PMID- 33811482 OWN - NLM STAT- MEDLINE DCOM- 20210720 LR - 20231213 IS - 2045-7634 (Electronic) IS - 2045-7634 (Linking) VI - 10 IP - 9 DP - 2021 May TI - Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma. PG - 3059-3067 LID - 10.1002/cam4.3880 [doi] AB - BACKGROUND: Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta 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-beta 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-beta 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 TGFbeta signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab. CI - (c) 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Harding, James J AU - Harding JJ AUID- ORCID: 0000-0002-7029-4310 AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Weill Cornell Medical College, New York, NY, USA. FAU - Do, Richard K AU - Do RK AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Weill Cornell Medical College, New York, NY, USA. FAU - Yaqubie, Amin AU - Yaqubie A AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Cleverly, Ann AU - Cleverly A AD - Elli Lilly and Company, Indianapolis, IN, USA. FAU - Zhao, Yumin AU - Zhao Y AD - Elli Lilly and Company, Indianapolis, IN, USA. FAU - Gueorguieva, Ivelina AU - Gueorguieva I AD - Elli Lilly and Company, Indianapolis, IN, USA. FAU - Lahn, Michael AU - Lahn M AD - Elli Lilly and Company, Indianapolis, IN, USA. FAU - Benhadji, Karim A AU - Benhadji KA AD - Elli Lilly and Company, Indianapolis, IN, USA. FAU - Kelley, Robin K AU - Kelley RK AD - Helen Diller Cancer Center, University of California San Francisco, San Francisco, CA, USA. FAU - Abou-Alfa, Ghassan K AU - Abou-Alfa GK AUID- ORCID: 0000-0002-1522-8054 AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Weill Cornell Medical College, New York, NY, USA. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20210402 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 RN - 0 (AFP protein, human) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Pyrazoles) RN - 0 (Quinolines) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0 (alpha-Fetoproteins) RN - 700874-72-2 (LY-2157299) RN - EC 2.7.10.1 (KDR protein, human) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2) RN - EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type I) RN - EC 2.7.11.30 (TGFBR1 protein, human) SB - IM MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal, Humanized/*administration & dosage/adverse effects/pharmacokinetics MH - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects MH - Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology MH - Female MH - Humans MH - Liver Neoplasms/*drug therapy/metabolism/pathology MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Nausea/chemically induced MH - Prospective Studies MH - Pyrazoles/*administration & dosage/adverse effects/pharmacokinetics MH - Quinolines/*administration & dosage/adverse effects/pharmacokinetics MH - Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors MH - Response Evaluation Criteria in Solid Tumors MH - Vascular Endothelial Growth Factor A/metabolism MH - Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors MH - Vomiting/chemically induced MH - alpha-Fetoproteins/analysis MH - Ramucirumab PMC - PMC8085979 OTO - NOTNLM OT - HCC OT - Phase 1 OT - TGF-beta OT - VEGF OT - galunisertib OT - hepatocellular carcinoma OT - ramucirumab COIS- JJH has received research support from Bristol Myers Squibb, and has received consulting fees from Eli Lilly, Exelexis, Eisai, Bristol Myers Squibb, CytomX, Imvax, and Merck. RKD and AY report no relevant relationships with commercial entities. AC, YZ, IG, and ML are employees of and own stock in Elli Lilly. KAB is an employee of and owns stock in Taiho Oncology. RKK has received personal fees from Genentech/Roche and Gilead, and research funding from Adaptimmune, Agios, AstraZeneca, Bayer, Bristol Myers Squibb, EliLilly, Exelixis, EMD Serono, Merck, Novartis, QED, Taiho, Partner Therapeutics, and Ipsen. GKA has received research support from ActaBiologica, Agios, Astra Zeneca, Bayer, Beigene, Berry Genomics, BMS, Casi, Celgene, Exelixis, Genentech/Roche, Halozyme, Incyte, Mabvax, Puma, QED, Sillajen, and Yiviva; and consulting fees from Agios, Astra Zeneca, Autem, Bayer, Beigene, Berry Genomics, Celgene, CytomX, Debio, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Gilead, Helio, Incyte, Ipsen, Loxo, Merck, MINA, Polaris, QED, Redhill, Silenseed, Sillajen, Sobi, Therabionics, Twoxar, Vector, and Yiviva. EDAT- 2021/04/04 06:00 MHDA- 2021/07/21 06:00 PMCR- 2021/04/02 CRDT- 2021/04/03 06:03 PHST- 2021/03/15 00:00 [revised] PHST- 2020/12/29 00:00 [received] PHST- 2021/03/16 00:00 [accepted] PHST- 2021/04/04 06:00 [pubmed] PHST- 2021/07/21 06:00 [medline] PHST- 2021/04/03 06:03 [entrez] PHST- 2021/04/02 00:00 [pmc-release] AID - CAM43880 [pii] AID - 10.1002/cam4.3880 [doi] PST - ppublish SO - Cancer Med. 2021 May;10(9):3059-3067. doi: 10.1002/cam4.3880. Epub 2021 Apr 2.