A Phase II Trial of Intrapatient Dose-Escalated Sorafenib in Patients With Metastatic Renal Cell Carcinoma

Sorafenib has been demonstrated in second-line setting with limited significant adverse events at a dose of 400 mg twice a day (b.i.d.) in patients with metastatic renal cell carcinoma; yet, the question remains if higher doses will have greater clinical activity with manageable adverse events. Forty-six patients who failed cytokine treatment received dose escalation sorafenib that started at 400 mg b.i.d. and ending with 800 mg b.i.d.; they were evaluated for response rate, progression-free survival, and overall survival. The high-dose sorafenib was tolerated by the patients, and 8 patients achieved complete response, 13 patients achieved partial response, and 21 patients had stable disease. Purpose: Sorafenib has been demonstrated as second-line therapy, with limited significant adverse events at a dose of 400 mg twice a day (b.i.d.) in patients with metastatic renal cell carcinoma. This study evaluated the ability of patients to dose-escalate, response rate, progression-free survival (PFS), and overall survival. Methods: The initial dose of sorafenib was 400 mg b.i.d.. Dose escalation of sorafenib to 600 mg b.i.d. occurred from days 29-56 and increased to 800 mg b.i.d. on day 57 and beyond as tolerated. Dose modifications were performed for toxicity per the National Cancer Institute Common Toxicity Criteria version 3.0. The patients were evaluated every 2 cycles (8 weeks) by using Response Evaluation Criteria in Solid Tumors version 1.0. Results: Forty-four patients were evaluable for response. Median age was 62.5 years, 39 patients had a Karnofsky Perfomance Status of 100%. Twenty-two patients received no prior therapy. Of the evaluable patients, 42 were dose escalated to 600 mg b.i.d., and 74% (31) of these were further dose escalated to 800 mg b.i.d.. Eight patients had a complete response (CR), 13 patients demonstrated a partial response (PR), and 21 patients had stable disease. Common treatment-related adverse events included hypertension, hand-foot syndrome, skin rash, diarrhea, dry skin, alopecia, and facial redness. Discussion: The majority of patients were escalated to 600 mg b.i.d. or 800 mg b.i.d.. Intrapatient dose-escalated sorafenib has promising antitumor activity as demonstrated by a 48% CR-PR rate (21 patients). Antitumor activity is further suggested by a prolonged PFS >= 6 months in 64% (28) of patients. Significant antitumor activity and reversible adverse events has been demonstrated in escalated doses of sorafenib.