Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Sunitinib”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2007

Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma.

On January 26, 2006, sunitinib (Sutent) received regular approval as monotherapy for the treatment of patients with gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate (Gleevec). Time-to-tumor progression (TTP) of sunitinib-treated patients was superior to that of placebo-treated patients. Median TTP of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (p < .0001). Partial responses were observed in 6.8% of sunitinib-treated patients and no placebo-treated patients. Sunitinib also received accelerated approval on January 26, 2006, as monotherapy for treatment of advanced renal cell carcinoma (RCC). In two single-arm trials of sunitinib in patients with metastatic RCC, partial responses were observed in 25.5% (95% confidence interval [CI], 17.5, 34.9) and 36.5% (95% CI, 24.7, 49.6) of patients. Median response durations in the two trials were 27.1 weeks (95% CI, 24.4, incalculable) and 54 weeks (95% CI, 34.3, 70.1). Treatment-emergent adverse events in sunitinib-treated patients included diarrhea, mucositis, skin abnormalities, altered taste, electrolyte abnormalities, hypertension, and diminution in left ventricular ejection fraction. Cardiac safety of sunitinib in patients with preexisting cardiac abnormalities remains unknown. Based on nonclinical findings, physicians prescribing sunitinib should monitor for adrenal insufficiency in patients who undergo stressors such as surgery, trauma, or severe infection. Caution should be exercised when administering sunitinib in combination with known CYP3A4 inducers or inhibitors.

Adult↗
PubMed2006

The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling.

We studied antitumor effects of receptor tyrosine kinase inhibitor sunitinib (formerly SU11248) against a variety of hematologic malignancies including the following leukemias: eosinophilic (EOL-1), acute myeloid (THP-1, U937, Kasumi-1), biphenotypic (MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, PALL-2), blast crisis of chronic myeloid (KU812, Kcl-22, K562), and adult T-cell (MT-1, MT-2, MT-4), as well as non-Hodgkin's lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine uptake studies showed that sunitinib was active against EOL-1, MV4-11, and Kasumi-1 cells, which possessed activating mutations of the PDGFRalpha, FLT-3, and c-KIT genes, respectively, with IC(50)s of <30 nmol/L. In addition, sunitinib inhibited the proliferation of freshly isolated leukemia cells from patients possessing mutations in FLT3 gene. Annexin V staining showed that sunitinib induced apoptosis of these cells. Sunitinib inhibited phosphorylation of FLT3 and PDGFRalpha in conjunction with blockade of mammalian target of rapamycin signaling in MV4-11 and EOL-1 cells, respectively. Interestingly, rapamycin analogue RAD001 enhanced the ability of sunitinib to inhibit the proliferation of leukemia cells and down-regulate levels of mammalian target of rapamycin effectors p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in these cells. Taken together, sunitinib may be useful for treatment of individuals with leukemias possessing activation mutation of tyrosine kinase, and the combination of sunitinib and RAD001 represents a promising novel treatment strategy.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Sunitinib.

Sunitinib and its active metabolite (SU012662) are selective inhibitors of multiple receptor tyrosine kinases associated with tumour growth and angiogenesis. The clinical efficacy of oral sunitinib has been demonstrated in patients with advanced gastrointestinal stromal tumours (GIST). In a phase III, randomised, double-blind, placebo-controlled, multicentre trial in patients with metastatic and/or unresectable GIST following unsuccessful imatinib therapy, the median time to tumour progression and median progression-free survival time were > or =4-fold longer in patients receiving sunitinib 50 mg/day than in those receiving placebo, in 6-week cycles consisting of 4 weeks of treatment followed by a 2-week rest period. Sunitinib also exhibited antitumour activity in patients with advanced renal cell carcinoma (RCC) following unsuccessful cytokine therapy. In two multicentre, single-arm, phase II clinical trials in patients with cytokine-refractory metastatic RCC, partial responses were reported in 40% and 43% of patients receiving sunitinib 50 mg/day for 4 weeks followed by 2 weeks without treatment in 6-week cycles; 27% and 22% of patients achieved stable disease for > or =3 months. Sunitinib was more effective than interferon-alpha as a first-line therapy in patients with metastatic RCC. In a large, well designed, phase III trial in previously untreated patients, progression-free survival was significantly longer in patients receiving sunitinib 50 mg/day in 6-week cycles (4 weeks of treatment followed by a 2-week rest period) compared with those receiving interferon-alpha 9MU three times weekly (47.3 vs 24.9 weeks). In general, sunitinib was well tolerated in patients with GIST and RCC, with adverse events usually being of mild or moderate severity.

Antineoplastic Agents↗
PubMed2006

Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors.

BACKGROUND: Sunitinib malate is an oral tyrosine kinase inhibitor recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Because the ret proto-oncogene is also inhibited by this agent, clinical evaluation of thyroid function was performed. OBJECTIVE: To describe the prevalence and clinical presentation of thyroid dysfunction related to sunitinib therapy. DESIGN: Prospective, observational cohort study. SETTING: Tertiary care hospital. PATIENTS: 42 patients treated for a median of 37 weeks (range, 10 to 167 weeks). MEASUREMENTS: Following analysis of serial thyroid-stimulating hormone (TSH) measurements collected prospectively during a clinical trial of sunitinib, the authors determined the proportion of patients with thyroid dysfunction. RESULTS: Abnormal serum TSH concentrations were documented in 26 of 42 patients (62%): 15 (36%) developed persistent, primary hypothyroidism; 4 (10%) developed isolated TSH suppression; and 7 (17%) experienced transient, mild TSH elevations. The risk for hypothyroidism increased with the duration of sunitinib therapy. Six of 15 (40%) hypothyroid patients had suppressed TSH concentrations before developing hypothyroidism, suggesting thyroiditis. Two hypothyroid patients evaluated with thyroid ultrasonography had no visualized thyroid tissue despite normal baseline thyroid function. LIMITATIONS: The exploratory nature of this study precluded more frequent biochemical and sonographic analysis that may better define the mechanism of sunitinib-associated thyroid dysfunction. CONCLUSION: Hypothyroidism is a frequent complication of sunitinib therapy. Regular surveillance of thyroid function is warranted in patients receiving the drug. Although the mechanism by which this complication occurs is unknown, the observations of preceding TSH suppression and subsequent absence of visualized thyroid tissue in some patients suggest that sunitinib may induce a destructive thyroiditis through follicular cell apoptosis. This provides a rationale for further investigation of sunitinib treatment in patients with advanced thyroid cancer.

Adult↗
PubMed2007

Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.

BACKGROUND: Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted. METHODS: We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety. RESULTS: The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001). CONCLUSIONS: Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).

Adult↗
PubMed2006

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.

BACKGROUND: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS: 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION: We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Adult↗
PubMed2006

Sunitinib in patients with metastatic renal cell carcinoma.

CONTEXT: Current treatment options for metastatic renal cell carcinoma (RCC) are limited and there is a need to identify novel and effective therapies. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, which has shown activity in an initial study of cytokine-refractory metastatic RCC patients. OBJECTIVE: To confirm the antitumor efficacy of sunitinib as second-line treatment in patients with metastatic clear-cell RCC, the predominant cell type of this malignancy. DESIGN, SETTING, AND PATIENTS: Open-label, single-arm, multicenter clinical trial. Patients were enrolled between February and November 2004, with follow-up continuing until disease progression, unacceptable toxicity, or withdrawal of consent. The reported data apply through August 2005. Patients (N = 106) had metastatic clear-cell RCC, which had progressed despite previous cytokine therapy. INTERVENTION: Repeated 6-week cycles of sunitinib, 50 mg per day given orally for 4 consecutive weeks followed by 2 weeks off per treatment cycle. MAIN OUTCOME MEASURES: Assessment of clinical response, degree of tumor regression on imaging studies using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Primary end point was overall objective response rate (complete plus partial). Secondary end points were progression-free survival and safety. Response was evaluated by independent third-party core imaging laboratory and by treating physicians (investigator assessment). RESULTS: All 106 patients received sunitinib and were included in the intent-to-treat population for safety analyses. Of these, 105 patients were evaluable for efficacy analyses. The objective response rate according to an independent third-party assessment resulted in 36 patients with partial response (34%; 95% confidence interval, 25%-44%), and a median progression-free survival of 8.3 months (95% confidence interval, 7.8-14.5 months). The most common adverse events experienced by patients were fatigue in 30 (28%) and diarrhea 21 (20%). Neutropenia, elevation of lipase, and anemia were the most common laboratory abnormalities observed in 45 (42%), 30 (28%), and 27 (26%) patients, respectively. CONCLUSION: The results of this trial demonstrate the efficacy and manageable adverse-event profile of sunitinib as a single agent in second-line therapy for patients with cytokine-refractory metastatic clear-cell RCC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00077974.

Adult↗
PubMed2007

Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib.

Sunitinib is an inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors, and it has antitumor activity in metastatic renal cell carcinoma and gastrointestinal stromal tumors. To further investigate the fatigue associated with sunitinib therapy, thyroid function tests were performed on patients with metastatic renal cell carcinoma who were receiving sunitinib. Seventy-three patients with metastatic renal cell carcinoma were treated with sunitinib at the Cleveland Clinic Taussig Cancer Center, and 66 of them had thyroid function test results available. Fifty-six (85%) of the 66 patients had one or more abnormality in their thyroid function test results, consistent with hypothyroidism, and 47 (84%) of the 56 patients with abnormal thyroid function tests had signs and/or symptoms possibly related to hypothyroidism. Thyroid hormone replacement was undertaken in 17 patients, and symptoms improved in nine of them. Thyroid function test abnormalities appear to be common in patients with metastatic renal cell carcinoma treated with sunitinib, and routine monitoring is warranted.

Adult↗
PubMed2006

Sunitinib: a newly approved small-molecule inhibitor of angiogenesis.

The advent of targeted therapies has allowed treatment to be directed at signaling pathways integral to tumor growth and survival. Sunitinib (SU11248, sunitinib malate; Pfizer Inc., New York, NY, USA) is a novel oral small-molecule multitargeted receptor tyrosine kinase inhibitor that has demonstrated direct antitumor activity and antiangiogenic action. It targets the vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), stem-cell factor receptor and Fms-like tyrosine kinase receptor 3 receptor tyrosine-kinases. In January 2006, sunitinib malate was granted approval by the U.S. Food and Drug Administration for the treatment of gastrointestinal stromal tumor after disease progression on, or intolerance to, imatinib mesylate, as well as for the treatment of metastatic renal cell cancer. This review will discuss the development of sunitinib, particularly in acute myeloid leukemia, imatinib-resistant gastrointestinal stromal tumors and renal cell cancer. The review will also discuss ongoing trials with sunitinib in other malignancies such as neuroendocrine tumors and breast cancer, as well as its potential future development in combination therapy with other agents and in other malignancies.

Antineoplastic Agents↗
PubMed2006

Sunitinib relieves renal cell carcinoma spinal cord compression.

A 66-year-old previously healthy female was diagnosed with renal cell carcinoma (RCC) metastic to the 4th, 6th and 12th thoracic vertebrae. Despite external beam radiotheraphy (20G in 5 fractions), she progressed to spinal cord compression within 4 weeks and was wheelchair bound. Radiation and surgery were not considered suitable, but sunitinib was initiated. After two 6-week sunitinib cycles, she is fully ambulatory. She reports grade I fatigue and occasional epistaxis, as sole side effects. This case demonstrates that despite the rapid progression of the disease, which escaped the effect of radiation within four weeks, sunitinib resulted in complete clinical symptom resolution, which was confirmed radiographically. Moreover, it appears that the novel therapies for metastatic RCC may restore quality and quantity of life to many of those, whose disease previously appeared too advanced to treat.

Aged↗
PubMed2006

FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248).

Somatic mutations of FLT3 resulting in constitutive kinase activation are the most common acquired genomic abnormality found in acute myeloid leukemia (AML). The majority of these mutations are internal tandem duplications (ITD) of the juxtamembrane region (JM). In addition, a minority of cases of AML are associated with mutation of the FLT3 activation loop (AL), typically involving codons D835 and/or I836. We hypothesized that other novel mutations of FLT3 could also contribute to leukemogenesis. We genotyped 109 cases of AML and identified two novel gain-of-function mutations. The first mutation, N841 H, is similar to previously described mutations involving amino-acid substitutions of codon 841. The other novel mutation, FLT3 K663Q, is the first AML-associated gain-of-function mutation located outside the JM and AL domains. Of note, this mutation was potently inhibited by Sunitinib (SU11248), a previously described FLT3 kinase inhibitor. Sunitinib reduced the proliferation and induced apoptosis of transformed Ba/F3 cells expressing FLT3 K663Q. The potency of Sunitinib against FLT3 K663Q was similar to its potency against FLT3 ITD mutations. We conclude that FLT3 mutations in AML can involve novel regions of the TK1. Future studies are needed to define the incidence and prognostic significance of FLT3 mutations outside the well-established JM and AL regions.

Acute Disease↗
PubMed2006

Sunitinib malate.

Recently, there has been a growing interest in understanding the role of receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), in promoting tumor angiogenesis, tumor growth and metastasis. Sunitinib (sunitinib malate; SU11248; SUTENT; Pfizer Inc, New York, NY, USA) is a novel, orally bio-available, oxindole, multi-targeted tyrosine kinase inhibitor with high binding affinity for VEGFR and PDGFR which has shown anti-tumor and anti-angiogenic activities. This drug recently received approval from the US Food and Administration (FDA) in two indications simultaneously: advanced renal cell carcinoma (adRCC) and gastrointestinal stromal tumors (GIST), in patients who are resistant or intolerant to the treatment with imatinib. The present article reviews the recent pharmacologic and clinical data related to the use of this new promising drug in the field of oncology.

Antineoplastic Agents↗
PubMed2006

Long-term response with sunitinib for metastatic renal cell carcinoma.

A 65-year-old man with metastatic renal cell carcinoma developed progressive disease after treatment with interferon-alpha. He began treatment with sunitinib, a multitargeted tyrosine kinase inhibitor, on clinical trial. The patient achieved a partial response after two cycles of therapy, with a durable response continuing after 2 years of treatment. This case report illustrates the long-term response to sunitinib for patients with metastatic renal cell carcinoma.

Aged↗
PubMed2006

ZD6474 induces growth arrest and apoptosis of GIST-T1 cells, which is enhanced by concomitant use of sunitinib.

ZD6474 (Zactima, AstraZeneca, Macclesfield, UK) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases, with additional activity versus rearranged during transfection (RET). This study explored the effect of ZD6474 in gastrointestinal stromal tumor-T1 (GIST-T1) cells that possess a gain of function mutation in exon 11 of the c-KIT gene. ZD6474 induced growth arrest and apoptosis of GIST-T1 cells in association with blockade of c-Kit and its downstream effectors, including Akt and extracellular signal-regulated kinase (ERK). ZD6474 treatment also blocked the mammalian target of rapamycin (mTOR), which lies downstream of Akt and ERK. Interestingly, when ZD6474 was combined with sunitinib (SU11248; Sutent, Pfizer, Kalamazoo, MI, USA), a class III and V receptor tyrosine kinase inhibitor, the ZD6474-mediated growth inhibition was potentiated in association with further down-regulation of the mTOR targets p-p70S6K and p-4E-BP-1. The combination of ZD6474 and sunitinib should be investigated further.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Sunitinib malate for the treatment of solid tumours: a review of current clinical data.

Receptor tyrosine kinases (RTKs) play important roles in the regulation of cellular growth, and mutated or overexpressed RTKs have been implicated in various human cancers. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antitumour and antiangiogenic activity that recently received approval from the FDA for the treatment of advanced renal cell carcinoma and of gastrointestinal stromal tumours after disease progression on or intolerance to imatinib mesilate therapy. Sunitinib has also demonstrated promising clinical activity in the treatment of other advanced solid tumours. The present review provides an updated summary of emerging clinical experience with this promising new anticancer agent.

Animals↗
PubMed2006

Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects.

The effect of food on the oral bioavailability of sunitinib malate (SU11248, an oral, multi-targeted tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activities) was assessed in a randomized open-label, two-way crossover study. A 50-mg dose of SU11248 was administered to 16 healthy subjects after a 10-h fast in one period and after a high-fat, high-calorie meal in the other period. The 90% confidence intervals (CIs) for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were within the 80-125% bioequivalence range, indicating the absence of a food effect. SU11248 exposure increased slightly in the fed compared with the fasted state (ratios of fed/fasted geometric least square means: Cmax 104%, AUC0-last and AUC0-infinity both 112%). There was a delay in the formation/absorption of the active metabolite SU12662 in the fed state (mean Cmax decreased 23%), but exposure remained unaffected (90% CIs for AUC0-last and AUC0-infinity were within 80-125%). These results indicate that SU11248 can be administered with or without food.

Adolescent↗
PubMed2006

Clinical activity of sorafenib and sunitinib in renal cell carcinoma refractory to previous vascular endothelial growth factor-targeted therapy: two case reports.

Sunitinib and sorafenib are multitargeted receptor tyrosine kinase inhibitors of the vascular endothelial growth factor and platelet-derived growth factor receptor families with antiangiogenic and antitumor activity in metastatic renal cell carcinoma. The utility of these agents in patients refractory to previous treatment with the other agent is unknown. We report 2 cases highlighting that efficacy of these agents is possible after failure of the other agent. Further prospective study is needed.

Antineoplastic Agents↗