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A Phase I Study of the Pan-Notch Inhibitor CB-103 for Patients with Advanced Adenoid Cystic Carcinoma and Other Tumors
DC Field | Value | Language |
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dc.contributor.author | 김혜련 | - |
dc.date.accessioned | 2024-05-30T06:54:00Z | - |
dc.date.available | 2024-05-30T06:54:00Z | - |
dc.date.issued | 2023-09 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/199429 | - |
dc.description.abstract | 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. | - |
dc.description.statementOfResponsibility | open | - |
dc.language | English | - |
dc.publisher | American Association for Cancer Research | - |
dc.relation.isPartOf | CANCER RESEARCH COMMUNICATIONS | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.subject.MESH | Aggression | - |
dc.subject.MESH | Antineoplastic Agents* | - |
dc.subject.MESH | Carcinoma, Adenoid Cystic* / drug therapy | - |
dc.subject.MESH | Disease Progression | - |
dc.subject.MESH | Hematologic Neoplasms* | - |
dc.subject.MESH | Humans | - |
dc.title | A Phase I Study of the Pan-Notch Inhibitor CB-103 for Patients with Advanced Adenoid Cystic Carcinoma and Other Tumors | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine (의과대학) | - |
dc.contributor.department | Dept. of Internal Medicine (내과학교실) | - |
dc.contributor.googleauthor | Glenn J Hanna | - |
dc.contributor.googleauthor | Anastasios Stathis | - |
dc.contributor.googleauthor | Elena Lopez-Miranda | - |
dc.contributor.googleauthor | Fabricio Racca | - |
dc.contributor.googleauthor | Doris Quon | - |
dc.contributor.googleauthor | Serge Leyvraz | - |
dc.contributor.googleauthor | Dagmar Hess | - |
dc.contributor.googleauthor | Bhumsuk Keam | - |
dc.contributor.googleauthor | Jordi Rodon | - |
dc.contributor.googleauthor | Myung-Ju Ahn | - |
dc.contributor.googleauthor | Hye Ryun Kim | - |
dc.contributor.googleauthor | Andreas Schneeweiss | - |
dc.contributor.googleauthor | Josep-Maria Ribera | - |
dc.contributor.googleauthor | Daniel DeAngelo | - |
dc.contributor.googleauthor | Jose Manuel Perez Garcia | - |
dc.contributor.googleauthor | Javier Cortes | - |
dc.contributor.googleauthor | Oliver Schönborn-Kellenberger | - |
dc.contributor.googleauthor | Dirk Weber | - |
dc.contributor.googleauthor | Pavel Pisa | - |
dc.contributor.googleauthor | Michael Bauer | - |
dc.contributor.googleauthor | Laura Beni | - |
dc.contributor.googleauthor | Maria Bobadilla | - |
dc.contributor.googleauthor | Raj Lehal | - |
dc.contributor.googleauthor | Michele Vigolo | - |
dc.contributor.googleauthor | Florian D Vogl | - |
dc.contributor.googleauthor | Elena Garralda | - |
dc.identifier.doi | 10.1158/2767-9764.CRC-23-0333 | - |
dc.contributor.localId | A01166 | - |
dc.relation.journalcode | J04585 | - |
dc.identifier.eissn | 2767-9764 | - |
dc.identifier.pmid | 37712875 | - |
dc.contributor.alternativeName | Kim, Hye Ryun | - |
dc.contributor.affiliatedAuthor | 김혜련 | - |
dc.citation.volume | 3 | - |
dc.citation.number | 9 | - |
dc.citation.startPage | 1853 | - |
dc.citation.endPage | 1861 | - |
dc.identifier.bibliographicCitation | CANCER RESEARCH COMMUNICATIONS, Vol.3(9) : 1853-1861, 2023-09 | - |
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