JOURNAL OF INTERFERON & CYTOKINE RESEARCH 24:37–41 (2004) © Mary Ann Liebert, Inc. A Phase II Trial of Temozolomide and IFN-a in Patients with Advanced Renal Cell Carcinoma USHA SUNKARA, JANET R. WALCZAK, LORI SUMMERSON, THERESA ROGERS, MARIO EISENBERGER, SAMUEL DENMEADE, ROBERTO PILI, CAROL ANN HUFF, VICTORIA SINIBALDI, and MICHAEL A. CARDUCCI ABSTRACT The combination of temozolomide (TEM) and interferon-a (IFN-a) previously demonstrated a 30% response rate in metastatic melanoma. A single institution, phase II trial evaluating the efficacy of TEM/IFN in pa- tients with advanced renal cell carcinoma (RCC) was conducted. Safety and tumor response were the main outcomes. Eligible patients received 200 mg/m 2 /day TEM orally on days 1–5 every 28 days, with IFN 2.5 mil- lion U/m 2 /day subcutaneously (s.c.) three alternate days/week for days 1–15 first cycle, then 5 million U/m 2 /day s.c. 3 alternate days/week throughout each 28-day cycle. Efficacy was evaluated every 8 weeks, and dose-lim- iting toxicities (DLTs) were treated with dose reductions of the culprit drug. Sixteen patients (ages 37–67) were initially enrolled. Of the 14 evaluable patients, there was one minor response. Best response was stable disease, with 7 patients remaining on study for $6 months. Five were alive for more than 2 years, and 2 re- main alive at 45 and 50 months after enrollment. DLTs included TEM-induced myelosuppression and IFN- induced fever/chills. Other toxicities were mild to moderate (grades 1–3). The combination of TEM/IFN proved quite tolerable. This regimen appears inactive in terms of response in this population with poor prognosis, but the patients with stable disease $6 months remain of interest. 37 INTRODUCTION T HE INCIDENCE OF RENAL CELL CANCER (RCC) in the United States was estimated to be approximately31,900 new cases in 2003. (1) It is the third most common genitourinary cancer, and roughly 12,000 deaths occur each year. (1) At the time of diagnosis, approximately 45% of patients have disease local- ized to the kidney,25% have locally advanceddisease,and 30% have distant metastases. At present, surgical resection of all dis- cernable disease is the only potentially curative therapy. The 5- year survival rate has been reported to range from 83.3% in pa- tients with nonmetastatic, low-risk disease (Fuhrman grade 1–2 and excellentperformancestatus) to 44% for patients with non- metastatic high-risk disease (Furhman grade .1 and good to excellent performance status) to 0% in patients with metastatic high-risk disease. (2) Selected patients with stage IV disease oc- casionally have prolonged disease-free survival after resection of solitary metastases. For those patients with unresectable dis- ease, therapeutic options are limited in both number and effi- cacy. The 5-year survival rate for patients with stage IV dis- ease is ,5%. (3) Given that patientsare frequentlyasymptomatic when the cancer is in its early stage, they often seek medical attention when the disease is widespread. Over 250 different chemotherapy and hormonal therapy agents have not been successfulin reported phase II clinical tri- als since 1983. (4,5) Interleukin-2 (IL-2) is the only U.S. FDA- approved agent for the treatment of advanced renal cancer. Re- sponse rates with IL-2, in regimens ranging from high-dose bolus administration to lower dosing subcutaneously (s.c.), range from 15% to 20%. (6) Interferon- a2b (IFN), another im- munotherapy agent, has also been studied in advanced RCC, either alone or in combination with IL-2. (7,8) The overall re- sponse rate has been 10%–15%, with a median survival of ,12 months. (8) A longer survival time with IFN has been noted in those patients with higher performance status, primarily lung- only metastases, and previous nephrectomy. (9) Because RCC is quite resistant to standard chemotherapy, the addition of other antitumor agents to an IFN immunotherapy regimen should be investigated.Motzer et al. (10) have proposed that IFN should be viewed as the standard therapy to which new agents in phase II and III trials are compared with regard to progression-free and overall survival. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231-1000.