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A phase II randomized dose escalation trial of sorafenib in patients with advanced hepatocellular carcinoma.

ABSTRACT: Sorafenib has proven survival benefits in patients with advanced hepatocellular carcinoma (HCC). The viability of continuing sorafenib at a higher dosage in patients who experienced radiologic disease progression was investigated.Patients who experienced disease progression while on sorafenib 400 mg twice daily were randomized to sorafenib 600 mg twice daily (n = 49) or best supportive care (n = 52). The primary end point was progression-free survival (PFS). Time to progression, overall survival, and safety were also evaluated.The study did not meet its primary end point. The difference in PFS between the sorafenib arm (3.91 months) and the best supportive care arm (2.69 months) did not reach statistical significance (p = 0.086). Adverse events were mainly grade 1-2 and similar across both groups. In the sorafenib arm, the most frequent events were diarrhea (80%), weight loss (75%), fatigue (67%), hand-foot-skin reaction (49%), abdominal pain (37%), and stomatitis (26%).Escalated-dose sorafenib in patients with advanced HCC who progressed while on sorafenib, failed to provide any clinical benefit. Second-line treatment still remains an open issue to be explored in appropriate clinical trials.

SUBMITTER: Rimassa L

PROVIDER: S-EPMC3639524 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A phase II randomized dose escalation trial of sorafenib in patients with advanced hepatocellular carcinoma.

Rimassa Lorenza L Pressiani Tiziana T Boni Corrado C Carnaghi Carlo C Rota Caremoli Elena E Fagiuoli Stefano S Foa Paolo P Salvagni Stefania S Cortesi Enrico E Chiara Tronconi Maria M Personeni Nicola N Bozzarelli Silvia S Chiara Banzi Maria M Fanello Silvia S Romano Lutman Fabio F Giordano Laura L Santoro Armando A

The oncologist 20130411 4

<h4>Background</h4>Sorafenib has proven survival benefits in patients with advanced hepatocellular carcinoma (HCC). The viability of continuing sorafenib at a higher dosage in patients who experienced radiologic disease progression was investigated.<h4>Methods</h4>Patients who experienced disease progression while on sorafenib 400 mg twice daily were randomized to sorafenib 600 mg twice daily (n = 49) or best supportive care (n = 52). The primary end point was progression-free survival (PFS). Ti ...[more]

PMID: 23580239

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Project description:BackgroundThe mammalian target of rapamycin (mTOR) 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 mTOR 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.MethodsWe conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d. 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.ResultsTwenty-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 mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP.ConclusionsThe 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 mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.

Project description:BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg⁻¹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand-foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS₆ 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.

Project description:Lessons learnedTrebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2.BackgroundAng-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC).MethodsPatients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2.ResultsThirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts.ConclusionThere was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

Project description:ImportancePrevious communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC).ObjectiveTo determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease.Design, setting, and participantsThis unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS.Interventions or exposuresPatients received either 60 mg/m2 of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL.Main outcomes and measuresThe primary end point was OS, and progression-free survival (PFS) was a secondary end point.ResultsOf 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib.Conclusions and relevanceThis multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC.Trial registrationClinicalTrials.gov identifier: NCT01015833.

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A phase II randomized dose escalation trial of sorafenib in patients with advanced hepatocellular carcinoma.

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A phase II randomized dose escalation trial of sorafenib in patients with advanced hepatocellular carcinoma.

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