scholarly journals Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling

Liver Cancer ◽  
2021 ◽  
pp. 1-11
Author(s):  
Robin K. Kelley ◽  
Nancy M. Joseph ◽  
Halla S. Nimeiri ◽  
Jimmy Hwang ◽  
Laura M. Kulik ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Advanced Hepatocellular Carcinoma ◽  
Next Generation ◽  
Serious Adverse Events ◽  
Multikinase Inhibitor

<b><i>Background:</i></b> The mammalian target of rapamycin (<i>mTOR</i>) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of <i>mTOR</i> pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose. <b><i>Methods:</i></b> We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d<i>.</i> The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint. <b><i>Results:</i></b> Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor <i>mTOR</i> pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP. <b><i>Conclusions:</i></b> The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of <i>mTOR</i> pathway mutations was not associated with treatment response in an exploratory subgroup analysis.

Donafenib versus sorafenib as first-line therapy in advanced hepatocellular carcinoma: An open-label, randomized, multicenter phase II/III trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4506-4506 ◽  
Author(s):  
Feng Bi ◽  
Shukui Qin ◽  
Shanzhi Gu ◽  
Yuxian Bai ◽  
Zhendong Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Objective Response ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
First Line Therapy ◽  
Line Therapy ◽  
Number Of Patients

4506 Background: Sorafenib is still the standard first-line therapy for advanced hepatocellular carcinoma (HCC). Donafenib, a novel multikinase inhibitor, showed potential benefits in a previous phase Ib study in HCC. Methods: In this open-label, randomized phase II/III trial (ZGDH3), patients with unresectable or metastatic HCC, a Child-Pugh liver function score ≤ 7, and no prior systemic therapy were enrolled from 37 sites across China and randomized (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). Efficacy analysis was primarily based on the full analysis set (FAS). Results: Between March 2016 and April 2018, 668 patients were randomized (donafenib, 334; sorafenib, 334) and included in the intention-to-treat (ITT) set, of whom 659 were analysed by FAS (328 vs 331). Donafenib was associated with a significantly longer median OS than sorafenib in both FAS (12.1 months vs 10.3 months, hazard ratio 0.831, 95% confidence interval 0.699–0.988, p = 0.0363) and ITT (12.0 months vs 10.1 months, 0.839, 0.706–0.996, p = 0.0446). There were no significant differences in median progression-free survival (3.7 months vs 3.6 months, p = 0.2824), objective response rate (4.6% vs 2.7%, p = 0.2448), and disease control rate (30.8% vs 28.7%, p = 0.5532). Grade 3 or worse adverse events (AEs) occurred in 191 (57.4%) and 224 (67.5%) patients ( p = 0.0082), respectively, and AEs of special interest and those leading to treatment interruption occurred in 287 (86.2%) vs 309 (93.1%, p = 0.0049) and 101 (30.3%) vs 141 (42.5%, p = 0.0013). A numerically lower number of patients reported serious AEs (55 [16.5%] vs 67 [20.2%], p = 0.2307) with donafenib. Common AEs with donafenib included hand-foot skin reaction (50.5%), aspartate aminotransferase increased (40.5%), blood bilirubin increased (39.0%), platelet count decreased (37.8%), and diarrhea (36.6%). Conclusions: Donafenib significantly improves OS over sorafenib with favourable safety and tolerability. Donafenib is a promising superior first-line therapy for advanced HCC. Funding: Zelgen. Clinical trial information: NCT02645981 .

Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma

2011 ◽  
Vol 69 (3) ◽  
pp. 773-780 ◽  
Author(s):  
Iacopo Petrini ◽  
Monica Lencioni ◽  
Miriam Ricasoli ◽  
Mauro Iannopollo ◽  
Cinzia Orlandini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Advanced Hepatocellular Carcinoma

Randomized phase II trial of TACE plus everolimus as first-line therapy in localized unresectable hepatocellular carcinoma (HCC): The TRACER trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4149-TPS4149
Author(s):  
Ronnie Tung Ping Poon ◽  
Li-Tzong Chen ◽  
Hong-Ling Xue ◽  
Bayane Tannir ◽  
Jia Hua Wang ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Data Monitoring Committee ◽  
Preclinical Study ◽  
Clinical Trial Registry ◽  
Double Blind ◽  
First Line Therapy

TPS4149 Background: Transcatheter Arterial Chemoembolization (TACE) has shown benefit in improving survival and is a widely used treatment for unresectable HCC. However, TACE induces hypoxia leading to up-regulation of HIF-1α and VEGF signaling, and tumor progression. Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR) and its downstream signaling including HIF-1α. Everolimus has also been shown to increase chemosensitivity of HCC in preclinical study (Cancer Lett; 273(2):201-9). Combining everolimus with TACE may delay tumor progression. TRACER (Tace with Rad001 in Asian Centers for Evaluation and Research) aims to evaluate the efficacy and safety of everolimus plus TACE in patients with localised unresectable HCC. Methods: TRACER is a multinational, randomized, double-blind, placebo-controlled phase II trial. Patients aged ≥18 years newly diagnosed with localized unresectable Child A HCC; ECOG PS of <2; ≥1 unidimensional lesion measurable according to RECIST; and adequate bone marrow, liver, and renal function. Exclusion criteria include main portal vein invasion and/or extrahepatic spread; prior local or systemic treatment for HCC, or contraindications to TACE. Eligible patients who have successfully undergone the first TACE are randomized 1:1 to oral everolimus 7.5mg or matching placebo daily. TACE is repeated every 10 weeks or so. A short everolimus dose interruption of 48 hours before and after each TACE has been designed to allow recovery from complications of TACE. For standardization, doxorubicin-eluting beads are being used in every TACE. Patients shall exit the trial upon tumor progression, unacceptable toxicity, death, or trial discontinuation. All endpoints will be assessed on an ITT basis. The primary endpoint is time to progression base on Modified RECIST Criteria. Secondary endpoints include objective response rate, overall survival, and incidence of extrahepatic spread, safety and exploratory biomarkers. An independent data monitoring committee has been established to safeguard the trial subjects. Estimated total enrollment is 80, of which 12 subjects have been enrolled. (Clinical Trial Registry Number: NCT01379521.)

Hepatic arterial infusion of oxaliplatin plus raltitrexed in patients with unresectable hepatocellular carcinoma (HAIROX): A phase II, single-arm, prospective study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4574-4574
Author(s):  
Shiguang Chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trial ◽  
Adverse Events ◽  
Phase Ii ◽  
Objective Response ◽  
Hepatic Arterial Infusion ◽  
Arterial Infusion ◽  
Intention To Treat ◽  
Unresectable Hepatocellular Carcinoma ◽  
Treat Population

4574 Background: Chemoembolisation and oral sorafenib are the recommended treatment for unresectable hepatocellular carcinoma (HCC); however, some patients respond poorly to these. Hepatic arterial infusion (HAI) chemotherapy may have potential benefit in these patients. We aimed to investigate the efficacy and safety of HAI of oxaliplatin plus raltitrexed in patients with unresectable HCC. Methods: In this phase II, single-arm clinical trial, we enrolled patients aged 18–70 years with unresectable HCC at the Fujian Cancer Hospital (China). We performed HAI with oxaliplatin (100 mg/m2 for 4 hours) and raltitrexed (3 mg/m2 for 1 hour). Treatment was repeated every 3 weeks and was discontinued either because of disease progression, unacceptable toxicity levels, or refusal of further treatment. We used Simon’s two-stage design. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1. Results: Fifty-one patients were screened between January 5, 2018 and August 7, 2019. Of these, 39 patients (34 men and 5 women; median age, 53 years) were enrolled and included in the intention-to-treat population. Objective response was achieved in 18 (51.4%) of 35 patients in the per-protocol population and in 18 (46.2%) of 39 patients in the intention-to-treat population. Treatment-related grade 4 adverse events or deaths were not reported, and the observed grade 3 adverse events were elevated aspartate aminotransferase levels (5[12.8%]), elevated alanine aminotransferase levels (1 [2.6%]), leukopenia (1 [2.6%]), thrombocytopenia (1 [2.6%]), and abdominal infection (1 [2.6%]). Conclusions: HAI of oxaliplatin plus raltitrexed showed promising efficacy and acceptable toxicity levels in patients unresectable HCC, and further evaluation is warranted. Clinical trial information: ChiCTR-OOC-17014182 . [Table: see text]

scholarly journals A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma

Cancer ◽  
2002 ◽  
Vol 94 (12) ◽  
pp. 3186-3191 ◽  
Author(s):  
Charles S. Fuchs ◽  
Jeffrey W. Clark ◽  
David P. Ryan ◽  
Mathew H. Kulke ◽  
Haesook Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Advanced Hepatocellular Carcinoma
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