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Seminars in Liver Disease Feb 2013Treatment of advanced-stage hepatocellular carcinoma (HCC) remains a challenge because of the complex nature of the disease and the lack of available therapies. The... (Review)
Review
Treatment of advanced-stage hepatocellular carcinoma (HCC) remains a challenge because of the complex nature of the disease and the lack of available therapies. The antiangiogenic multikinase inhibitor sorafenib is the first therapy to demonstrate a significant overall survival benefit in advanced HCC. However, new agents for both first- and second-line treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation, and survival provide many opportunities for the development of molecularly targeted therapies. Many novel agents are under investigation in phase III trials in advanced HCC, including antiangiogenic multikinase inhibitors (e.g., brivanib, sunitinib, linifanib) and inhibitors of the mammalian target of rapamycin (mTOR) pathway (e.g., everolimus). Although these therapies have demonstrated some utility as single agents in advanced HCC, rational combinations of therapies are likely to provide greater success. Current research efforts are directed at combining agents targeting different molecular pathways (e.g., sorafenib in combination with erlotinib) and combining molecularly targeted agents with systemic chemotherapy or transarterial chemoembolization (TACE). Therapies targeting other molecular pathways in HCC are in early development; future research will focus on discovering additional targets for therapy and identifying biomarkers that predict the success of current therapies.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Combined Modality Therapy; Humans; Liver Neoplasms; Molecular Targeted Therapy; Patient Selection; Precision Medicine; Predictive Value of Tests; Signal Transduction; Treatment Outcome
PubMed: 23457035
DOI: 10.1055/s-0033-1333632 -
American Society of Clinical Oncology... 2013Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, and its prevalence and impact are even more profound because sorafenib is the only... (Review)
Review
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, and its prevalence and impact are even more profound because sorafenib is the only systemic therapy proven to prolong survival in patients with advanced disease. Randomized phase III trials of other novel targeted agents including sunitinib, linifanib, brivanib, and the combination of sorafenib plus erlotinib have failed to improve overall survival compared with sorafenib as a single agent in the first line setting, as well as compared with placebo in the second-line setting, in the case of brivanib. These negative studies are a sobering reminder of the challenges to clinical research in HCC, including the competing comorbidity of liver dysfunction, marked clinical and biologic heterogeneity, and the unreliability of surrogate endpoints to accurately predict survival. To address these challenges, HCC-specific phase I/Ib cohorts must be used to define the maximum tolerated dose and drug exposure in this organ dysfunction population with high background rates of adverse events and little tolerance for superimposed treatment-related toxicity. Pooled analyses of contemporary randomized trials and database studies should be undertaken to define the strongest prognostic factors for stratification in future phase III studies. Research blood and archival tumor specimens should be collected from patients on clinical trials to intensify the search for biomarkers of responsive or resistant subsets, in parallel with ongoing efforts to improve on radiographic response assessment. Collectively, these and other new strategies are needed to make progress in identifying active novel therapeutics for patients with HCC.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Drug Design; Humans; Liver Neoplasms; Molecular Targeted Therapy; Risk Factors; Signal Transduction; Treatment Outcome
PubMed: 23714481
DOI: 10.14694/EdBook_AM.2013.33.e137 -
Annals of Oncology : Official Journal... Jun 2011This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.
A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.
BACKGROUND
This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.
PATIENTS AND METHODS
Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD.
RESULTS
Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts.
CONCLUSION
In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.
Topics: Adult; Aged; Aged, 80 and over; Alanine; Angiogenesis Inhibitors; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Receptors, Fibroblast Growth Factor; Receptors, Vascular Endothelial Growth Factor; Triazines
PubMed: 21131369
DOI: 10.1093/annonc/mdq599 -
Liver Cancer Sep 2012Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase... (Review)
Review
Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase inhibitor, are unprecedented and underscore the importance of improving our understanding of how signaling networks interact in transformed cells. Numerous signaling modules are de-regulated in HCC, including some related to growth factor signaling (e.g., IGF, EGF, PDGF, FGF, HGF), cell differentiation (WNT, Hedgehog, Notch), and angiogenesis (VEGF). Intracellular mediators such as RAS and AKT/MTOR may also play a role in HCC development and progression. Different molecular mechanisms have been shown to induce aberrant pathway activation. These include point mutations, chromosomal aberrations, and epigenetically driven down-regulation. The use of novel molecular technologies such as next-generation sequencing in HCC research has enabled the identification of novel pathways previously underexplored in the HCC field, such as chromatin remodeling and autophagy. Considering recent failures of molecular therapies in advanced clinical trials (e.g., sunitinib, brivanib), survey of these and other new pathways may provide alternative therapeutic targets.
PubMed: 24159576
DOI: 10.1159/000342405 -
Cancer Medicine Aug 2023Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI-induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI-induced hypertension by monitoring associated changes in the circulating metabolome.
PATIENTS AND METHODS
Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment-induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography-mass spectrometry to identify treatment-related metabolomic changes associated with TKI-induced hypertension, compared to pre-treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS-DA).
RESULTS
In the brivanib treated group, 95 patients had treatment-related hypertension within 12 weeks of initiating treatment. TKI-induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression-free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI-induced hypertension. The OPLS-DA model for brivanib-induced hypertension was significant and robust (R Y score = 0.89, Q Y score = 0.70, CV-ANOVA = 2.01 e-7). Notable metabolomic features previously reported in pre-eclampsia and associated with vasoconstriction were found.
CONCLUSION
TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity.
Topics: Humans; Metabolomics; Colorectal Neoplasms; Metabolome; Triazines; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37329221
DOI: 10.1002/cam4.6248 -
European Journal of Cancer (Oxford,... Jun 2010Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target...
Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors.
PURPOSE
Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target specific agents that result in a substantial decrease in tumour growth when given alone. Tamoxifen activates SERM stimulated breast and endometrial tumour growth. Tamoxifen and brivanib alaninate have side-effects that can affect therapeutic outcomes. The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive, oestrogen stimulated tumour xenografts (MCF-7 E2 tumours). Experiments were conducted to evaluate the response of SERM stimulated breast (MCF-7 Tam, MCF-7 Ral) and endometrial tumours (EnCa 101) to demonstrate the activity of brivanib alaninate in SERM resistant models.
EXPERIMENTAL DESIGN
In the current study, tumour xenografts were minced and bi-transplanted into the mammary fat pads of athymic, ovariectomised mice. Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumour growth. Doses of 125 microg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated. An experiment was designed to evaluate the effect of the two agents together when started at the time of tumour implantation. An additional experiment was done in which tumours were already established and then treated, to obtain enough tumour tissue for molecular analysis.
RESULTS
Brivanib alaninate was effective at inhibiting tumour growth in SERM sensitive (MCF-7 E2) and SERM stimulated (EnCa 101, MCF-7 Ral, MCF-7 Tam) models. The effect of the low dose drug combination as an anti-tumour strategy for SERM sensitive (MCF-7 E2) in early treatment was as effective as higher doses of either drug used alone. In established tumours, the combination is successful at decreasing tumour growth, while neither agent alone is effective. Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumours that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA. Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate. There was also increased necrosis in tumours treated with brivanib alaninate.
CONCLUSION
Historically, tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER. Tamoxifen and a low dose of an angiogenesis inhibitor, brivanib alaninate, can potentially be combined not only to maximise therapeutic efficacy but also to retard SERM resistant tumour growth.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Mice; Mice, Nude; Neoplasm Transplantation; Pyrroles; Random Allocation; Receptor, Fibroblast Growth Factor, Type 1; Reverse Transcriptase Polymerase Chain Reaction; Tamoxifen; Transplantation, Heterologous; Triazines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 20303261
DOI: 10.1016/j.ejca.2010.02.018 -
Chinese Clinical Oncology Feb 2021Therapeutic options for advanced, unresectable hepatocellular carcinoma (HCC) have changed dramatically over the last 3 years. While surgical resection, orthotropic...
Therapeutic options for advanced, unresectable hepatocellular carcinoma (HCC) have changed dramatically over the last 3 years. While surgical resection, orthotropic liver transplantation, and localized therapeutic options such as ablation, radiation therapy, and embolization remain therapeutics of choice in localized disease, systemic therapy is the only option in advanced, metastatic HCC. Since the United States Food and Drug Administration (US FDA) approval of sorafenib in 2008, targeted therapies such as sunitinib, tivantinib, brivanib, erlotinib, and linifanib; monoclonal antibody- bevacizumab showed no meaningful improvement in treatment of HCC. However, with improved understanding on the molecular pathophysiology and tumor heterogeneity of HCC, we have made progress in expanding the therapeutic options in advanced HCC. Targeted therapy with lenvatinib, cabozantinib, and regorafenib; monoclonal antibody ramucirumab; immunotherapies nivolumab and pembrolizumab have demonstrated promising results in the clinical trials. The current work outlines the molecular mechanisms and tumorigenesis of HCC, a detailed discussion of the trial results of the approved therapies in HCC, future perspectives and potential options to overcome the challenges of systemic therapy in HCC.
Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Sorafenib
PubMed: 32434345
DOI: 10.21037/cco-20-117 -
Medicine Dec 2016A variety of targeted drug therapies in clinical trials have been proven to be effective for the treatment of hepatocellular carcinoma (HCC). Our study aims to compare... (Comparative Study)
Comparative Study Meta-Analysis Review
Short-term and long-term efficacy of 7 targeted therapies for the treatment of advanced hepatocellular carcinoma: a network meta-analysis: Efficacy of 7 targeted therapies for AHCC.
BACKGROUND
A variety of targeted drug therapies in clinical trials have been proven to be effective for the treatment of hepatocellular carcinoma (HCC). Our study aims to compare the short-term and long-term efficacies of different targeted drugs in advanced hepatocellular carcinoma (AHCC) treatment using a network meta-analysis approach.
METHODS
PubMed, Embase, Ovid, EBSCO, and Cochrane central register of controlled trials were searched for randomized controlled trials (RCTs) of different targeted therapies implemented to patients with AHCC. And the retrieval resulted in 7 targeted drugs, namely, sorafenib, ramucirumab, everolimus, brivanib, tivantinib, sunitinib, and sorafenib+erlotinib. Direct and indirect evidence were combined to evaluate stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR), overall response ratio (ORR), overall survival (OS), and surface under the cumulative ranking curve (SUCRA) of patients with AHCC.
RESULTS
A total of 11 RCTs were incorporated into our analysis, including 6594 patients with AHCC, among which 1619 patients received placebo treatment and 4975 cases had targeted therapies. The results revealed that in comparison with placebo, sorafenib, and ramucirumab displayed better short-term efficacy in terms of PR and ORR, and brivanib was better in ORR. Regarding long-term efficacy, sorafenib and sorafenib+erlotinib treatments exhibited longer OS. The data of cluster analysis showed that ramucirumab or sorafenib+erlotinib presented relatively better short-term efficacy for the treatment of AHCC.
CONCLUSION
This network meta-analysis shows that ramucirumab and sorafenib+erlotinib may be the better targeted drugs for AHCC patients, and sorafenib+erlotinib achieved a better long-term efficacy.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Disease-Free Survival; Erlotinib Hydrochloride; Female; Humans; Liver Neoplasms; Male; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Sorafenib; Survival Analysis; Treatment Outcome; Ramucirumab
PubMed: 27930578
DOI: 10.1097/MD.0000000000005591 -
Gynecologic Oncology Sep 2017Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy...
BACKGROUND
Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients.
METHODS
Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response.
RESULTS
Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension.
CONCLUSIONS
Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.
Topics: Adult; Aged; Aged, 80 and over; Alanine; Antineoplastic Agents; Carcinoma; Disease Progression; Disease-Free Survival; Early Termination of Clinical Trials; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Response Evaluation Criteria in Solid Tumors; Retreatment; Survival Rate; Triazines; Uterine Cervical Neoplasms
PubMed: 28728751
DOI: 10.1016/j.ygyno.2017.05.033 -
Frontiers in Pharmacology 2015Tyrosine kinases (TKs) is a family of tyrosine protein kinases with important functions in the regulation of a broad variety of physiological cell processes.... (Review)
Review
Tyrosine kinases (TKs) is a family of tyrosine protein kinases with important functions in the regulation of a broad variety of physiological cell processes. Overactivity of TK disturbs cellular homeostasis and has been linked to the development of certain diseases, including various fibrotic diseases. In regard to liver fibrosis, several TKs, such as vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor, and epidermal growth factor receptor kinases, have been identified as central mediators in collagen production and potential targets for anti-liver fibrosis therapies. Given the essential role of TKs during liver fibrogenesis, multitargeted inhibitors of aberrant TK activity, including sorafenib, erlotinib, imatinib, sunitinib, nilotinib, brivanib and vatalanib, have been shown to have potential for treating liver fibrosis. Beneficial effects are observed by researchers of this field using these multitargeted TK inhibitors in preclinical animal models and in patients with liver fibrosis. The present review will briefly summarize the anti-liver fibrosis effects of multitargeted TK inhibitors and molecular mechanisms.
PubMed: 26834633
DOI: 10.3389/fphar.2015.00300