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Double-Blind Randomized Phase II Study of the Combination of Sorafenib and Dacarbazine in Patients With Advanced Melanoma: A Report From the 11715 Study Group

David F. McDermott, Jeffrey A. Sosman, Rene Gonzalez, F. Stephen Hodi, Gerald P. Linette, Jon Richards, James W. Jakub, Muralidhar Beeram, Stefano Tarantolo, Sanjiv Agarwala, Gary Frenette, Igor Puzanov, Lee Cranmer, Karl Lewis, John Kirkwood, J. Michael White, Chenghua Xia, Kiran Patel, Evan Hersh

From the Beth Israel Deaconess Medical Center; Dana Farber Cancer Institute, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of Colorado Health Sciences Center, Aurora, CO; Washington University School of Medicine, St Louis, MO; Lutheran General Cancer Care Center, Park Ridge, IL; Lakeland Regional Cancer Center, Lakeland, FL; University of Texas Health Science Center, San Antonio, TX; Nebraska Methodist Hospital, Omaha, NB; St Luke's Health System, Bethlehem; University of Pittsburgh Cancer Institute, Pittsburgh, PA; Carolinas Hematology-Oncology Associates, Charlotte, NC; University of Arizona Cancer Center, Tucson AZ; Onyx Pharmaceuticals, Inc, Emeryville, CA; and Bayer HealthCare Pharmaceuticals, West Haven, CT

Corresponding author: David F. McDermott, MD, Clinical Director of Biologic Therapy Program, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, East KS-159, Boston, MA; e-mail: dmcdermo{at}bidmc.harvard.edu

	ABSTRACT

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Purpose This phase II study evaluated the efficacy and safety of sorafenib plus dacarbazine in patients with advanced melanoma.

Patients and Methods This randomized, double-blind, placebo-controlled, multicenter study enrolled chemotherapy-naïve patients with stage III (unresectable) or IV melanoma. A total of 101 patients received placebo plus dacarbazine (n = 50) or sorafenib plus dacarbazine (n = 51). On day 1 of a 21-day cycle, patients received intravenous dacarbazine 1,000 mg/m² for a maximum of 16 cycles. Oral sorafenib 400 mg or placebo was administered twice a day continuously. The primary end point was progression-free survival (PFS) by independent assessment. Secondary and tertiary end points included time to progression (TTP), response rate, and overall survival (OS).

Results Median PFS in the sorafenib plus dacarbazine arm was 21.1 weeks versus 11.7 weeks in the placebo plus dacarbazine arm (hazard ratio [HR], 0.665; P = .068). There were statistically significant improvements in PFS rates at 6 and 9 months, and in TTP (median, 21.1 v 11.7 weeks; HR, 0.619) in favor of the sorafenib plus dacarbazine arm. No difference in OS was observed (median, 51.3 v 45.6 weeks in the placebo plus dacarbazine and sorafenib plus dacarbazine arms, respectively; HR, 1.022). The regimen was well tolerated and had a manageable toxicity profile.

Conclusion Sorafenib plus dacarbazine was well tolerated in patients with advanced melanoma and yielded an encouraging improvement in PFS. Based on these findings, additional studies with the combination are warranted in this patient population.

	INTRODUCTION

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In 2007, an estimated 59,940 new cases of melanoma were diagnosed and approximately 8,110 patients died of the disease in the United States.¹ Worldwide, the incidence of melanoma continues to rise at a rate of approximately 3% per year.² If detected and treated at an early stage, melanoma has a cure rate of approximately 90%.³ In contrast, the prognosis for advanced disease is poor with an average 5-year survival rate of 18% and a median survival of 7.8 months.^4-6 Given these statistics, there is an urgent need to identify more effective therapeutic agents for the treatment of advanced melanoma.

While there is no widely accepted standard of care for metastatic melanoma, dacarbazine is the most commonly used cytotoxic agent. Dacarbazine has a moderate toxicity profile, but has a low objective response rate of 5% to 20% with a median progression-free survival (PFS) of 1.5 to 1.6 months and no improvement in overall survival (OS).^7-10 Several investigators have attempted to combine targeted therapy and dacarbazine chemotherapy in an attempt to improve treatment response. Immunotherapy regimens, specifically those containing interferon-alfa and interleukin-2, and biochemotherapy have also been studied extensively in melanoma.^11-18 To date, no current therapy, single-agent or combination, has resulted in improved survival compared with dacarbazine.^6,7,19

The Ras-Raf-MEK-ERK signaling pathway is activated in the vast majority of melanomas. Melanomas have been reported to be dependent on the activation of this pathway for replication and survival.^20-23 Sorafenib is an inhibitor of Raf kinase in vitro and in vivo, with significant dose-dependent antitumor activity in human tumor xenografts.^24,25 While sorafenib has limited single-agent activity in advanced melanoma, the combination of sorafenib and dacarbazine resulted in manageable toxicity and encouraging antitumor activity in phase I and open-label phase II studies.^26-29 To further evaluate the safety and efficacy of adding sorafenib to dacarbazine in patients with advanced melanoma, we conducted a randomized phase II, double-blind, placebo-controlled trial.

	PATIENTS AND METHODS

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Patients
Eligible patients were at least 18 years old, had histologically or cytologically confirmed unresectable stage III or stage IV melanoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, measurable disease defined by at least one lesion that could be accurately and serially measured per modified Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, adequate bone marrow, liver, and renal function, and life expectancy of at least 12 weeks. Patients were excluded if they had primary ocular or mucosal melanoma, congestive heart failure, cardiac arrhythmias, active coronary heart disease or ischemia, uncontrolled hypertension, or active CNS metastases. Prior immuno, biologic, or vaccine therapy was allowed, but patients could not have received chemotherapy or prior treatment with inhibitors of the Ras or vascular endothelial growth factor pathways.

Study Design
This randomized, double-blind, placebo-controlled, multicenter, phase II study (clinicaltrials.gov identifier: NCT00110994) was conducted at 17 centers in the United States between April 2005 (first patient first visit) and October 2006 (data cutoff date). Patients were stratified by American Joint Committee on Cancer stage (III unresectable or IV M1a/M1b or IV M1c) and ECOG performance status (0 or 1) and randomly assigned in a 1:1 manner to receive placebo plus dacarbazine or sorafenib plus dacarbazine. Simple stratified randomization with permuted blocks of size 4 was used by the sponsor to create a prospective randomization schedule that was provided to the vendor for the telephone-based interactive voice recognition system (IVRS). Random assignment of eligible patients was performed by designated personnel at each participating site using the IVRS in a double-blind fashion such that the investigator, sponsor, and patient did not know the treatment assignment.

Sorafenib and placebo tablets were supplied by Bayer HealthCare Pharmaceuticals. Dacarbazine was supplied by the study site pharmacy. Patients in both arms received dacarbazine 1,000 mg/m² by intravenous infusion on day 1 of a 21-day treatment cycle for up to a maximum of 16 cycles. Sorafenib (400 mg [2 tablets, 200 mg each]) or placebo was administered orally twice a day from day 1 to day 21 continuously. Patients continued to receive therapy during the treatment period until unacceptable toxicity, tumor progression, or death occurred. Toxicity related dose modifications were performed in accordance with protocol-specified guidelines.

This study was conducted in accordance with the Declaration of Helsinki, the Investigational New Drug and Bioresearch Regulations of the Food and Drug Administration, the good clinical practice guidelines, and all applicable local laws and regulations. The study protocol and amendments were approved by local institutional review boards or independent ethics committees. Signed informed consent was obtained from patients before initiation of study treatment.

Study Outcomes
Efficacy. The primary end point of the study was PFS. The secondary and tertiary end points were OS, time to progression (TTP), objective response rate, PFS rates at months 6 and 9, duration of response, and change from baseline in ECOG performance status. In this study, PFS was defined as the time from random assignment until objective tumor progression or death; OS as the time from random assignment until death. TTP was defined as the time from random assignment until objective tumor progression; deaths were censored in the calculation of TTP. Measurements were made at baseline and every 6 weeks thereafter and at the end of the treatment period, if applicable. Disease progression and tumor response were evaluated using modified RECIST guidelines by an independent review committee (IRC). Briefly, all radiographic scans and investigator assessments of cutaneous lesions and lesions assessed by physical examination (with photographic documentation) were collected by investigators and sent to the IRC. The scans were read by at least two blinded radiologists; an independent blinded oncologist integrated the independent blinded radiological assessment with the investigator assessment of the lesions to determine objective response, best overall response, and date of progression. The assessment of best response and progression was also performed by the investigator.

Safety. Safety profile was based on observed adverse events, clinical laboratory tests, results of physical examinations, vital signs assessments (including heart rate, blood pressure, respiration rate, and temperature), ECGs, and weight. Safety assessments were carried out before initiation of treatment, on days 8 and 15 during the first two cycles and, every 3 weeks thereafter, and at the end of treatment, if applicable.

Statistical Analysis
Determination of sample size. Using historical data, a median PFS of 2.5 months was assumed for the placebo plus dacarbazine arm. Based on a log-rank test with a two-sided significance level of .05, 77 PFS events would provide 86% power for an alternative hazard ratio (HR) of 0.5 (sorafenib plus dacarbazine/placebo plus dacarbazine). With 77 PFS events, the critical value of the observed HR for statistical significance would be 0.64. A total sample size of 98 patients was sufficient to achieve the target number of PFS events, assuming an exponential distribution for PFS, a 12-month accrual period, and 3.5 additional months of follow-up.

Efficacy analysis. All patients randomly assigned to treatment (intent-to-treat [ITT] population) were included in the primary efficacy analyses. For analysis of efficacy outcomes, a two-sided significance level of .05 was used. For the primary end point of PFS, the treatment arms were compared using a log-rank test. Two-sided 95% CIs were calculated for median PFS and the estimated probability of PFS rate at months 6 and 9 based on the Kaplan-Meier estimates. The HR and a two-sided 95% CI for the HR were calculated. Time to progression, duration of response, and OS were analyzed using the same methods as for PFS. These end points were used as supportive evidence for the primary end point. The final analysis of PFS was performed when approximately 77 events (progression or death) were observed; the final analysis of OS was performed when all patients had been observed for at least 15 months. Incidence of best response and change from baseline in performance status at the visit at which best response was first noted, and at the end of treatment (worse, improved, no change) were analyzed using Fisher's exact test. Except when specified, missing data were not estimated or carried forward in any statistical analyses.

Safety analyses. All patients randomly assigned to treatment and receiving any study medication (valid-for-safety population) were included in the safety analyses. In addition to summaries of adverse events classified and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 3.0, term and category, safety analyses included evaluation of clinically significant laboratory test results and vital signs.

	RESULTS

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A total of 101 patients with histologically or cytologically confirmed advanced melanoma were randomly assigned between the two treatment arms. The detailed patient disposition is shown in Figure 1; the baseline characteristics of patients are presented in Table 1. All randomly assigned patients were included in the ITT and valid-for-safety populations.

View larger version (36K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient disposition.

Efficacy
A total of 81 patients experienced disease progression or had died at the time of PFS analysis. The IRC assessed median PFS was 11.7 weeks for the placebo plus dacarbazine arm and 21.1 weeks for the sorafenib plus dacarbazine arm (Table 2; Fig 2A) resulting in an estimated HR of 0.665 (sorafenib plus dacarbazine/placebo plus dacarbazine; P = .068). There were no meaningful differences between the treatment arms in the timing of radiological scans compared with the scheduled time. The median time to first scan was 43 days for the placebo plus dacarbazine arm and 42 days for the sorafenib plus dacarbazine arm. The IRC assessment of PFS was comparable to investigator-assessed PFS in both arms. The treatment arms differed significantly in terms of TTP. The median TTP was 11.7 weeks for the placebo plus dacarbazine arm and 21.1 weeks for the sorafenib plus dacarbazine arm (Table 2, Fig 2B) resulting in an estimated HR of 0.619 (sorafenib plus dacarbazine/placebo plus dacarbazine; P = .039). The treatment arms, placebo plus dacarbazine and sorafenib plus dacarbazine, respectively, also differed significantly in terms of PFS rate at 6 months, 19.5% and 41.0%, and at 9 months, 12.2% and 22.2% (Table 2). Overall best response and duration of partial response assessed by the IRC are presented in Table 2. While no statistically significant differences were observed, trends favoring the sorafenib plus dacarbazine arm were seen with both end points. A total of 73 patients had died at the time of the final OS analysis. The median OS was 51.3 weeks for the placebo plus dacarbazine arm and 45.6 weeks for the sorafenib plus dacarbazine arm (Table 2, Fig 2C) resulting in an estimated HR of 1.022 (sorafenib plus dacarbazine/placebo plus dacarbazine; P = .927). There was no significant difference in change from baseline in ECOG performance status.

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier curves for (A) progression-free survival assessed by an independent review committee; (B) time to progression assessed by an independent review committee; and (C) overall survival.

View this table: [in this window] [in a new window]   Table 4. Treatment-Emergent Grade 3/4 Adverse Events With Incidence 5% in Either Arm and the Corresponding Incidence of Adverse Events of All Grades

	DISCUSSION

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Randomized phase II clinical trials are often limited by their small sample sizes to detect true treatment differences between the study arms. In this study, we observed improvements in PFS and TTP on the addition of sorafenib to dacarbazine, however, these findings did not translate into an improvement in OS. Consistent with a small sample size, the CI for the hazard ratio for OS was wide (.645 to 1.617). Thus, an improvement in OS for patients receiving sorafenib plus dacarbazine in larger clinical trials cannot be excluded based on the results of this study.

Another limitation of randomized phase II trials is the increased likelihood of imbalances between the treatment arms because the study design does not usually allow for extensive stratification of even the most common prognostic factors. In this study, patients were stratified by American Joint Committee on Cancer stage and ECOG performance status. At baseline, the two treatment arms were well balanced except for lactate dehydrogenase (LDH) levels and time since diagnosis of metastatic disease. There were more patients with high LDH levels in the placebo plus dacarbazine arm; however, this finding may be the result of a greater incidence of missing LDH data in the sorafenib plus dacarbazine arm. The median time since diagnosis of metastatic disease was longer for patients in the placebo plus dacarbazine arm (6.8 v 4.1 months). This difference may be partially attributed to a greater percentage of patients in the placebo plus dacarbazine arm having received prior systemic therapy (immuno, biologic, or vaccine therapy). It is possible that these imbalances between the two treatment arms may have biased the outcome of this trial.

Recently, results of a randomized phase III study of sorafenib in combination with carboplatin and paclitaxel in patients (N = 270) with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen were presented.³¹ Unfortunately, no improvements in PFS and OS were observed with the addition of sorafenib to the carboplatin-paclitaxel regimen in this patient population. A phase III cooperative group trial (E2603) is currently investigating the sorafenib, carboplatin, and paclitaxel combination in chemotherapy-naïve patients with advanced melanoma. It remains to be seen if the encouraging efficacy results observed on adding sorafenib to dacarbazine in chemotherapy-naïve patients in this trial will hold true when sorafenib is added to the carboplatin and paclitaxel regimen in a similar treatment setting.

In regard to tolerability and safety, patients in the sorafenib plus dacarbazine arm were on the study for a longer period of time (median, 19 v 12 weeks); as expected, dose reductions occurred more frequently for patients receiving sorafenib. A similar trend was observed in exposure to and dose reductions of dacarbazine. While the incidence of adverse events, especially thrombocytopenia and neutropenia, was greater in the sorafenib plus dacarbazine arm, the combination was well tolerated with a manageable toxicity profile. Although in this study, CNS hemorrhage was reported in four patients in the sorafenib plus dacarbazine arm, it has not been observed in other advanced melanoma trials employing sorafenib plus dacarbazine or temozolomide.^27-29,32 Further, in the aforementioned phase III study of paclitaxel and carboplatin with or without sorafenib in patients with advanced melanoma, CNS hemorrhage was observed for two of 134 sorafenib plus carboplatin plus paclitaxel patients and one of 134 placebo plus carboplatin plus paclitaxel patients.³¹

Based on the results of this study, the combination of sorafenib and dacarbazine in chemotherapy-naïve patients with advanced melanoma yielded encouraging efficacy results and was well tolerated with a manageable toxicity profile. The findings observed in this study are consistent with those obtained in a single-arm phase II trial utilizing the same combination of agents.²⁸ Given these encouraging results, randomized phase III trials of sorafenib and dacarbazine in the treatment of advanced melanoma are warranted to unequivocally establish the benefit of this treatment combination.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: Chenghua Xia, Bayer (C); Kiran Patel, Onyx (C) Consultant or Advisory Role: David F. McDermott, Bayer (C), Onyx (C); Jeffrey A. Sosman, Genentech (C); Rene Gonzalez, Onyx (C); Jon Richards, Onyx (C); Sanjiv Agarwala, Bayer (C), Onyx (C); Lee Cranmer, Gerson Lehrman Group (C); John Kirkwood, RheoGene (C), Intrexon (C), Pfizer (C), Eleos (C); J. Michael White, Onyx (C) Stock Ownership: Kiran Patel, Onyx Honoraria: Jeffrey A. Sosman, Bayer, Genentech, Wyeth; Rene Gonzalez, Onyx; Sanjiv Agarwala, Onyx, Bayer, Novartis; Igor Puzanov, Pfizer, Bayer, Onyx; Karl Lewis, Onyx; John Kirkwood, Schering-Plough, GlaxoSmithKline Research Funding: David F. McDermott, Bayer, Onyx; Rene Gonzalez, Onyx; F. Stephen Hodi, Bayer, Onyx; Gary Frenette, Onyx; John Kirkwood, Pfizer, Bayer, Bristol-Myers Squibb; Evan Hersh, Medarex, Onyx Expert Testimony: None Other Remuneration: Igor Puzanov, Bayer Schering Pharma

	AUTHOR CONTRIBUTIONS

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Conception and design: J. Michael White, Kiran Patel

Provision of study materials or patients: David F. McDermott, Jeffrey A. Sosman, Rene Gonzalez, F. Stephen Hodi, Gerald P. Linette, Jon Richards, James W. Jakub, Muralidhar Beeram, Stefano Tarantolo, Sanjiv Agarwala, Gary Frenette, Igor Puzanov, Lee Cranmer, Karl Lewis, Kiran Patel, Evan Hersh

Collection and assembly of data: David F. McDermott, Rene Gonzalez, F. Stephen Hodi, Gerald P. Linette, James W. Jakub, Muralidhar Beeram, Stefano Tarantolo, Igor Puzanov, Lee Cranmer, J. Michael White, Kiran Patel, Evan Hersh

Data analysis and interpretation: David F. McDermott, Rene Gonzalez, F. Stephen Hodi, Jon Richards, Sanjiv Agarwala, John Kirkwood, J. Michael White, Chenghua Xia, Kiran Patel

Manuscript writing: David F. McDermott, Jeffrey A. Sosman, Gerald P. Linette, Sanjiv Agarwala, Igor Puzanov, J. Michael White, Kiran Patel, Evan Hersh

Final approval of manuscript: David F. McDermott, Jeffrey A. Sosman, Rene Gonzalez, F. Stephen Hodi, Gerald P. Linette, Jon Richards, James W. Jakub, Muralidhar Beeram, Stefano Tarantolo, Sanjiv Agarwala, Gary Frenette, Igor Puzanov, Lee Cranmer, Karl Lewis, John Kirkwood, J. Michael White, Chenghua Xia, Kiran Patel, Evan Hersh

	ACKNOWLEDGMENTS

 
We thank the patients who enrolled in this study and their families. We acknowledge the critical review provided by Sarah Guadagno, PhD, and James Partyka, PharmD, Onyx Pharmaceuticals Inc, and the editorial assistance of Meenakshi Subramanian, PhD, Envision Pharma Inc.

	NOTES

 
Supported by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals Inc.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007 and at the 14th European Cancer Conference, Barcelona, Spain, September 23-27, 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43-66, 2007[Abstract/Free Full Text]

2. American Cancer Society: Cancer Facts and Figures, 2006. Atlanta, GA, American Cancer Society. http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf

3. Kim CJ, Reintgen DS, Balch CM: The new melanoma staging system. Cancer Control 9:9-15, 2002[Medline]

4. Balch CM, Reintgen DS, Kirkwood JM, et al: Cutaneous melanoma, in De Vita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 5). Philadelphia, PA, Lippincott, 1997, pp 1935-1993

5. Gimotty PA, Botbyl J, Soong SJ, et al: A population-based validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 23:8065-8075, 2005[Abstract/Free Full Text]

6. Thompson JF, Scolyer RA, Kefford RF: Cutaneous melanoma. Lancet 365:687-701, 2005[Medline]

7. Bedikian AY, Millward M, Pehamberger H, et al: Bcl-2 Antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: The Oblimersen Melanoma Study Group. J Clin Oncol 24:4738-4745, 2006[Abstract/Free Full Text]

8. Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745-2751, 1999[Abstract/Free Full Text]

9. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158-166, 2000[Abstract/Free Full Text]

10. Eggermont AM, Kirkwood JM: Re-evaluating the role of dacarbazine in metastatic melanoma: What have we learned in 30 years? Eur J Cancer 40:1825-1836, 2004[CrossRef][Medline]

11. Lens MB, Dawes M: Interferon alfa therapy for malignant melanoma: A systematic review of randomized controlled trials. J Clin Oncol 20:1818-1825, 2002[Abstract/Free Full Text]

12. Atkins MB, Kunkel L, Sznol M, et al: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 6:S11-S14, 2000 (suppl 1)[Medline]

13. Atkins MB, Lotze MT, Dutcher JP, et al: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105-2116, 1999[Abstract/Free Full Text]

14. Tarhini AA, Agarwala SS: Interleukin-2 for the treatment of melanoma. Curr Opin Investig Drugs 6:1234-1239, 2005[Medline]

15. Keilholz U, Conradt C, Legha SS, et al: Results of interleukin-2-based treatment in advanced melanoma: A case record-based analysis of 631 patients. J Clin Oncol 16:2921-2929, 1998[Abstract/Free Full Text]

16. Atkins MB, Lee S, Flaherty LE, et al: A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. Proc Am Soc Clin Oncol 22:, 2003 (abstr 2847)

17. Keilholz U, Punt CJ, Gore M, et al: Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: A randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol 23:6747-6755, 2005[Abstract/Free Full Text]

18. Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial. J Clin Oncol 20:2045-2052, 2002[Abstract/Free Full Text]

19. Crosby T, Fish R, Coles B, et al: Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev CD001215, 2000

20. Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human cancer. Nature 417:949-954, 2002[CrossRef][Medline]

21. Karasarides M, Chiloeches A, Hayward R, et al: B-RAF is a therapeutic target in melanoma. Oncogene 23:6292-6298, 2004[CrossRef][Medline]

22. Haluska FG, Ibrahim N: Therapeutic targets in melanoma: Map kinase pathway. Curr Oncol Rep 8:400-405, 2006[Medline]

23. Gollob JA, Wilhelm S, Carter C, et al: Role of Raf kinase in cancer: Therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 33:392-406, 2006[CrossRef][Medline]

24. Wilhelm S, Carter C, Lynch M, et al: Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835-844, 2006[CrossRef][Medline]

25. Wilhelm SM, Carter C, Tang L, et al: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099-7109, 2004[Abstract/Free Full Text]

26. Eisen T, Ahmad T, Flaherty KT, et al: Sorafenib in advanced melanoma: A phase II randomised discontinuation trial analysis. Br J Cancer 95:581-586, 2006[CrossRef][Medline]

27. Eisen T, Ahmad T, Gore ME, et al: Phase I trial of BAY 43-9006 (sorafenib) combined with dacarbazine (DTIC) in metastatic melanoma patients. J Clin Oncol 23:712s, 2005 (abstr 7508)[CrossRef]

28. Eisen T, Marais R, Affolter A, et al: An open-label phase II study of sorafenib and dacarbazine as first-line therapy in patients with advanced melanoma. J Clin Oncol 25:479s, 2007 (abstr 8529)[CrossRef]

29. Lorigan P, Corrie P, Chao D, et al: Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients. J Clin Oncol 24:456s, 2006 (abstr 8012)

30. Rigel DS, Carucci JA: Malignant melanoma: Prevention, early detection, and treatment in the 21st century. CA Cancer J Clin 50:215-236, 2000[Abstract]

31. Agarwala SS, Keilholz U, Hogg D, et al: Randomized phase III study of paclitaxel plus carboplatin with or without sorafenib as second-line treatment in patients with advanced melanoma. J Clin Oncol 25:474s, 2007 (abstr 8510)

32. Amaravadi R, Schuchter LM, McDermott DF, et al: Updated results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma. J Clin Oncol 25:478s, 2007 (abstr 8527)

Submitted October 23, 2007; accepted January 3, 2008.

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				I. D. Davis, B. Brady, R. F. Kefford, M. Millward, J. Cebon, B. K. Skrumsager, U. Mouritzen, L. T. Hansen, K. Skak, D. Lundsgaard, et al. Clinical and Biological Efficacy of Recombinant Human Interleukin-21 in Patients with Stage IV Malignant Melanoma without Prior Treatment: A Phase IIa Trial Clin. Cancer Res., March 15, 2009; 15(6): 2123 - 2129. [Abstract] [Full Text] [PDF]

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				A. Sharma, A. K. Sharma, S. V. Madhunapantula, D. Desai, S. J. Huh, P. Mosca, S. Amin, and G. P. Robertson Targeting Akt3 Signaling in Malignant Melanoma Using Isoselenocyanates Clin. Cancer Res., March 1, 2009; 15(5): 1674 - 1685. [Abstract] [Full Text] [PDF]

				E. Winer, J. Gralow, L. Diller, B. Karlan, P. Loehrer, L. Pierce, G. Demetri, P. Ganz, B. Kramer, M. Kris, et al. Clinical Cancer Advances 2008: Major Research Advances in Cancer Treatment, Prevention, and Screening--A Report From the American Society of Clinical Oncology J. Clin. Oncol., February 10, 2009; 27(5): 812 - 826. [Abstract] [Full Text] [PDF]

				L. Jilaveanu, C. Zito, S. J. Lee, K. L. Nathanson, R. L. Camp, D. L. Rimm, K. T. Flaherty, and H. M. Kluger Expression of Sorafenib Targets in Melanoma Patients Treated with Carboplatin, Paclitaxel and Sorafenib Clin. Cancer Res., February 1, 2009; 15(3): 1076 - 1085. [Abstract] [Full Text] [PDF]

				J. Poust Targeting metastatic melanoma Am. J. Health Syst. Pharm., December 15, 2008; 65(24_Supplement_9): S9 - S15. [Abstract] [Full Text] [PDF]

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