1. Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma
- Author
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Harding, James J, K., Richard, Yaqubie, Amin, Cleverly, Ann, Zhao, Yumin, Gueorguieva, Ivelina, Lahn, Michael, Benhadji, Karim A, Kelley, Robin K, and Abou‐Alfa, Ghassan K
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Clinical Research ,Digestive Diseases ,Liver Disease ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,Hepatocellular ,Female ,Humans ,Liver Neoplasms ,Male ,Maximum Tolerated Dose ,Middle Aged ,Nausea ,Prospective Studies ,Pyrazoles ,Quinolines ,Receptor ,Transforming Growth Factor-beta Type I ,Response Evaluation Criteria in Solid Tumors ,Vascular Endothelial Growth Factor A ,Vascular Endothelial Growth Factor Receptor-2 ,Vomiting ,alpha-Fetoproteins ,galunisertib ,HCC ,hepatocellular carcinoma ,Phase 1 ,ramucirumab ,TGF‐ ,β ,VEGF ,TGF-β ,Biochemistry and Cell Biology ,Oncology and carcinogenesis - Abstract
BackgroundPreclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF-targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC).MethodsThis is a multicenter, open-label, phase 1b study of galunisertib, an inhibitor of TGF-β receptor 1, and ramucirumab, an anti-VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha-fetoprotein and TGF-β kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1-14 of a 28-day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks.ResultsEight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose-limiting toxicities were observed. Treatment-related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment-related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose-proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively.ConclusionCombination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFβ signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.
- Published
- 2021