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Hiroyuki Uetake, Kenichi Sugihara, Kei Muro, Toshiyuki Sunaya, Yuka Horiuchi-Yamamoto, Hajime Takikawa
BACKGROUND: Regorafenib (Stivarga) is an oral multikinase inhibitor currently approved for patients with metastatic colorectal cancer or gastrointestinal stromal tumor. Although hepatotoxicity has been a known product profile feature of regorafenib since its initial approval, its clinical features are limited to those found in the clinical trials. PATIENTS AND METHODS: The present study was conducted in 2 analysis sets: a safety analysis set for metastatic colorectal cancer from solicited postmarketing surveillance (PMS) in Japan (n = 1227) and an analysis set for serious hepatic adverse drug reactions (n = 210) from all patients registered for regorafenib use...
September 28, 2017: Clinical Colorectal Cancer
Meihui Cao, Feifei Li, Yue Wang, Jingdong Zhang
Regorafenib (Stivarga) is an oral small-molecule multikinase inhibitor commonly used against a variety of cancers. We performed a meta-analysis of all phase 3 randomized controlled trials (RCTs) of regorafenib to quantify the increased risk of SAEs and FAEs. We carried out a systematic search of electronic databases for studies published from inception to February 2017 without any restrictions. Eligibility criteria included phase 3 RCTs of tumors comparing regorafenib, alone or in combination with non-targeted chemotherapy (regorafenib arm) versus placebo or non-targeted chemotherapy (control arm)...
December 2017: Investigational New Drugs
Li-Ching Fan, Hao-Wei Teng, Chung-Wai Shiau, Wei-Tien Tai, Man-Hsin Hung, Shung-Haur Yang, Jeng-Kai Jiang, Kuen-Feng Chen
Epithelial-to-mesenchymal transition (EMT) is well-known to evoke cancer invasion/metastasis, leading to a high frequency of mortality in patients with metastatic colorectal cancer (mCRC). Protein tyrosine phosphatase (PTPase)-targeted therapy has been identified as a novel cancer therapeutic. Previously, we proved that sorafenib with anti-EMT potency prevents TGF-β1-induced EMT/invasion by directly activating SH2-domain-containing phosphatase 1 (SHP-1)-dependent p-STAT3Tyr705 suppression in hepatocellular carcinoma...
September 27, 2016: Oncotarget
Li-Ching Fan, Hao-Wei Teng, Chung-Wai Shiau, Wei-Tien Tai, Man-Hsin Hung, Shung-Haur Yang, Jeng-Kai Jiang, Kuen-Feng Chen
STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo...
September 2015: Neoplasia: An International Journal for Oncology Research
Saravanan K Krishnamoorthy, Valerie Relias, Sunit Sebastian, Vijay Jayaraman, Muhammad Wasif Saif
Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is an oral multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases including vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR1, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), RAF, KIT, RET and BRAF. Its antiangiogenic effect is greater than that of its related drug, sorafenib. Regorafenib has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (mCRC) in patients who have failed treatment with fluoropyrimidine, oxaliplatin and irinotecan based chemotherapy, an anti-VEGF therapy and, if KRAS wild type, an anti-EGFR therapy...
September 2015: Therapeutic Advances in Gastroenterology
Matt Shirley, Gillian M Keating
Regorafenib (Stivarga(®)) is an orally administered small molecule inhibitor of multiple protein kinases, including kinases involved in oncogenesis and tumour angiogenesis. It was initially approved for use in patients with previously treated metastatic colorectal cancer. Based on the findings of the phase III GRID clinical trial, approval for regorafenib has been expanded to include the treatment of advanced gastrointestinal stromal tumours (GISTs) following the failure of imatinib and sunitinib. In the GRID trial, regorafenib significantly improved progression-free survival and was associated with a significantly higher disease control rate than placebo...
June 2015: Drugs
Jane L Roberts, Mehrad Tavallai, Aida Nourbakhsh, Abigail Fidanza, Tanya Cruz-Luna, Elizabeth Smith, Paul Siembida, Pascale Plamondon, Kelly A Cycon, Christopher D Doern, Laurence Booth, Paul Dent
Prior tumor cell studies have shown that the drugs sorafenib (Nexavar) and regorafenib (Stivarga) reduce expression of the chaperone GRP78. Sorafenib/regorafenib and the multi-kinase inhibitor pazopanib (Votrient) interacted with sildenafil (Viagra) to further rapidly reduce GRP78 levels in eukaryotes and as single agents to reduce Dna K levels in prokaryotes. Similar data were obtained in tumor cells in vitro and in drug-treated mice for: HSP70, mitochondrial HSP70, HSP60, HSP56, HSP40, HSP10, and cyclophilin A...
October 2015: Journal of Cellular Physiology
Mehrad Tavallai, Hossein A Hamed, Jane L Roberts, Nichola Cruickshanks, John Chuckalovcak, Andrew Poklepovic, Laurence Booth, Paul Dent
We determined whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over-expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs...
September 2015: Journal of Cellular Physiology
Sibo Tian, Michael Nissenblatt, Sharad Goyal
Stereotactic body radiation therapy (SBRT) delivers large doses of radiation with great accuracy, but is known to have deleterious effects on the vascular compartment of irradiated tissues. Combining SBRT with targeted anti-angiogenesis agents, while able to increase therapeutic efficacy, may unexpectedly precipitate vascular-based toxicities. In this report, we describe a patient with colon cancer who developed transverse myelopathy from regorafenib 2 years after receiving SBRT for three metastatic liver lesions...
December 2014: Journal of Gastrointestinal Oncology
Jean-Baptiste Rey, Vincent Launay-Vacher, Christophe Tournigand
Regorafenib (BAY 73-4506, Stivarga® Bayer HealthCare Pharmaceutical Inc) is an oral multikinase inhibitor with a distinct and wide-ranging profile of tyrosine kinase inhibition, resulting in antiangiogenic and antiproliferative properties in tumors. Single-agent regorafenib administered as a 160-mg daily dose for the first 21 days of a 28-day cycle is approved for use in patients with pretreated metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumor (GIST) progressing on imatinib and sunitinib, following publication of data from the phase III CORRECT and GRID studies respectively...
June 2015: Targeted Oncology
Frank-Thorsten Hafner, Daniel Werner, Michael Kaiser
BACKGROUND: Regorafenib (BAY 73-4506, commercial name Stivarga(®)) is an oral multikinase inhibitor developed by Bayer Pharma AG (Germany) that targets angiogenic, stromal and oncogenic receptor tyrosine kinases. An isotope dilution liquid chromatography-tandem mass spectrometry method has been developed and validated for the simultaneous determination of regorafenib and its two major metabolites BAY 75-7495 (M-2) and BAY 81-8752 (M-5) in lithium-heparinized human plasma. RESULTS: Analysis was performed after protein precipitation on a triple-quadrupole tandem mass spectrometer...
2014: Bioanalysis
Thomas J Ettrich, Thomas Seufferlein
Regorafenib (BAY 73-4506, Stivarga®) is an oral diphenylurea multikinase inhibitor that targets angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic receptor tyrosine kinases (KIT, RET, and RAF). Regorafenib is the first small-molecule multikinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. Consequently, regorafenib was FDA approved for this indication. In addition, regorafenib treatment resulted in a significant improvement in progression-free survival (PFS) compared with placebo in patients with metastatic gastrointestinal stromal tumors (GIST) after progression on standard treatments and is also an FDA approved indication...
2014: Recent Results in Cancer Research
Paul Dent
Sorafenib (Nexavar) is a multi-kinase inhibitor that was developed as an inhibitor of RAF-1, in the ERK1/2 pathway, but which was subsequently shown to inhibit class III tyrosine kinase receptors. (1) More recently regorafenib (Stivarga) has been developed, which is a further fluorinated version of sorafenib with greater bioavailability and similar inhibitory properties against RAF-1/class III RTKs. (2) Some of the anti-tumor effects of sorafenib have been ascribed to anti-angiogenic actions of this agent on endothelial associated kinases such as VEGFR2...
January 2014: Cancer Biology & Therapy
Natalie J Carter
Regorafenib (Stivarga) is an inhibitor of multiple protein kinases, including those involved in oncogenesis, tumour angiogenesis and maintenance of the tumour microenvironment. The drug is approved as monotherapy for the treatment of metastatic colorectal cancer (mCRC) in patients who have previously received all standard systemic anticancer treatments (US, EU and Canada) or in patients with unresectable, advanced or recurrent colorectal cancer (Japan). In the randomized, controlled COloRectal cancer treated with REgorafenib or plaCebo after failure of standard Therapy (CORRECT) trial, regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle plus best supportive care (BSC) was associated with a significantly longer median overall survival than placebo plus BSC in patients with previously treated, progressive mCRC...
January 2014: Drugs & Aging
Katherine A Lyseng-Williamson
Regorafenib (Stivarga(®)), a new inhibitor of multiple kinases, is indicated as third-line treatment in patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib and sunitinib in the USA. In a phase III trial in patients with progressive GIST after failure of standard therapies, regorafenib plus best supportive care increased median progression-free survival by >5-fold relative to best supportive care alone. Although regorafenib is associated with several specific drug-related adverse events, it is reasonably well tolerated if recommendations for dose modifications (i...
October 2013: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
(no author information available yet)
No abstract text is available yet for this article.
April 29, 2013: Medical Letter on Drugs and Therapeutics
(no author information available yet)
No abstract text is available yet for this article.
March 2013: Oncology (Williston Park, NY)
Marvin M Goldenberg
Bosutinib (Bosulif) tablets for chronic myelogenous leukemia; linaclotide (Linzess) for irritable bowel syndrome/constipation and chronic idiopathic constipation; and regorefenib (Stivarga) tablets for metastatic colorectal cancer.
November 2012: P & T: a Peer-reviewed Journal for Formulary Management
(no author information available yet)
No abstract text is available yet for this article.
October 2012: Oncology (Williston Park, NY)
Brian I Carr, Rosalba D'Alessandro, Maria G Refolo, Palma A Iacovazzi, Catia Lippolis, Caterina Messa, Aldo Cavallini, Mario Correale, Antonio Di Carlo
Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multikinase inhibitors, regorafenib (Stivarga) and sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration, and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1-1 µM drug concentrations...
June 2013: Journal of Cellular Physiology
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