A phase I/II study of capecitabine combined with peginterferon alfa-2a in sorafenib-refractory advanced hepatocellular carcinoma patients.

346 Background: Several studies have demonstrated the effectiveness of combining a pyrimidine fluoride drug with interferon. Therefore, this study examined the dose of capecitabine in combination with peginterferon alfa-2a (PEG-IFN α-2a) (Phase I part) and evaluated its safety and efficacy in sorafenib-refractory advanced hepatocellular carcinoma patients (Phase II part). Methods: Capecitabine was administrated daily on days 1–14 and PEG-IFN α-2a was given on days 1, 8, and 15. The cycles were repeated every 21 days. Patients were scheduled to received capecitabine (mg/m2/day) and PEG-IFN α-2a (μg/week) at one of three dose levels in phase I: 1200/90, 1600/90, and 2000/90 (levels 1–3, respectively). Results: Thirty patients were enrolled. The recommended dose was level 3. Of the 24 patients given the drug at the recommended dosage, two (8%) showed partial responses, nine (38%) had stable disease, ten (42%) had progressive disease, and three (13%) were not evaluated. The median time to progression was 3.0 months. The most common toxicities were decreased white blood cell, neutrophil, and platelet counts, palmar-plantar erythrodysesthesia syndrome, and fatigue. Dose modification was required in ten (42%) patients. Four (17%) patients discontinued treatment because of severe adverse events. Conclusions: Capecitabine at 2000 mg/m2/day combined with PEG-IFN α-2a 90 μg/week had moderate, but manageable toxicity. Further investigation is needed to refine the efficacy. Clinical trial information: UMIN000005697.

Download Full-text

Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial

Radiation Oncology ◽

10.1186/s13014-020-01742-w ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Kai-Lin Yang ◽

Mau-Shin Chi ◽

Hui-Ling Ko ◽

Yi-Ying Huang ◽

Su-Chen Huang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Phase I ◽

Response Rate ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Normal Liver ◽

Maximum Tolerated Dose ◽

Outcome Analysis ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc

Abstract Background To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1–3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC). Methods This phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local–regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS). Results Total nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months. Conclusions Axitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort. Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461

Download Full-text

Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study

Journal of Clinical Oncology ◽

10.1200/jco.2012.47.3009 ◽

2013 ◽

Vol 31 (28) ◽

pp. 3509-3516 ◽

Cited By ~ 359

Author(s):

Josep M. Llovet ◽

Thomas Decaens ◽

Jean-Luc Raoul ◽

Eveline Boucher ◽

Masatoshi Kudo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Controlled Trial ◽

Objective Response ◽

Phase Iii ◽

Advanced Hepatocellular Carcinoma ◽

Time To Progression ◽

Fibroblast Growth Factor Receptors ◽

Double Blind ◽

Dual Inhibitor

Purpose Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. Patients and Methods In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. Results Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). Conclusion In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

Download Full-text

CheckMate 040 Cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis

Journal of Hepatology ◽

10.1016/j.jhep.2021.04.047 ◽

2021 ◽

Author(s):

Masatoshi Kudo ◽

Ana Matilla ◽

Armando Santoro ◽

Ignacio Melero ◽

Antonio Cubillo Gracián ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Phase I ◽

Advanced Hepatocellular Carcinoma

Download Full-text

The Efficacy of Continued Sorafenib Treatment after Radiologic Confirmation of Progressive Disease in Patients with Advanced Hepatocellular Carcinoma

PLoS ONE ◽

10.1371/journal.pone.0146456 ◽

2016 ◽

Vol 11 (1) ◽

pp. e0146456 ◽

Cited By ~ 8

Author(s):

Yoshiyuki Wada ◽

Yuko Takami ◽

Masaki Tateishi ◽

Tomoki Ryu ◽

Kazuhiro Mikagi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Progressive Disease ◽

Advanced Hepatocellular Carcinoma ◽

Sorafenib Treatment

Download Full-text

Adoptive Transfer of Autologous Invariant NKT Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial

The Oncologist ◽

10.1002/onco.13899 ◽

2021 ◽

Author(s):

Yao Gao ◽

Jia Guo ◽

Xuli Bao ◽

Fang Xiong ◽

Yanpin Ma ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trial ◽

Phase I ◽

Adoptive Transfer ◽

Nkt Cells ◽

Phase I Clinical Trial ◽

Advanced Hepatocellular Carcinoma ◽

Invariant Nkt Cells

Download Full-text

Combining radiation therapy with anti-PD-1 for patients with advanced hepatocellular carcinoma: An open-label, single-center, single-arm clinical study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16117 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16117-e16117

Author(s):

Jian-Xu Li ◽

Ting-Shi Su ◽

Xiao-Feng Lin ◽

Yi-Tian Chen ◽

Shi-Xiong Liang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trial ◽

Radiation Therapy ◽

Clinical Study ◽

Cancer Staging ◽

Advanced Hepatocellular Carcinoma ◽

Single Center ◽

Open Label ◽

Grade 3 ◽

Clinical Trial Information

e16117 Combining radiation therapy with anti-PD-1 for patients with advanced hepatocellular carcinoma: an open-label, single-center, single-arm clinical study Jian-Xu Li, Ting-Shi Su, Xiao-Feng Lin, Yi-Tian Chen, Shi-Xiong Liang, Bang-De Xiang; Guangxi Medical University Cancer Hospital, Nanning, China Abstract Research Funding: Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China. Guangxi Medical and Health Appropriate Technology Development and Application Project (No. S2019039), Guangxi, China. Background: Based on the results of recent studies, the PD-1 monoclonal antibodies have been approved to treat the patients with advanced hepatocellular carcinoma (HCC) by the FDA. Radiation therapy (RT) can enhance responsiveness to PD-1 monoclonal antibody by potential mechanisms. A phase Ⅱa study was conducted to assess the safety and the efficacy of combining RT with anti-PD-1 for patients with advanced hepatocellular carcinoma. Methods: Patients with advanced HCC were eligible. Stereotactic body radiation therapy (SBRT) were adopted, and the dose of radiation were Dt-PGTV 30-50 Gy/10fractions. Camrelizumab (200mg) were given intravenously every 3 weeks since the first day of RT until disease progression, or intolerable toxicity. Adverse events (AEs) and objective response rate (ORR) were summarized to assess the safety and efficacy. Results: From April 2020 to November 2020, 17 patients were enrolled (median age 54, range 32-69). 15 (88%) patients were male. 14 (82%) had ECOG performance score of 0. All the patients had Child-Pugh score A. 16 patients staged as Barcelona Clinic Liver Cancer staging C or China Liver Cancer staging Ⅲ. Extrahepatic metastases were identified in 11 (65%) patients. 13 (77%) patients were Hepatitis B virus infected. 15 (88%) patients had previously 2 lines or more chemotherapy. 9 (53%) patients had Alpha-fetoprotein level≥400 ng/ml. The ORR was 47%. The best response assessed by RECIST 1.1 was partial response (8 patients). Four patients had grade 3 immune-related adverse events (irAEs), including increased aspartate aminotransferase and alanine transaminase (n =1)，decreased hemoglobin (n =1)，decreased platelet count (n =1)，decreased neutrophil count (n =1). All grade 3 irAEs were mitigated with proper treatment. None treatment-related deaths occurred. Conclusions: In this study, RT combined with anti-PD-1 had an acceptable safety profile and indicated an effective treatment option in patients with unresectable HCC. Clinical trial information: NCT04193696. Clinical trial information: NCT04193696.

Download Full-text

A real-world study of camrelizumab in the treatment of hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16121 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16121-e16121

Author(s):

Yong-Yi Zeng ◽

Wu-hua Guo ◽

Zhibo Zhang ◽

Xi Shi ◽

Yongjie Su ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trial ◽

Real World ◽

Group Performance ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Chinese Patients ◽

Advanced Hepatocellular Carcinoma ◽

Phase Ii Studies ◽

Clinical Trial Information

e16121 Background: Programmed cell death protein‐1(PD-1) targeted immunotherapy is a promising treatment strategy for advanced hepatocellular carcinoma. Anti-PD-1 inhibitor camrelizumab showed antitumour activity in phase II studies of advanced hepatocellular carcinoma, with manageable toxicities. This study evaluates safety and efficacy of camrelizumab in patients with advanced hepatocellular carcinoma. Methods: This is a multicentre, real‐world trial done at thirty-three centres in Fujian Province, China. Eligible patients were aged 18 to 75 years was diagnosed by China Liver Cancer Staging(CNLC) 2019 clinical diagnostic criteria or with a histological or cytological diagnosis of advanced hepatocellular carcinoma, unresectable or had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were received camrelizumab 200 mg intravenously every 2 weeks plus other treatments, such as molecular targeted drug, transcatheyer artetial chemoembolization, radiotherapy and chemotherapy. The primary endpoints were progression-free survival. Safety was analysed in all treated patients. Follow-up is ongoing. Results: Between Mar 12, 2020, and Dec 25, 2020, 63 patients were screened for eligibility, of whom 41 eligible patients received camrelizumab were recruited and among whom 15 received apatinib, 16 received lenvatinib, 2 received sorafenib and 1 received regorafenib. Median followup was 5.28 months (IQR 1.63–10.20). Objective response was reported in 12 (29.3%; 95% CI 16.1–45.5) of 41 patients. Disease control was reported in 34 (82.9%; 95% CI 67.9–92.8) of 41 patients. The median PFS was not reached, and expected more than 9 months. Grade 3 or 4 treatment-related adverse events occurred in 21 (51.2%) of 41 patients; the most common were increased gamma-glutamyltransferase (15 [36.6%]) and increased aspartate aminotransferase (7 [17%]). One death was judged by the investigators to be potentially treatment-related (due to upper gastrointestinal bleeding). Conclusions: Camrelizumab showed promising efficacy and safety in pretreated Chinese patients with advanced hepatocellular carcinoma, and might represent a new treatment option for these patients. Clinical trial information: ChiCTR2000041405. Research Sponsor: Jiangsu Hengrui Medicine Co., Ltd. Clinical trial information: ChiCTR2000041405.

Download Full-text