Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma Journal Article
| Authors: | Harding, J. J.; Do, R. K.; Yaqubie, A.; Cleverly, A.; Zhao, Y.; Gueorguieva, I.; Lahn, M.; Benhadji, K. A.; Kelley, R. K.; Abou-Alfa, G. K. |
| Article Title: | Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma |
| Abstract: | Background: Preclinical 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). Methods: This 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. Results: Eight 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. Conclusion: Combination 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. © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. |
| Keywords: | adult; clinical article; aged; constipation; fatigue; hepatocellular carcinoma; advanced cancer; diarrhea; drug efficacy; drug safety; gastrointestinal hemorrhage; hepatic encephalopathy; liver cell carcinoma; prospective study; multiple cycle treatment; pain; transforming growth factor beta; nausea; vomiting; cohort analysis; antineoplastic activity; abdominal pain; chill; coughing; dyspnea; fever; bilirubin; confusion; thorax pain; multicenter study; muscle weakness; peripheral edema; xerostomia; virus infection; headache; drug blood level; maximum tolerated dose; phase 1 clinical trial; disease control; portal vein thrombosis; epistaxis; neuroectoderm tumor; phase 1; cerebrovascular accident; upper respiratory tract infection; alpha fetoprotein; dysgeusia; sore throat; vegf; hcc; tgf-β; oncological parameters; nocturia; response evaluation criteria in solid tumors; stomach distension; ramucirumab; objective response rate; human; male; female; priority journal; article; galunisertib; alpha fetoprotein blood level; pancreatic neuroectodermal tumor; viral syndrome |
| Journal Title: | Cancer Medicine |
| Volume: | 10 |
| Issue: | 9 |
| ISSN: | 2045-7634 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2021-05-01 |
| Start Page: | 3059 |
| End Page: | 3067 |
| Language: | English |
| DOI: | 10.1002/cam4.3880 |
| PUBMED: | 33811482 |
| PROVIDER: | scopus |
| PMCID: | PMC8085979 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2021 -- Source: Scopus |
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