reportedly low. Gastrointestinal toxicities associated with GSIs were not observed with CB-103. CB-103 has an independent mechanism from GSIs, resulting in a distinct AE profile (anemia, visual changes) which also appears manageable. This is important to highlight as the broader advanced ACC population (regardless of Notch status) is often offered treatment with oral VEGFR tyrosine kinase inhibitors (TKI) such as lenvatinib and axitinib which have reported discontinuation rates of 20% or greater for toxicity (Ferrarotto and colleagues have characterized the poor prognosis and aggressive disease phenotype that distinguishes Another potential target in ACC-I is the apoptotic protein In conclusion, the novel oral pan-NOTCH inhibitor CB-103 demonstrated a manageable safety profile with good tolerability and biological activity despite limited antitumor activity as monotherapy in this first-in-human study. We observed some evidence of disease stabilization in an aggressive ACC-I type population where prognosis is poor, and therapies are urgently needed. Further enrichment for 