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Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 3958-3964 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.5916 Phase I/II Trial of Temsirolimus Combined With Interferon Alfa for Advanced Renal Cell Carcinoma
From the Memorial Sloan-Kettering Cancer Center, New York; Our Lady of Mercy Cancer Center/New York Medical College, Bronx, NY; Fox Chase Cancer Center, Philadelphia; Wyeth Research, Collegeville, PA; Robert W. Franz Cancer Research Center, Portland, OR; Beth Israel Deaconess Medical Center, Boston, MA; Institut Gustave-Roussy, Villejuif; Centre Leon Berard, Lyon; University Hospital of Strasbourg-Hautepierre, Strasbourg, France; and Wyeth Research, Cambridge, MA Address reprint requests to Robert J. Motzer, MD, Genitourinary Oncology Service, Division of Solid Tumor Oncology, Departments of Medicine and Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: motzerr{at}mskcc.org
Purpose: Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC. Patients and Methods: Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information. Results: Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months. Conclusion: The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.
Treatment of advanced renal cell carcinoma (RCC) with cytokines, particularly interferon alfa (IFN) and interleukin-2 (IL-2), has been standard practice.1 Based on improved understanding of RCC biology and the need for more effective therapy, novel agents are currently being developed.2,3 Mammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates cell growth and proliferation.3-5 Expression of hypoxia-inducible factor and hypoxia-inducible factor–target genes are also upregulated via mTOR.4,6,7 The hypoxia-inducible pathway is important in the pathobiology of RCC.6 Temsirolimus, a novel mTOR inhibitor, has been studied in RCC and other advanced malignancies.8-17 A phase II trial of temsirolimus in patients with advanced refractory RCC demonstrated antitumor activity, acceptable tolerability, and encouraging survival rates.8 Preclinical models of renal tumor xenografts in nude mice receiving temsirolimus showed marked reduction in tumor vascularization, suggesting its antitumor activity may result partly from inhibition of angiogenesis. IFN has demonstrated antiangiogenic activity and has been effective in treating human RCC. Temsirolimus combined with IFN to treat human RCC (A498 line) xenograft-bearing nude mice showed a synergistic effect of tumor regression compared with only tumor stabilization for each compound alone.18 This phase I dose-escalation study was performed in patients with advanced RCC to determine safety and to establish a recommended dose for temsirolimus combined with IFN. An expanded cohort was treated at the recommended dose to assess further tolerability, preliminary antitumor activity, and pharmacokinetics. This was the first study investigating targeted therapy combined with biologic therapy in advanced RCC.19,20
Patients Eligible patients had stage IV RCC with disease progression and may have received up to two regimens of prior immunotherapy, chemotherapy, or other systemic therapy. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST),21 and adequate hepatic, renal, and bone marrow function (AST/ALT  3x the institutional upper limit of normal or 5x the institutional upper limit of normal if liver metastases were present; total bilirubin 1.5 mg/dL; serum creatinine < 2 mg/dL or estimated creatinine clearance  60 mL/min; hemoglobin 9 g/dL; absolute neutrophil count 1,500 cells/µL; and platelet count 100,000/µL). Serum cholesterol had to be 350 mg/dL with triglycerides 400 mg/dL. Exclusion criteria comprised CNS metastases, immunosuppressive agents used within 3 weeks of study, unstable angina or myocardial infarction in the previous 6 months, or history of life-threatening arrhythmia.
Study Design
This phase I, open-label study was divided into two sequential parts. In part 1, cohorts of at least six patients were enrolled sequentially to receive one of six ascending dose levels of intravenous (IV) temsirolimus once per week with ascending doses of subcutaneous IFN three times per week. In part 2, an additional cohort (
Treatment and Dose-Escalation Plan Patients were evaluated for adverse events based on the National Cancer Institute Common Toxicity Criteria, version 2.0. Treatment-emergent adverse events were those not present at baseline or those present but worsening in severity and/or frequency during treatment. Escalation in dose levels was based on a safety evaluation of the previous cohort after one cycle (4 weeks) of treatment. Dose escalation occurred until two or more patients in a cohort experienced a dose-limiting toxicity, defined as a grade 3 or 4 temsirolimus/IFN-related toxicity occurring within the first treatment cycle and requiring dose reduction. Grade 3 constitutional symptoms during the first week of IFN administration and toxicities not believed to be related to the dose were not considered dose-limiting toxicities. If at least two of six patients experienced dose-limiting toxicities at a given dose level, the maximum-tolerated dose was exceeded and additional patients were entered at the prior dose level.
Antitumor Activity Progression-free survival was measured from the first temsirolimus dose until the date of documented disease progression or death, whichever occurred first. For analysis of progression-free survival, patients not known to have experienced progression or to have died were censored at their last tumor assessment. Overall survival was measured from the first temsirolimus dose until death, and censored at the last date the patient was known to be alive. For these time-to-event end points, medians and 95% CIs were estimated using Kaplan-Meier methods.
Statistics
Pharmacokinetics Temsirolimus and sirolimus concentrations were measured simultaneously using a validated procedure14,15 (SFBC Taylor Technology Inc, Princeton, NJ). Drug concentrations were analyzed using a noncompartmental method to determine values for peak concentration (Cmax), time to peak concentration, half-life, area under the curve (AUC), apparent clearance (CL/fm), and steady-state volume of distribution (Vdss), where fm is the bioavailability factor of the metabolite.22 The study was powered to assess drug levels in a descriptive manner only and was not intended to formally evaluate drug interactions.
The study enrolled 71 patients from February 2002 through December 2003. Among these patients, 39 (55%) had received prior therapy, and 36 received IL-2. Only one patient, who was in the recommended-dose cohort, had received IFN previously. In total, 39 patients were treated at the recommended dose level, including those in both the dose-escalation and expanded cohorts (Table 1).
Summary of Treatment During the dose-escalation phase, six dose levels of temsirolimus/IFN were evaluated (Table 2). No dose-limiting toxicities or significant safety concerns were observed during the first 4 weeks for the first three dose levels, up to temsirolimus 15 mg/IFN 6 MU. Dose-limiting toxicities of grade 3 stomatitis (n = 1), grade 3 fatigue with pneumonia (n = 1), and grade 3 nausea/vomiting with dehydration and syncope (n = 1) occurred with temsirolimus 25 mg/IFN 6 MU, temsirolimus 15 mg/IFN 9 MU, and temsirolimus 20 mg/IFN 6 MU, respectively. In addition to these dose-limiting toxicities in the initial 4 weeks, other patients had clinically significant safety considerations (Table 2). Considering all the adverse events observed, we concluded that temsirolimus 15 mg/IFN 6 MU should be the recommended dose even though the predefined criteria for the maximum-tolerated dose had not been met. Thirty-nine patients were enrolled to receive the recommended dose, and 37 of these patients received temsirolimus.
All 71 patients enrolled onto this study received at least one dose of IFN, and 69 patients (97%) completed the initial 4 weeks (cycle 1) of treatment (three doses of temsirolimus, 4 weeks of IFN). Most patients (59%) received at least 24 weeks of temsirolimus treatment (mean, 39.7 weeks; range, 3 to 164 weeks). For patients who were enrolled to receive the recommended dose of temsirolimus 15 mg/IFN 6 MU, the mean number of temsirolimus doses was 27.7 (range, 0 to 116 doses), and for the 37 of 39 patients who received temsirolimus, the mean weekly dose intensity was 9.9 mg (range, 4.2 to 13.6 mg); the mean number of IFN doses was 89.8 (range, 9 to 360 doses) and mean weekly (administered three times per week) IFN dose intensity was 12.9 MU (range, 5.1 to 18.8 MU).
Adverse Events
Interstitial pneumonia occurred in five patients (7%); four patients experienced grade 1 or 2 and one patient experienced grade 3 interstitial pneumonia (5 mg/IFN 6 MU dose level). At study entry, the latter patient had shortness of breath, with bilateral lung infiltrates, pleural effusion, and cough. After receiving IFN and 3 weekly (once weekly for 3 weeks) doses of temsirolimus, shortness of breath and pleural effusion worsened and the patient developed moderate pericardial effusion. Because this adverse event occurred after cycle 1, it was not considered to be a dose-limiting toxicity in the dose-escalation part of the study. The patient withdrew from the study, was treated with corticosteroids and antibiotics, and underwent a lung biopsy that revealed numerous collections of foamy histiocytes within alveolar spaces and interalveolar septae, along with multiple foci of metastatic carcinoma consistent with primary disease. The patient was treated subsequently with fluorouracil and died as a result of progressive disease 3 weeks later. Temsirolimus dose reductions were required because of treatment-related adverse events in 38 (55%) of the 69 patients who received the drug. One, two, or three dose reductions were required for 27 (39%), eight (12%), and three (4%) patients, respectively. Reasons for temsirolimus dose reduction were thrombocytopenia (eight patients; 12%), elevated triglycerides (six patients; 9%), stomatitis (four patients; 6%), neutropenia (two patients; 3%), hyperglycemia (one patient; 1%), rash (one patient; 1%), and other clinical laboratory abnormalities (such as elevated liver aminotransferases) and other adverse events (such as pneumonia). More than one reason was reported for some patients. In the recommended-dose cohort, 19 patients (51%) required at least one temsirolimus dose reduction and 28 patients (76%) required at least one temsirolimus dose delay because of toxicity. Nineteen patients (27%) withdrew because of adverse events after a median of 88 days on study (range, 30 to 639 days), including 12 (31%) of the 39 patients in the recommended-dose cohort. Two or more patients discontinued treatment because of asthenia (six patients; 8%), pulmonary adverse events (five patients; 7%), anemia (two patients; 3%), confusion (two patients; 3%), rash (two patients; 3%), or elevated liver aminotransferases (two patients; 3%). More than one adverse event was reported for some patients. Among the 19 patients who withdrew, 11 (16%) discontinued because of temsirolimus-related adverse events and eight (11%) discontinued because of adverse events considered to be unrelated to temsirolimus treatment. Among the 12 patients who received the recommended dose and withdrew, eight (75%) discontinued because of temsirolimus-related adverse events and four (25%) discontinued because of adverse events unrelated to treatment. Two patients died while on study, but neither death was related to treatment.
Response Forty-two patients (68%) had a reduction in target tumor burden. Figure 1 shows the maximum percentage change in target tumor burden for each patient with postbaseline measurements (n = 62). Percentage change in target tumor burden was calculated using the sum of the longest diameters of target lesions as defined by RECIST (Fig 1).21
Median progression-free survival was 9.1 months (95% CI, 6.2 to 13.0) for the entire population (Fig 2A). Median overall survival was 18.8 months (95% CI, 15.0 to 25.0 months; Fig 2B). For patients in the recommended-dose cohort, median progression-free survival was 7.6 months (95% CI, 5.5 to 11.0 months) and median overall survival was 22.1 months (95% CI, 11.0 to 26.0 months).
Pharmacokinetics Whole-blood concentrations for temsirolimus were available from 31 patients. Temsirolimus Cmax, AUC, CL, and Vdss increased with temsirolimus dose, as did sirolimus Cmax and AUC (data not shown). At the recommended dose of temsirolimus 15 mg/IFN 6 MU, the temsirolimus mean Cmax, AUC, CL, and Vdss were 407 ng/mL (standard deviation [SD], 130 ng/mL), 1,506 ng·h/mL (SD, 422 ng·h/mL), 11 L/h (SD, 3 L/h), and 157 L (SD, 60 L), respectively. The sirolimus mean Cmax and AUC were 60.8 ng/mL (SD, 19.5 ng/mL) and 5,159 ng·h/mL (3,262 ng·h/mL), respectively. These values and the modest interpatient variability were comparable to those previously reported for single-agent temsirolimus in patients with cancer.8,9,15,17
This study established the recommended dose and safety profile for administering temsirolimus in combination with IFN to patients with advanced RCC. A safety review of all available data, which included adverse events reported after cycle 1, established temsirolimus 15 mg/IFN 6 MU as the recommended dose to assess safety further in an expanded cohort. Among the 39 patients treated at the recommended dose, temsirolimus dose reduction, dose delays, and withdrawal due to toxicity were required in 51%, 76%, and 21%, respectively. The types of adverse events occurring in this study are associated with single-agent IFN (eg, chills, nausea and vomiting, asthenia, and anorexia)23-25 and with single-agent temsirolimus (eg, rash, stomatitis, asthenia, anorexia, and hypertriglyceridemia)8,15 in patients with advanced RCC. In our study, no difference with regard to toxicity was recognized between interferon alfa-2a and interferon alfa-2b when used in combination with temsirolimus. Overall, the most frequently occurring grade 3 or 4 treatment-related adverse events were leukopenia (32%), hypophosphatemia (27%), asthenia and anemia (21% each), and hypertriglyceridemia (15%). Dyspnea and pneumonitis will require additional vigilance in future studies of temsirolimus. The frequency and severity of asthenia, anemia, and leukopenia were higher with combination therapy compared with those previously reported with temsirolimus monotherapy.8 The recommended temsirolimus dose for combination with IFN is 40% lower than the monotherapy dose being studied in advanced RCC. In cancer patients, temsirolimus Cmax and AUC increase in a less than proportional manner with increasing dose.8,15 With temsirolimus 15 mg/IFN 6 MU, temsirolimus blood concentrations (mean Cmax, 407 ng/mL [SD, 130 ng/mL] ng/mL; AUC, 1,506 ng·h/mL [SD, 422 ng·h/mL] ng·h/mL) were comparable to those obtained with 25-mg temsirolimus monotherapy [mean Cmax, 595 ng/mL [SD, 102 ng/mL]; AUC, 1,580 ng·h/mL [SD, 270 ng·h/mL]), which showed antitumor activity in patients with advanced RCC.8 Blood concentrations were also in the range of concentrations that inhibit tumor cell proliferation in vitro (concentration that inhibits 50% range, 0.0005 to 5.9 µmol/L) and cause delay of tumor growth in animals.26,27 Thus, the recommended temsirolimus dose for this combination seemed to be capable of optimal biologic activity. Patients with advanced RCC who received the combination of temsirolimus and IFN had a median progression-free survival interval of 9.1 months. This compares favorably with values obtained in a phase II study of single-agent temsirolimus 25, 75, and 250 mg in 111 previously treated advanced RCC patients.8 In that study, median progression-free survival was 6.3, 6.7, and 5.2 months, respectively. For IFN first-line therapy, the median time to progression is less than 5 months, and median progression-free survival for various agents including cytokines administered as second-line therapy is less than 3 months.25,28 Analysis of overall survival data in this study is limited by the possibility that some patients subsequently may have entered trials with other agents. Temsirolimus is one of several targeted agents showing activity against advanced RCC. The antitumor activity of temsirolimus displayed in this study and in the single-agent phase II study8 bears some similarity to the antitumor activities observed with sorafenib29 and sunitinib30 in that disease stabilization is an important component of the clinical benefit achieved with these agents. In summary, the mTOR inhibitor temsirolimus is the first of a new class of agents showing antitumor activity against advanced RCC. The study reported here established the feasibility of a novel treatment strategy for advanced RCC, combining a targeted therapy with biologic therapy. On the basis of the safety review of all data, temsirolimus 15 mg/IFN 6 MU was established as the recommended dose and was used in a phase III study.31 Clinical trials with temsirolimus in combinationwith other targeted agents will define further its role in the treatment of advanced RCC.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Laurence Moore, Wyeth Research; Timothy O'Toole, Wyeth Research; Joseph P. Boni, Wyeth Research Leadership: N/A Consultant: Robert J. Motzer, Wyeth Research; Gary R. Hudes, Wyeth Research; Bernard J. Escudier, Wyeth Research; Sylvie Negrier, Bayer Healthcare, Pfizer Inc; Janice P. Dutcher, Wyeth Research Stock: N/A Honoraria: Bernard J. Escudier, Wyeth Research Research Funds: Robert J. Motzer, Wyeth Research; Janice P. Dutcher, Wyeth Research Testimony: N/A Other: N/A
Conception and design: Robert J. Motzer, Gary R. Hudes, Bernard J. Escudier Administrative support: Timothy O'Toole Provision of study materials or patients: Robert J. Motzer, Gary R. Hudes, Brendan D. Curti, David F. McDermott, Bernard J. Escudier, Sylvie Negrier, Brigitte Duclos, Laurence Moore, Joseph P. Boni, Janice P. Dutcher Collection and assembly of data: Brendan D. Curti, Bernard J. Escudier, Laurence Moore, Timothy O'Toole, Joseph P. Boni, Janice P. Dutcher Data analysis and interpretation: Robert J. Motzer, Gary R. Hudes, Laurence Moore, Timothy O'Toole, Joseph P. Boni, Janice P. Dutcher Manuscript writing: Robert J. Motzer, Gary R. Hudes, Laurence Moore, Timothy O'Toole, Joseph P. Boni Final approval of manuscript: Robert J. Motzer, Gary R. Hudes, Brendan D. Curti, David F. McDermott, Bernard J. Escudier, Sylvie Negrier, Brigitte Duclos, Laurence Moore, Joseph P. Boni, Janice P. Dutcher
We thank the patients, their families, and the clinical personnel who participated in this study, and Laure Galand, Kristi Zonno, Bonnie Marshall, Gary Dukart, Charles Zacharchuk, Nicole Hinton, Ed Faith, Steven Kong, and Ron Yannuzzi from Wyeth Research, and Peloton Advantage for assistance with manuscript preparation.
Supported by Wyeth Research, Cambridge, MA. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 1, 2003, Chicago, IL, and at the 40th Annual Meeting of the American Society of Clinical Oncology, June 7, 2004, New Orleans, LA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 353:2477-2490, 2005 2. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002 3. Patel PH, Chaganti RS, Motzer RJ: Targeted therapy for metastatic renal cell carcinoma. Br J Cancer 94:614-619, 2006[Medline] 4. Bjornsti MA, Houghton PJ: The TOR pathway: A target for cancer therapy. Nat Rev Cancer 4:335-348, 2004[CrossRef][Medline] 5. Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al: Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66:5549-5554, 2006 6. Pantuck AJ, Zeng G, Belldegrun AS, et al: Pathobiology, prognosis, and targeted therapy for renal cell carcinoma: Exploiting the hypoxia-induced pathway. Clin Cancer Res 9:4641-4652, 2003 7. Thomas GV, Tran C, Mellinghoff IK, et al: Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12:122-127, 2006[CrossRef][Medline] 8. Atkins MB, Hidalgo M, Stadler WM, et al: Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909-918, 2004 9. Boni JP, Leister C, Bender G, et al: Population pharmacokinetics of CCI-779: Correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther 77:76-89, 2005[CrossRef][Medline] 10. Chan S, Scheulen ME, Johnston S, et al: Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23:5314-5322, 2005 11. Chang SM, Wen P, Cloughesy T, et al: Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357-361, 2005[CrossRef][Medline] 12. Galanis E, Buckner JC, Maurer MJ, et al: Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A North Central Cancer Treatment Group Study. J Clin Oncol 23:5294-5304, 2005 13. Peralba JM, DeGraffenried L, Friedrichs W, et al: Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887-2892, 2003 14. Punt CJ, Boni J, Bruntsch U, et al: Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 14:931-937, 2003 15. Raymond E, Alexandre J, Faivre S, et al: Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336-2347, 2004 16. Witzig TE, Geyer SM, Ghobrial I, et al: Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23:5347-5356, 2005 17. Hidalgo M, Buckner JC, Erlichman C, et al: A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12:5755-5763, 2006 18. Gibbons JJ: CCI-779 potentiates the inhibitory effect of the anti-angiogenesis drug interferon-alpha on the growth of a human renal cell carcinoma in nude mice: RPT-49843. Pearl River, NY, Wyeth Research, 2006 19. Dutcher JP, Hudes G, Motzer R, et al: Preliminary report of a phase 1 study of intravenous (IV) CCI-779 given in combination with interferon-alfa (IFN) to patients with advanced renal cell carcinoma (RCC). Proc Am Soc Clin Oncol 21:213, 2003 (abstr 854) 20. Smith JW, Ko Y-J, Dutcher J, et al: Update of a phase 1 study of intravenous CCI-779 given in combination with interferon-alfa to patients with advanced renal cell carcinoma. J Clin Oncol 22:385s, 2004 (suppl; abstr 4513) 21. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 22. Jusko WJ: Guidelines for collection and analysis of pharmacokinetic data, in: Evans WE, Schentag JJ, Jusko WJ, eds: Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring (ed 3). Vancouver, WA, Applied Therapeutics Inc, 1992 23. Interferon-alpha and survival in metastatic renal carcinoma: Early results of a randomised controlled trial—Medical Research Council Renal Cancer Collaborators. Lancet 353:14-17, 1999[CrossRef][Medline] 24. De Mulder PH, Oosterhof G, Bouffioux C, et al: EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma: The EORTC Genitourinary Group. Br J Cancer 71:371-375, 1995[Medline] 25. Motzer RJ, Murphy BA, Bacik J, et al: Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 18:2972-2980, 2000 26. Podsypanina K, Lee RT, Politis C, et al: An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/– mice. Proc Natl Acad Sci U S A 98:10320-10325, 2001 27. Shi Y, Gera J, Hu L, et al: Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 62:5027-5034, 2002 28. Motzer RJ, Bacik J, Schwartz LH, et al: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454-463, 2004 29. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505-2512, 2006 30. Motzer RJ, Michaelson MD, Redman BG, et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24, 2006 31. Hudes G, Carducci M, Tomczak P, et al: A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma. J Clin Oncol 24:2s, 2006 (suppl; abstr LBA4) Submitted January 10, 2007; accepted June 11, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
