Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011991 (diarrhea)
 57,543 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for 6 months in 12% of patients (6% stabilized for 1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.
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PMID:Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome? 1642 38

Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated.
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PMID:Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. 1647 53

Sorafenib is a small molecule inhibitor of several kinases involved in tumour proliferation and tumour angiogenesis including Raf, VEGFR and platelet derived growth factor receptor. In vivo Raf kinase inhibition has been observed in pharmacodynamic studies. Sorafenib is one of several VEGF-targeting compounds with recently demonstrated substantial anti-tumour effects in metastatic renal cell carcinoma. Delay in time to disease progression has been demonstrated in cytokine-refractory metastatic renal cell carcinoma, and further investigation is ongoing in a wide variety of tumour types. Sorafenib is well tolerated, with common toxicities including rash, diarrhoea, hand-foot skin reaction, fatigue and hypertension, when administered as the standard dose of 400 mg b.i.d.
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PMID:Sorafenib. 1650 17

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.
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PMID:Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. 1747 Jun 85

Sorafenib is an orally available multikinase inhibitor active on vascular endothelial growth factor receptor-2 and -3, platelet-derived growth factor receptor-beta, B-RAF, C-RAF, flt3 and C-Kit. Phase I studies showed its activity on renal cell carcinoma (RCC) and other neoplasms and identified the schedule of 400 mg (two tablets) b.i.d. as better tolerated and potentially active. The original design selected for the principal phase II trial, randomization discontinuation trial, showed the particular activity profile of this drug: low objective response rates but significant increases in progression-free survival [PFS, which frequently translate in increased overall survival (OS)]. A pattern of response completely agrees with an antiangiogenic (cytostatic) agent. The potential efficacy of sorafenib was confirmed in immunotherapy-refractory advanced RCC cases by 'TARGETs', the largest randomized double-blind study ever carried out in kidney cancer. With a doubled PFS, a trend in OS and a modest toxicity profile, mainly grade 1-2 skin toxicity and diarrhea, sorafenib has been recently approved from the Food and Drug Administration and European Agency for the Evaluation of Medicinal Products for the second-line treatment of advanced RCC. Numerous trials are ongoing to test new schedules and drug combinations, while promising results were recently achieved also in hepatocellular carcinoma. With drugs such as sorafenib, angiogenesis could become an Achilles's heel for RCC.
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PMID:Protein kinase inhibitors in the treatment of renal cell carcinoma: sorafenib. 1759 26

Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.
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PMID:Sorafenib and sunitinib: novel targeted therapies for renal cell cancer. 1765 13

(1) Kidney cancer is infrequent. Most renal malignancies are adenocarcinomas. The prognosis varies markedly from one patient to another. Interferon alfa generally increases survival time by a few months in patients with locally advanced or metastatic cancers, but it has a negative impact on quality of life. (2) Sorafenib inhibits several kinases implicated in angiogenesis and tumour growth. It was recently approved for second-line treatment of advanced-stage kidney cancer. (3) A double-blind placebo-controlled trial involving 903 patients evaluated second-line sorafenib therapy at an oral dose of 400 mg twice a day. Patients with a poor prognosis were not eligible. (4) Sorafenib increased overall survival time by about three months (50% mortality was reached at 19 months in the sorafenib group and at 16 months in the placebo group). The median progression-free survival time also increased by about three months (5.5 months with sorafenib versus about 3 months with placebo). The impact of sorafenib on quality of life was not reported. (5) An indirect comparison shows a higher rate of tumour regression with sunitinib than with sorafenib (25% versus 2%), and also longer progression-free survival (3 to 4 months longer with sunitinib). However, there was no difference between the two drugs in overall survival time, which is the most relevant outcome. Note that no practical conclusions can be drawn from indirect comparisons of this type, as they are subject to too many biases. (6) The main adverse events among patients treated with sorafenib in this trial were cutaneous disorders (about 30% of patients), diarrhoea (about 20%), hypertension (10%), and bleeding (10%). Cases of myocardial ischaemia and neuropathies also occurred. (7) Sorafenib is teratogenic in several animal species. (8) Sorafenib is metabolised by the cytochrome P450 isoenzyme CYP 3A4. The risk of clinically relevant drug interactions is poorly documented. (9) For second-line treatment of patients with kidney cancer and no factors of poor prognosis, available data favour the use of sorafenib, which is better assessed than sunitinib.
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PMID:Sorafenib: new drug. Second-line treatment of kidney cancer: better evaluated than sunitinib. 1772 34

Sorafenib is an orally active multikinase inhibitor that targets serine and threonine, and tyrosine kinases that are involved in tumor-cell signal transduction and tumor angiogenesis. This phase I trial was conducted to evaluate the pharmacokinetics (PK), safety, and preliminary efficacy of sorafenib in Japanese patients with hepatocellular carcinoma (HCC) with underlying liver dysfunction. Patients with unresectable HCC, Child-Pugh status A or B, and adequate organ functions were treated. A single dose of sorafenib was administered, followed by a 7-day wash-out period, after which patients received either sorafenib 200 mg (cohort 1) or 400 mg (cohort 2) twice daily. The PK were investigated after a single dose and during steady state. The efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors. A total of 27 patients were evaluated for PK, safety, and efficacy. Although both area under the concentration-time curve for 0-12 h and maximal concentration at steady state were slightly lower in Child-Pugh B patients than in Child-Pugh A patients, the difference was not considered to be clinically relevant. Common adverse drug events included elevated lipase, amylase, rash or desquamation, diarrhea, and hand-foot skin reaction. A dose-limiting toxicity of hand-foot skin reaction was observed in one patient (cohort 2). Among the 24 patients evaluable for tumor response, one patient (4%) achieved a partial response, 20 (83%) had stable disease, and three (13%) had progressive disease. Sorafenib demonstrated a favorable tolerability and safety profile in Japanese HCC patients. Moreover, promising preliminary antitumor activity has been observed. Finally, there were no clinically relevant differences in PK between Child-Pugh A and B patients.
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PMID:Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. 1795 9

Diagnosis of renal cell carcinoma (RCC) frequently occurs at advanced stages, severely limiting the success of treatment, and median survival is barely more than a year. Previously, treatment of renal cancer was limited to nephrectomy or immunotherapy (interleukin or interferon-alpha), which was effective in a small subset of patients but often was accompanied by severe side effects. New orally administered targeted therapies have become available, offering broader benefits to patients with advanced RCC. Sorafenib is an oral, multikinase inhibitor recently approved by the U.S. Food and Drug Administration as treatment for advanced RCC based on its extension of median progression-free survival from 12-24 weeks. Oncology nurses must ensure patient adherence and manage side effects of emerging treatments. This article reviews the management of skin rash, hand-foot skin reaction, hypertension, diarrhea, and fatigue in patients receiving sorafenib. In addition, a case study of a patient receiving sorafenib is presented.
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PMID:Sorafenib: a promising new targeted therapy for renal cell carcinoma. 1856 57

Until 2006, immunotherapy (interferon-alpha or interleukin 2) was the standard medical treatment for metastatic renal cell carcinoma (RCC), and its results were disappointing: despite a few cases of complete response with prolonged survival, median survival was one year. Better understanding of the molecular mechanisms of tumor angiogenesis, especially in clear cell carcinoma, has led to the development of multiple targeted therapies to inhibit key effectors: vascular endothelial growth factor (VEGF), VEGF receptor, and mTOR (target of rapamycin). Two inhibitors targeting several protein kinases, including the VEGF receptor, have increased progression-free survival in patients with metastatic RCC and are now commercially available: sunitinib (Sutent) as first-line treatment and sorafenib (Nexavar) as second-line treatment. These targeted therapies will certainly affect overall survival, but it is too early for any firm conclusions. Their side-effects, usually low or moderate, include asthenia, anorexia, diarrhea, hand-and-foot syndrome and hypertension. Optimal management is required to ensure prolonged exposure. Other drugs have been effective: bevacizumab (Avastin), a monoclonal antibody inhibiting VEGF, increases progression-free survival as second-line treatment, and temsirolimus (Torisel), an mTOR protein kinase inhibitor, increases overall survival in the population of patients with poor prognosis. These targeted drugs will serve as the basis for development of future therapeutic strategies.
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PMID:[Renal cell carcinoma and antiangiogenic therapies]. 1803 17


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