Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment.

OBJECTIVE: To assess both clinical and biological efficacy and toxicity of sorafenib in patients with metastatic renal cell carcinoma (mRCC) previously treated with an anti-angiogenic vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. METHODS: Sorafenib is an orally active multikinase inhibitor approved for the treatment of mRCC. Drug-focused translational research on tissues (i.e. B-RAF) and plasma (VEGFR-α, circulating endothelial cells, endothelial progenitor cells) was performed to define biological predictive and prognostic markers and their related kinetics. Patients with mRCC pretreated with an anti-angiogenic treatment, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 and adequate organ function were eligible. Patients received sorafenib 400 mg twice a day continuously in 4-week cycles. Patients with no progressive disease at 12 weeks continued to receive sorafenib at the standard dose, whereas progressing patients received an increased dose (600 mg twice a day) with early disease restaging after 4 weeks. Patients who progressed at 600 mg twice a day went off study. Efficacy (overall tumour control) was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: In all, 19 patients were entered. The baseline characteristics were as follows: ECOG PS 0-1 94.8%; median (range) age 62 (41-81) years; nephrectomy 100%; surgery for metastatic disease 26.4%; clear cell 79.1%; papillary cell 15.7%; sarcomatoid/high grade 5.2%; two or more metastatic sites 84%. Overall, 11 patients (58%) had disease control at 6 months without significant correlation between response to prior therapy and hypertension. Progression-free survival (PFS) of 8.3 months was observed. Of six patients for whom the dose was escalated due to early progression, three benefitted with PFS of >3 months. Three (15.7%) of 19 patients had a V600E mutation and one had a K601E mutation; PFS appeared to be substantially shorter in these patients compared with 15 patients with wild-type B-RAF (2.5 vs 9.1 month, P < 0.05). The most common toxicity (National Cancer Institute Common Toxicity Criteria, NCIC 3.0, all patients) was grade ≥1 diarrhoea and grade 2-3 hand-foot syndrome in 11 patients. Grade 3 mucositis was observed in one patient. CONCLUSIONS: Sorafenib at doses of 400-600 mg twice a day continuously results in acceptable and well tolerated salvage treatment after VEGFR tyrosine kinase inhibitor failure. In progressive patients, treatment with a higher dose could be a valid option and B-RAF mutations may be an interesting predictive marker to be studied in a larger randomized trial.

Darbepoetin alfa administered every three weeks (Q3W) in anemic cancer patients receiving chemotherapy (CT).

BACKGROUND: Darbepoetin alfa, has a longer halflife than epoetin alfa (rHuEPO) due to its increased sialylated carbohydrate content and can be administered less frequently. Its advantage in terms of response is not entirely clear. PATIENTS AND METHODS: From August 2005 until October 2006, 64 anemic patients (hemoglobin < or =11.5 g/dl) with advanced metastatic cancer receiving chemotherapy (CT), median age 65 years (range 33-77), median Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (range 0-1), were treated with subcutaneous (s.c.) darbepoetin alfa 500 microg every 3 weeks (Q3W) and a single intravenous (i.v.) dose of 125 mg of elemental iron at the beginning of the treatment period followed by an oral daily iron supplement (200 mg of elementary iron). The treatment effect was evaluated as a response (Hb increase > or =1 g/dl) or a major response (Hb increase > or =2 g/dl) after 2, 4, 6 and 8 weeks. The patients were questioned about fatigue. RESULTS: After 8 weeks of treatment, a treatment response was observed in 11 out of the 29 evaluable patients (38%) with a major response in 10%. The mean Hb change was 0 g/dl, +0.9 g/dl, +0.75 g/dl and +0.7 g/dl respectively at 2, 4, 6 and 8 weeks. Blood transfusions were required in 9 patients (31%). At baseline, 39 out of the 64 patients (61%) reported grade 1 or 2 fatigue. At 8 weeks the patients with a major response did not show any evidence of fatigue. CONCLUSION: Darbepoetin alfa Q3W is moderately effective in reducing anemia in heavily pretreated and advanced stage chemotherapy treated patients.