No abstract

SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.

At the dose of 50 mg/d (4 weeks on, 2 weeks off), sunitinib displays manageable toxicity. Antitumor activity supports further studies in patients with renal cell carcinoma, gastrointestinal, neuroendocrine, and stromal tumors. Future studies may consider including prospective imaging techniques such as high frequency ultrasound to monitor tumor density.

The results of this meta-analysis indicate that increased exposure to sunitinib is associated with improved clinical outcomes (longer TTP, longer OS, greater chance of antitumor response), as well as some increased risk of adverse effects. A sunitinib 50-mg starting dose seems reasonable, providing clinical benefit with acceptably low risk of adverse events.

Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.

Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and plateletderived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2-or a 1-week rest period. At the starting dose level of 50 mg (n ‫؍‬ 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations.

Background: Sunitinib malate (SUTENT ® ) is an oral, multitargeted tyrosine kinase inhibitor, approved multinationally for the treatment of advanced RCC and of imatinib-resistant orintolerant GIST. The purpose of this study was to explore potential biomarkers of sunitinib pharmacological activity via serial assessment of plasma levels of four soluble proteins from patients in a phase II study of advanced RCC: VEGF, soluble VEGFR-2 (sVEGFR-2), placenta growth factor (PlGF), and a novel soluble variant of VEGFR-3 (sVEGFR-3).

Purpose: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor. Following administration, sunitinib is metabolized by cytochrome P450 3A4 to an active metabolite (SU12662). The objective of this analysis was to assess sunitinib and SU12662 pharmacokinetics and to identify covariates that might explain variability in exposure following oral administration. Experimental Design: Data from 590 subjects (73 volunteers and 517 patients) in 14 studies were analyzed. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and gender, race, age, weight, creatinine clearance, Eastern Cooperative Oncology Group score, and tumor type. Simulations were done to determine the predicted effect of these covariates on exposure.Results: Separate models were developed for sunitinib and SU12662 (each a two-compartment model with first-order absorption and elimination). Sunitinib parameters were estimated as CL/F, 51.8 L/h andVd/F central , 2,030 liters. SU12662 parameters were estimated as CL/F, 29.6 L/h and Vd/F central , 3,080 liters. Tumor type (except acute myeloid leukemia), Asian race, gender, body weight, and elevated Eastern Cooperative Oncology Group score described a portion of the variability in CL/F for sunitinib and metabolite; gender and body weight explained some of the variability in Vd/F central for sunitinib and metabolite. Among patients, the predicted changes in sunitinib and metabolite AUC and C max as a result of the individual covariates ranged up to 17%. Conclusion: The magnitude of the predicted changes in exposure with the covariates studied minimizes the necessity for dose adjustment in any of these subpopulations.