A phase I/II trial to evaluate cabozantinib in patients with advanced hepatocellular carcinoma with Child-Pugh class B cirrhosis after first-line therapy.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS357-TPS357
Author(s):  
Thomas Enzler ◽  
Neehar Parikh ◽  
Chih-Yi Liao ◽  
Aparna Kalyan ◽  
David Hsieh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Systemic Treatment ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
Early Stage Disease ◽  
Advanced Hcc ◽  
Line Therapy ◽  
Class B ◽  
Pugh Class

TPS357 Background: Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer related death worldwide. HCC typically develops in patients with cirrhosis and has a 5-year survival estimate of 20%. Only patients with early stage disease may be eligible for a curative approach using local treatment and/or transplant. The majority of patient present with advanced HCC and will require systemic treatment for disease control. Several systemic therapies are FDA-approved for the treatment of HCC; however, they are only approved for patients with Child-Pugh class A cirrhosis. There are limited data and no approved second-line therapy for HCC with more advanced cirrhosis, including Child-Pugh class B, which represents a significant proportion of patients. The aim of this trial is to determine the safety and efficacy of cabozantinib, a multi-kinase inhibitor, in patients with HCC with Child-Pugh class B cirrhosis. Methods: This investigator-initiated, phase I/II study is enrolling 32 patients with advanced HCC, Child-Pugh B7 or B8, who have previously received first-line systemic treatment. Patients receive cabozantinib at one of 3 dose levels (20 mg, 40 mg, and 60 mg) with a starting dose level of 40 mg to evaluate the safety profile and obtain the recommended phase 2 dose (RP2D). The primary endpoint is assessment of dose-limiting toxicity with a null hypothesis greater than 35%. Secondary endpoints include ORR per RECIST v1.1, PFS, OS, and PK profile. Exploratory endpoints include whole exome/RNAseq analysis (including MET, VEGF, AXL, and immune signature), spatial profiling of immune markers by multiplex immunofluorescence, and specimen banking (tissue, blood and imaging). The trial design is based on the Time-To-Event modification of the Continual Reassessment Method (TiTE-CRM), which allows for continued monitoring of toxicity as a function of a dose-over-time, and is flexible with regard to the number of patients treated at a certain dose. The trial is open at University of Michigan as lead and coordinating site, and due to open at 3 additional high-volume centers. Clinical trial information: 04497038.

scholarly journals Potential of Lenvatinib for an Expanded Indication from the REFLECT Trial in Patients with Advanced Hepatocellular Carcinoma

Liver Cancer ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 382-396 ◽  
Author(s):  
Susumu Maruta ◽  
Sadahisa Ogasawara ◽  
Yoshihiko Ooka ◽  
Masamichi Obu ◽  
Masanori Inoue ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Function ◽  
Objective Response ◽  
Dose Intensity ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
High Burden ◽  
Advanced Hcc ◽  
Class B ◽  
Pugh Class

Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial. Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan. Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7–6.9 for first line, 4.8 months; 95% CI 3.8–5.9 for second or later line, p = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin – bilirubin scores. Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.

scholarly journals A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

2016 ◽  
Vol 23 (10) ◽  
pp. 2405-2413 ◽  
Author(s):  
Thomas C.C. Yau ◽  
Riccardo Lencioni ◽  
Wattana Sukeepaisarnjaroen ◽  
Yee Chao ◽  
Chia-Jui Yen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Multicenter Study ◽  
Single Agent ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

scholarly journals Posttreatment after lenvatinib in patients with advanced hepatocellular carcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 278-278
Author(s):  
Keisuke Koroki ◽  
Naoya Kanogawa ◽  
Susumu Maruta ◽  
Sadahisa Ogasawara ◽  
Masamichi Obu ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Radiological Progression ◽  
Advanced Hcc ◽  
Line Therapy ◽  
Pugh Class ◽  
Third Line

278 Background: In clinical practice, the major disadvantage of lenvatinib to treat advanced hepatocellular carcinoma (HCC) is the lack of a posttreatment agent that has shown clear effectiveness. Thus, the establishment of second-line treatment after lenvatinib treatment failure is an urgent clinical issue to be addressed in systemic therapy in patients with advanced HCC. The study used real-world clinical data to explore candidate drugs that might be appropriate as second-line treatment after lenvatinib. Methods: We retrospectively reviewed the medical records of all patients with advanced HCC who received lenvatinib as the first-line agent in seven institutions in Japan between 23 March 2018 and 31 September 2019. Results: During the study period, 178 patients with advanced HCC received lenvatinib as first-line systemic therapy. At the time of lenvatinib administration, most patients were Eastern Cooperative Oncology Group Performance Status grade 0 or 1 (94.9%) and Child–Pugh class A (84.3%). According to the baseline radiological assessments, 25.3% and 36.0% of patients had macrovascular invasion and extrahepatic metastasis, respectively. Overall survival and progression-free survival (PFS) for lenvatinib treatment were 13.3 months (95% CI: 11.5–15.2) and 6.7 months (95% CI: 5.1–8.3), respectively. Of the 151 patients who discontinued lenvatinib, 71 (47.0%) converted to posttreatment. The conversion rates from lenvatinib to a second-line agent and from a second-line agent to a third-line agent were 41.4% and 42.4%, respectively. Based on multivariate analysis, lenvatinib response was defined as complete or partial according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Lenvatinib discontinuation due to radiological progression, according to mRECIST, was associated with a significantly higher probability of conversion to posttreatment after lenvatinib. Of the 63 patients who received second-line systemic therapy, 53 (84.1%) were administered sorafenib, with a PFS, response rate (RR), and disease control rate (DCR) of 1.8 months (95% CI: 0.6–3.0), 1.8%, and 20.8%, respectively. According to the Cox proportional hazards regression model, lenvatinib discontinuation due to radiological progression, Child–Pugh class B, and intrahepatic tumor volume > 50% at the time of sorafenib administration significantly contributed to a shorter PFS. Of the 22 patients who received regorafenib after lenvatinib discontinuation, five cases were as second-line therapy, and 17 were as third-line therapy. PFS, RR, and DCR for regorafenib treatment were 3.2 months (range, 1.5–4.9 months), 13.6%, and 36.3%, respectively. Conclusions: Sorafenib was not considered a candidate posttreatment agent after lenvatinib, except in a limited number of patients who discontinued lenvatinib without radiological progression. Regorafenib is a potential posttreatment agent after lenvatinib.

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

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

Analysis of Post-Progression Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib

Oncology ◽  
2020 ◽  
Vol 98 (11) ◽  
pp. 787-797 ◽  
Author(s):  
Yuwa Ando ◽  
Tomokazu Kawaoka ◽  
Yosuke Suehiro ◽  
Kenji Yamaoka ◽  
Yumi Kosaka ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multivariate Analysis ◽  
Liver Function ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Class A ◽  
Line Therapy ◽  
Pugh Class ◽  
Ecog Ps

<b><i>Background:</i></b> Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy. <b><i>Methods:</i></b> Patients (<i>n</i> = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled. <b><i>Results:</i></b> One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: <i>n</i> = 26; ramucirumab: <i>n</i> = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465–18.31, <i>p</i> = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (&#x3c;400 ng/mL; hazard ratio [HR] 0.297, 95% CI 0.099–0.886, <i>p</i> = 0.003), a relative tumor volume &#x3c;50% at the time of progression (HR 0.204, 95% CI 0.07–0.592, <i>p</i> = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12–0.746, <i>p</i> = 0.01) were significant prognostic factors. <b><i>Conclusion:</i></b> Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN.

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