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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT04862949
Other study ID # 2021-04-010-001
Secondary ID
Status Completed
Phase
First received
Last updated
Start date May 1, 2021
Est. completion date March 9, 2023

Study information

Verified date March 2023
Source CHA University
Contact n/a
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial Summary

Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related deaths globally and in Korea. Many patients diagnosed at advanced stage, and systemic therapy is mainstay of treatment in patients with advanced HCC. However, immune-checkpoint inhibitor (ICI) monotherapy did not significantly improve overall survival in phase III studies. According to previous retrospective analyses, ICI treatment in advanced HCC showed different organ-specific responses. The intrahepatic HCC was the least responsive organ to ICI treatment. The failure of phase III trials of ICI monotherapy may have been attributed to different organ-specific response pattern of ICIs. Combination of atezolizumab plus bevacizumab is expected to overcome the immunosuppressive microenvironment of liver and may enhance intrahepatic response of ICI.


Description:

In a previous retrospective analysis of pembrolizumab treated patients with advanced melanoma and NSCLC, patients with liver metastases showed poorer PFS compared with those without liver metastases with reduced ORR. Similar observations have also been reported in metastatic of triple-negative breast cancer patients, there were no responses in patients with liver metastases. Taken together the results of previous studies, hepatic metastases had reduced response to ICI compared with metastases at other organs, regardless of cancer types. In addition, ICI treatment in advanced HCC showed different organ-specific responses. The poorer response rate in liver to ICI might be affected by liver-specific immunosuppressive microenvironment (TME). To overcome the unfavorable immunosuppressive TME of the liver, combination strategies are needed to achieve enhanced anti-tumor immune responses or alleviated tumor-associated immunosuppression. Since the cause of death in most HCC patients was hepatic failure due to intrahepatic HCC or underlying liver cirrhosis, the response rate to ICI of intrahepatic tumor lesions is a crucial factor in determining the overall prognosis of advanced HCC. Therefore, we hypothesize that combination strategy of atezolizumab plus bevacizumab may increase organ specific response in patients with advanced HCC, and may improve survival outcomes accordingly. Objectives We hypothesize that combination strategy of atezolizumab plus bevacizumab may increase organ specific response in patients with advanced HCC, and may improve survival outcomes accordingly.


Recruitment information / eligibility

Status Completed
Enrollment 124
Est. completion date March 9, 2023
Est. primary completion date December 31, 2022
Accepts healthy volunteers No
Gender All
Age group 19 Years and older
Eligibility Inclusion Criteria: - Confirmed HCC pathological or non-invasive assessment according to American Association for the Study of Liver Diseases (AASLD) criteria - ECOG performance status 0 or 1 - Patients who received Atezolizumab and Bevacizumab combination therapy as first-line systemic treatment for unresectable HCC - Barcelona Clinic Liver Cancer (BCLC) stage B or C - Child-Pugh class A - Measurable lesion - Adequate hematologic and organ function Exclusion Criteria: - History of autoimmune disease - Concomitant anticoagulation at therapeutic doses. Low dose aspirin for - cardio protection is permitted.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Atezolizumab plus bevacizumab
Atezolizumab plus bevacizumab

Locations

Country Name City State
Korea, Republic of Cha Medical Center Seongnam-si Gyeonggi-do

Sponsors (2)

Lead Sponsor Collaborator
CHA University Hoffmann-La Roche

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (23)

Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, Cescon DW, Iwata H, Campone M, Nanda R, Hui R, Curigliano G, Toppmeyer D, O'Shaughnessy J, Loi S, Paluch-Shimon S, Tan AR, Card D, Zhao J, Karantza V, Cortes J. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019 Mar 1;30(3):397-404. doi: 10.1093/annonc/mdy517. — View Citation

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El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20. — View Citation

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):182-236. doi: 10.1016/j.jhep.2018.03.019. Epub 2018 Apr 5. No abstract available. Erratum In: J Hepatol. 2019 Apr;70(4):817. — View Citation

Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745. — View Citation

Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox J, Daniele B, Ebbinghaus SW, Chen E, Siegel AB, Zhu AX, Cheng AL; KEYNOTE-240 investigators. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020 Jan 20;38(3):193-202. doi: 10.1200/JCO.19.01307. Epub 2019 Dec 2. — View Citation

Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018 Mar 31;391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2. Epub 2018 Jan 5. — View Citation

Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007 Jun 20;25(18):2586-93. doi: 10.1200/JCO.2006.09.4565. — View Citation

Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018 Oct;52(Pt 2):117-124. doi: 10.1016/j.semcancer.2017.12.002. Epub 2017 Dec 8. — View Citation

Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP, Greten TF, Korangy F. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 2008 Jul;135(1):234-43. doi: 10.1053/j.gastro.2008.03.020. Epub 2008 Mar 21. Erratum In: Gastroenterology. 2011 Aug;141(2):779. — View Citation

Ji J, Eggert T, Budhu A, Forgues M, Takai A, Dang H, Ye Q, Lee JS, Kim JH, Greten TF, Wang XW. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology. 2015 Aug;62(2):481-95. doi: 10.1002/hep.27822. Epub 2015 Apr 28. — View Citation

Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH; Community of Population-Based Regional Cancer Registries. Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2014. Cancer Res Treat. 2017 Apr;49(2):292-305. doi: 10.4143/crt.2017.118. Epub 2017 Mar 9. — View Citation

Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G, Zou W. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2012 Oct;56(4):1342-51. doi: 10.1002/hep.25777. — View Citation

Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018 Oct;15(10):599-616. doi: 10.1038/s41571-018-0073-4. — View Citation

Lu LC, Hsu C, Shao YY, Chao Y, Yen CJ, Shih IL, Hung YP, Chang CJ, Shen YC, Guo JC, Liu TH, Hsu CH, Cheng AL. Differential Organ-Specific Tumor Response to Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. Liver Cancer. 2019 Nov;8(6):480-490. doi: 10.1159/000501275. Epub 2019 Aug 6. — View Citation

Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014 Jun;20(6):607-15. doi: 10.1038/nm.3541. Epub 2014 May 4. — View Citation

Pao W, Ooi CH, Birzele F, Ruefli-Brasse A, Cannarile MA, Reis B, Scharf SH, Schubert DA, Hatje K, Pelletier N, Spleiss O, Reed JC. Tissue-Specific Immunoregulation: A Call for Better Understanding of the "Immunostat" in the Context of Cancer. Cancer Discov. 2018 Apr;8(4):395-402. doi: 10.1158/2159-8290.CD-17-1320. Epub 2018 Mar 15. — View Citation

Tumeh PC, Hellmann MD, Hamid O, Tsai KK, Loo KL, Gubens MA, Rosenblum M, Harview CL, Taube JM, Handley N, Khurana N, Nosrati A, Krummel MF, Tucker A, Sosa EV, Sanchez PJ, Banayan N, Osorio JC, Nguyen-Kim DL, Chang J, Shintaku IP, Boasberg PD, Taylor EJ, Munster PN, Algazi AP, Chmielowski B, Dummer R, Grogan TR, Elashoff D, Hwang J, Goldinger SM, Garon EB, Pierce RH, Daud A. Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. Cancer Immunol Res. 2017 May;5(5):417-424. doi: 10.1158/2326-6066.CIR-16-0325. Epub 2017 Apr 14. — View Citation

Uka K, Aikata H, Takaki S, Shirakawa H, Jeong SC, Yamashina K, Hiramatsu A, Kodama H, Takahashi S, Chayama K. Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol. 2007 Jan 21;13(3):414-20. doi: 10.3748/wjg.v13.i3.414. — View Citation

Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, Zinzindohoue F, Yagita H, Tartour E, Taieb J, Terme M. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015 Feb 9;212(2):139-48. doi: 10.1084/jem.20140559. Epub 2015 Jan 19. — View Citation

Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D, Li XF, Zheng L. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology. 2013 Mar;57(3):1107-16. doi: 10.1002/hep.26192. Epub 2013 Jan 18. — View Citation

Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6. Epub 2018 Jun 3. Erratum In: Lancet Oncol. 2018 Sep;19(9):e440. — View Citation

* Note: There are 23 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Organ-specific response rate Organ-specific response rate were established to evaluate the heterogenous responses of different organ systems to immunotherapy in previous analysis. We select the largest lesions representative of involved organs (up to a maximum of two per organ and five total). Lesions of each organ were measured unidimensionally. Each lesion will be evaluated according to RECIST 1.1 (CR, complete disappearance or LN short axis diameter < 1.0cm; PR, =30% reduction; PD, =20% increase; SD, neither CR, PR nor PD). New lesions did not always indicate PD, and were added to those of the original target lesions to determine the total tumor burden. 1 year
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