Clinical trial NCT03892577: Real-world Study for Patients With Advanced Hepatobiliary Tumors
Official title: Real-world Study for Targeted Therapy and Immunotherapy in Patients With Advanced Hepatobiliary Tumors: a Multi-centers, Open-assess Observational Study.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Objective Response Rate
Progression-free Survival
Overall Survival
Disease Control Rate
Duration of Response
Five-year Survival Rate
Quality of Life
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
Collaborators: name: OrigiMed
First posted: 2019-03-27
Enrollment: 3000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients With Advanced Hepatobilary Tumors.

Brief summary: The investigators design a large sample size study in the real-world to explore whether targeted therapy and immunotherapy can improve the survival, quality of life and drug safety of patients with advanced hepatobiliary tumors, and analyze the correlation between genetic variation and the effectiveness of therapy.

Detailed description: This trial is a multicenter, non-random, open and observational real-world study. It is estimated that 2000 patients with advanced hepatobiliary tumors will be enrolled in about 20 research centers. And it is planned to complete the enrollment within 2 years and it is expected that all enrolled subjects will reach the observation end point in 5 years.

After primary screening of all the patients, the investigators will further collect next-generation sequence(NGS) data and immunohistochemical data from the subjects, and enroll patients with any type of the following three treatment program: 1. Monotherapy or combination therapy with the targeted drug related to genetic variation of the subject; 2. Treatment with pan-target anti-angiogenic drugs, such as sorafenib, regorafenib, lenvatinib, apatinib, etc; 3. Immunotherapy or immunotherapy combined with targeted therapy.

The investigators will collect subjects' data from assessment centers each month and the efficacy, quality of life, and safety of treatment will be evaluated.

This trial plans to conduct an interim analysis and final analysis after collecting 500 cases, 1000 cases, and 2000 subjects, 3000 subjects,and explore the clinical application value of targeted therapy and immunotherapy in advanced hepatobiliary tumors in real world.

Eligibility criteria: Inclusion Criteria:

Subjects must meet all of the following criteria：

1. ≥18 years old, gender is not limited, and life expectancy is at least 6 months.
2. Diagnosed as primary liver cancer or biliary malignant tumor by histopathology or confirmed by imaging as HCC (by the American Association for the Study of Liver Diseases or standard for the diagnosis and treatment of primary liver cancer 2017 in China).
3. The Barcelona staging classification: class B-C.
4. Child-Pugh classification: class A-B.
5. At least one measurable lesion (RECIST v1.1)
6. Unable to perform radical surgery or patient refuse surgery.
7. Subjects need palliative treatment, and have received or are undergoing any of the following three treatments:

   * Monotherapy or combination therapy with targeted drug associated with genetic variation in the subject.
   * Or, treat with pan-target anti-vascular drugs, such as sorafenib, regorafenib, lenvatinib, apatinib.
   * Or, immunotherapy or immunotherapy combined with targeted therapy or (and) classical chemotherapy.
8. Subjects volunteer to participate in the study and sign informed consent.

Exclusion Criteria:

Patients with one or more of the following criteria should be excluded:

1. Patients with early hepatobiliary tumor.
2. The Barcelona staging classification: class A.
3. Child-Pugh classification: class C.
4. Radical surgical resection.
5. CT or MRI shows unclear tumor boundary or no measurable lesions (RECIST v1.1).
6. Drug abuse, or any medical, psychological, or social condition that may affect the study, patient compliance, or even compromise the safety of the patient.
7. Conduct other experimental drug treatments other than this test within 4 weeks before the start of the study; or participate in another clinical study that has an impact on the results of this study.
8. Mental or medical instability makes patients unable or unwilling to sign informed consent.
9. Patients after comprehensive assessment are considered by the investigators to be unsuitable for participating in the study.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: two years
measure: Progression-free Survival (PFS)
timeFrame: six months
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: one year
measure: Disease Control Rate (DCR)
timeFrame: six months
measure: Incidence of Treatment-Emergent Adverse Event
timeFrame: one year
measure: Quality of Life (QoL) after treatment
timeFrame: one year
Other outcomes:
Locations:
city: Beijing
country: China
facility: Chinese Academy of Medical Sciences & Peking Union Medical College Hospital
state: Beijing
Study officials:
affiliation: Chinese Academy of Medical Sciences & Peking Union Medical College Hospital
name: Haitao Zhao
role: STUDY_CHAIR
References:
citation: Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016 Mar-Apr;66(2):115-32. doi: 10.3322/caac.21338. Epub 2016 Jan 25.
citation: Moriguchi M, Umemura A, Itoh Y. Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma. Clin J Gastroenterol. 2016 Aug;9(4):184-90. doi: 10.1007/s12328-016-0670-7. Epub 2016 Jul 11.
citation: Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857.
citation: Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10(1):25-34. doi: 10.1016/S1470-2045(08)70285-7. Epub 2008 Dec 16.
citation: Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, Raina V, Shukla NK, Thulkar S, Garg P, Chaudhary SP. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol. 2010 Oct 20;28(30):4581-6. doi: 10.1200/JCO.2010.29.3605. Epub 2010 Sep 20.
citation: Rodriguez R, Miller KM. Unravelling the genomic targets of small molecules using high-throughput sequencing. Nat Rev Genet. 2014 Dec;15(12):783-96. doi: 10.1038/nrg3796. Epub 2014 Oct 14.
citation: Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. doi: 10.1056/NEJMoa0908721.
citation: Hofstatter E, Mehra K, Yushak M, Pusztai L. Tumor profiling and the incidentalome: patient decisions and risks. Future Oncol. 2015;11(24):3299-305. doi: 10.2217/fon.15.260. Epub 2015 Nov 12.
citation: Endrullat C, Glokler J, Franke P, Frohme M. Standardization and quality management in next-generation sequencing. Appl Transl Genom. 2016 Jul 1;10:2-9. doi: 10.1016/j.atg.2016.06.001. eCollection 2016 Sep.
citation: Gadgeel SM. Personalized Therapy of Non-small Cell Lung Cancer (NSCLC). Adv Exp Med Biol. 2016;890:203-22. doi: 10.1007/978-3-319-24932-2_11.
citation: Millner LM, Strotman LN. The Future of Precision Medicine in Oncology. Clin Lab Med. 2016 Sep;36(3):557-73. doi: 10.1016/j.cll.2016.05.003.
citation: Drilon A, Wang L, Arcila ME, Balasubramanian S, Greenbowe JR, Ross JS, Stephens P, Lipson D, Miller VA, Kris MG, Ladanyi M, Rizvi NA. Broad, Hybrid Capture-Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches. Clin Cancer Res. 2015 Aug 15;21(16):3631-9. doi: 10.1158/1078-0432.CCR-14-2683. Epub 2015 Jan 7.
citation: Li S, Mao M. Next generation sequencing reveals genetic landscape of hepatocellular carcinomas. Cancer Lett. 2013 Nov 1;340(2):247-53. doi: 10.1016/j.canlet.2012.09.027. Epub 2012 Oct 12.
citation: Schulze K, Nault JC, Villanueva A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol. 2016 Nov;65(5):1031-1042. doi: 10.1016/j.jhep.2016.05.035. Epub 2016 Jun 2.
citation: Wang YY, Yang X, Wang YC, Long JY, Sun HS, Li YR, Xun ZY, Zhang N, Xue JN, Ning C, Zhang JW, Zhu CP, Zhang LH, Yang XB, Zhao HT. Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma. World J Gastroenterol. 2023 Mar 14;29(10):1614-1626. doi: 10.3748/wjg.v29.i10.1614.
citation: Yang X, Chen B, Wang Y, Wang Y, Long J, Zhang N, Xue J, Xun Z, Zhang L, Cheng J, Lei J, Sun H, Li Y, Lin J, Xie F, Wang D, Pan J, Hu K, Guan M, Huo L, Shi J, Yu L, Zhou L, Zhou J, Lu Z, Yang X, Mao Y, Sang X, Lu Y, Zhao H. Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients. Hepatol Int. 2023 Jun;17(3):709-719. doi: 10.1007/s12072-022-10480-y. Epub 2023 Feb 8.
citation: Zhu C, Xue J, Wang Y, Wang S, Zhang N, Wang Y, Zhang L, Yang X, Long J, Yang X, Sang X, Zhao H. Efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors plus Gemox chemotherapy in advanced biliary tract cancer. Front Immunol. 2023 Jan 18;14:1109292. doi: 10.3389/fimmu.2023.1109292. eCollection 2023.
citation: Xie F, Chen B, Yang X, Wang H, Zhang G, Wang Y, Wang Y, Zhang N, Xue J, Long J, Li Y, Sun H, Xun Z, Liu K, Chen X, Song Y, Yang X, Lu Z, Mao Y, Sang X, Lu Y, Zhao H. Efficacy of immune checkpoint inhibitors plus molecular targeted agents after the progression of lenvatinib for advanced hepatocellular carcinoma. Front Immunol. 2022 Dec 9;13:1052937. doi: 10.3389/fimmu.2022.1052937. eCollection 2022.
citation: Chen B, Lei J, Zhao H, Dong J, Zeng Z, Li Y, Yu L, Zhou L, Jia A, Lu Y, Cheng J. Efficacy and Safety of TKI Plus PD-1 Inhibitors in Elderly uHCC Patients: A Retrospective Study. J Hepatocell Carcinoma. 2022 Nov 8;9:1171-1185. doi: 10.2147/JHC.S387254. eCollection 2022.
citation: Ning C, Zhang X, Yang X, Sang X, Zhao H, Wang H. Conversion therapy of stage IVb unresectable gallbladder carcinoma. Hepatobiliary Surg Nutr. 2022 Apr;11(2):335-337. doi: 10.21037/hbsn-22-78. No abstract available.
citation: Zuo B, Yang X, Yang X, Bian J, Long J, Wang D, Ning C, Wang Y, Xun Z, Wang Y, Lu X, Mao Y, Sang X, Zhao H. A real-world study of the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer. Cancer Immunol Immunother. 2022 Aug;71(8):1889-1896. doi: 10.1007/s00262-021-03121-0. Epub 2022 Jan 13.
citation: Mao J, Wang D, Long J, Yang X, Lin J, Song Y, Xie F, Xun Z, Wang Y, Wang Y, Li Y, Sun H, Xue J, Song Y, Zuo B, Zhang J, Bian J, Zhang T, Yang X, Zhang L, Sang X, Zhao H. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. J Immunother Cancer. 2021 Dec;9(12):e003334. doi: 10.1136/jitc-2021-003334.
citation: Yang X, Xu H, Zuo B, Yang X, Bian J, Long J, Wang D, Zhang J, Ning C, Wang Y, Xun Z, Wang Y, Lu X, Mao Y, Sang X, Zhao H. Downstaging and resection of hepatocellular carcinoma in patients with extrahepatic metastases after stereotactic therapy. Hepatobiliary Surg Nutr. 2021 Aug;10(4):434-442. doi: 10.21037/hbsn-21-188.
citation: Yang X, Hu Y, Yang K, Wang D, Lin J, Long J, Xie F, Mao J, Bian J, Guan M, Pan J, Huo L, Hu K, Yang X, Mao Y, Sang X, Zhang J, Wang X, Zhang H, Zhao H. Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers. J Immunother Cancer. 2021 May;9(5):e001942. doi: 10.1136/jitc-2020-001942.
citation: Wang DX, Yang X, Lin JZ, Bai Y, Long JY, Yang XB, Seery S, Zhao HT. Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: A retrospective, real-world study conducted in China. World J Gastroenterol. 2020 Aug 14;26(30):4465-4478. doi: 10.3748/wjg.v26.i30.4465.
citation: Lin J, Yang X, Long J, Zhao S, Mao J, Wang D, Bai Y, Bian J, Zhang L, Yang X, Wang A, Xie F, Shi W, Yang H, Pan J, Hu K, Guan M, Zhao L, Huo L, Mao Y, Sang X, Wang K, Zhao H. Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma. Hepatobiliary Surg Nutr. 2020 Aug;9(4):414-424. doi: 10.21037/hbsn-20-338.