A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period

Britten, Carolyn D.; Kabbinavar, Fairooz; Hecht, J. Randolph; Bello, Carlo L.; Li, Jim; Baum, Charles M.; Slamon, Dennis J.

doi:10.1007/s00280-007-0498-4

Cited by 126 publications

(76 citation statements)

References 18 publications

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“…In agreement with previous reports (Mendel et al, 2003), nanomolar concentrations (10-100 nM) of sunitinib inhibited VEGF-induced phosphorylation of VEGFR2 in human endothelial cells ( Figure 1a) and VEGF-induced endothelial cell proliferation (Figure 1b). These concentrations are clinically relevant, as circulating concentrations of sunitinib measured in patients are in the nanomolar range and do not typically exceed 200 nM (Faivre et al, 2006;Britten et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

et al. 2010

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The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2.

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Section: Resultsmentioning

confidence: 99%

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

et al. 2010

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“…Our clinical trial is, to the best of our knowledge, the first phase 2 clinical trial that has examined the effect of sunitinib solely on DTC, ensuring a homogeneous study population. Two phase 1 clinical trials reported a PR in two patients with thyroid cancer (one patient in each study) after treatment with sunitinib (21,22). Several groups have initiated phase 2 clinical trials of sunitinib in thyroid cancer.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Phase 2 clinical trial of sunitinib as adjunctive treatment in patients with advanced differentiated thyroid cancer

Bikas

Kundra

Desale

et al. 2016

European Journal of Endocrinology

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Objective: Our objective was to evaluate the efficacy and safety of sunitinib following at least one course of radioactive iodine treatment in patients with advanced differentiated thyroid cancer (DTC). The study endpoints included best response rate (including best objective response rate) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, measurement of serum thyroglobulin (Tg), and toxicity evaluation. Design and methods: This was a single center, nonrandomized, open-label, phase 2 clinical trial. In total, 23 patients were enrolled and were treated with a starting daily, oral dose of 37.5 mg sunitinib. Patients were evaluated with imaging, laboratory tests, and physical examination periodically per protocol. Results: The mean best response was a decrease of 17.2% (S.D. 22.8) in tumor sum from baseline. Six (26%) patients achieved a partial response (PR), and 13 (57%) had stable disease (SD) for a clinical benefit rate (PRCSD) of 83%. The overall median PFS was 241 days (interquartile limits, 114-518). No statistically significant difference was observed between the medians of the baseline and post-treatment Tg values (PZ0.24). The most common adverse events included grades 1 and 2 decreases in blood cell counts (especially leukocytes), diarrhea, fatigue, hand-foot skin reaction, nausea, musculoskeletal pain, and hypertension.Conclusions: These data demonstrate that sunitinib exhibits significant anti-tumor activity in patients with advanced DTC. Since sunitinib was relatively well-tolerated, there is the potential for clinical benefit in these patients, and further investigation of this agent is warranted.

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“…In phase I clinical trials the incidence of CTC grade >=3 hypertension was 7.3%. [57] In single-agent phase II clinical trials with sunitinib the rates of grade 1-2 and grade 3 hypertension were 8.4% and 7.5% respectively. [58] In phase III clinical trials which established the efficacy of sunitinib in gastrointestinal stroma tumors (GISTs) and renal cell carcinoma grade 3 hypertension was more frequent in the sunitinib group than in the placebo group (3% versus 0%) or the interferon group (8% versus 1%).…”

Section: Mechanism Of Cardiotoxicity Of Sunitinbmentioning

confidence: 99%

“…[59,60] In phase I clinical trials of sunitinib two of 55 patients developed left ventricular dysfunction and heart failure. [57] In the phase II clinical trials of sunitinib in renal cell carcinoma 8.9% of patients developed a reduction in LVEF. [58] Grade 3 reductions in LVEF were seen in a phase III trial of renal cell carcinoma.…”

Section: Mechanism Of Cardiotoxicity Of Sunitinbmentioning

confidence: 99%