A Phase I Study of the Pan-Notch Inhibitor CB-103 for Patients with Advanced Adenoid Cystic Carcinoma and Other
Glenn J Hanna1, Anastasios Stathis2,3, Elena Lopez-Miranda4
1Department of Medical Oncology, Center for Head and Neck Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Purpose:
CB-103 selectively inhibits the CSL-NICD (Notch intracellular domain) interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose-escalation/expansion study aimed to determine safety, pharmacokinetics, and preliminary antitumor 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 (DLT), safety, tumor response, pharmacokinetics, 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 two or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed [elevated gamma-glutamyl transferase (GGT), visual change]; recommended phase II dose was declared as 500 mg twice daily (5 days on, 2 days off weekly). Grade 3-4 treatment-related adverse events occurred in 15 patients (19%), including elevated liver function tests (LFTs), anemia, and visual changes. Five (6%) discontinued drug for toxicity; with no drug-related deaths. There were no objective responses, but 37 (49%) had stable disease; including 23 of 40 (58%) patients with ACC. In the ACC cohort, median progression-free survival was 2.5 months [95% confidence interval (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 antitumor activity as monotherapy in this first-in-human study.
Significance:
CB-103 is a novel oral pan-Notch inhibitor that selectively blocks the CSL-NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This first-in-human dose-escalation and -confirmation study aimed to determine the safety, pharmacokinetics, and preliminary antitumor efficacy of CB-103. We observed a favorable safety profile with good tolerability and biological activity but limited clinical single-agent antitumor activity. Some disease stabilization was observed among an aggressive NOTCH-mutant ACC type-I subgroup where prognosis is poor and therapies are critically needed. Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs.
Insights
CB-103, a novel Notch inhibitor, showed a manageable safety profile and biological activity in advanced solid tumors. However, it demonstrated limited antitumor efficacy as a monotherapy, warranting further investigation in combination therapies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The Notch pathway plays a crucial role in oncogenesis, making it a target for cancer therapy.
- CB-103 is an oral pan-Notch inhibitor designed to block the CSL-NICD interaction and downregulate oncogenic Notch signaling.
Purpose of the Study:
- To assess the safety, pharmacokinetics, and preliminary antitumor activity of CB-103 in patients with advanced solid tumors and hematologic malignancies.
- To determine the recommended Phase II dose (RP2D) of CB-103.
Main Methods:
- A first-in-human, open-label, dose-escalation and expansion study.
- Oral administration of CB-103 in 28-day cycles with dose escalation until disease progression.
- Inclusion criteria required advanced solid tumors, including adenoid cystic carcinoma (ACC), or hematologic malignancies, with Notch-activating mutations for the confirmatory cohort.
Main Results:
- Seventy-nine patients were enrolled; the recommended Phase II dose was determined to be 500 mg twice daily (5 days on, 2 days off weekly).
- The most common Grade 3-4 treatment-related adverse events included elevated liver function tests and visual changes. No drug-related deaths occurred.
- No objective responses were observed, but 49% of patients achieved stable disease, including 58% of ACC patients. Median overall survival in the ACC cohort was 18.4 months.
Conclusions:
- CB-103 exhibits a manageable safety profile and demonstrates biological activity, evidenced by target gene downregulation.
- While CB-103 showed limited clinical antitumor activity as a monotherapy, it provided disease stabilization in a subset of NOTCH-mutant ACC patients.
- Future research should focus on NOTCH-mutant ACC and explore CB-103 in combination therapies for tumors with limited treatment options.
