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Randomized Dose-Escalation Study Evaluating Peginterferon Alfa-2a in Patients With Metastatic Malignant Melanoma

From the Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland; Department of Dermatology, Eberhard-Karls University, Tübingen, Germany; Department of Medicine, University of Washington, Seattle, WA; Department of Surgical Oncology, Daniel den Hoed Cancer Centre, University Hospital Rotterdam, Rotterdam, The Netherlands; and Departments of Biostatistics and Medical Science, Hoffmann-LaRoche Inc, Nutley, NJ.

Address reprint requests to Reinhard Dummer, MD, Dermatologische Klinik, Universitätsspital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland; e-mail: reinhard.dummer{at}usz.ch

	ABSTRACT

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PURPOSE: A pegylated interferon, peginterferon alfa-2a (PEG-IFN-2a; 40 kd), has the potential for improved tumor response and survival with lower toxicity than IFN. This open-label, randomized study evaluated the safety, tolerability, and efficacy of subcutaneous PEG-IFN-2a in patients with metastatic malignant melanoma (stage IV American Joint Committee on Cancer staging system).

PATIENTS AND METHODS: PEG-IFN-2a was administered subcutaneously at 180 (n = 48), 360 (n = 53), or 450 µg (n = 49) once weekly for 24 weeks, with maintenance therapy for responders. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR).

RESULTS: The major response rate (CR or PR) was 6% in the 180-µg group (CR, 2%; PR, 4%), 8% in the 360-µg group (CR, 2%; PR, 6%), and 12% in the 450-µg group (CR, 6%; PR, 6%). The times to achieve a major response, duration of major response, rate of disease progression, and 12-month survival were similar between groups, although overall median survival was significantly different among the three groups (P = .0136). More patients required dose adjustment for safety reasons in the higher dose groups, but PEG-IFN-2a was generally well tolerated, with few withdrawals because of adverse events (6%, 19%, and 16% in the 180-, 360-, and 450-µg groups, respectively). The most common adverse events were fatigue, pyrexia, and nausea.

CONCLUSION: PEG-IFN-2a at doses up to 450 µg once weekly has shown good tolerability and similar efficacy to conventional IFN and monochemotherapy in stage IV metastatic melanoma.

	INTRODUCTION

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Malignant melanoma is becoming a major public health problem. Data from the United States and Europe show that the lifetime risk of developing malignant melanoma has increased from one in 800 individuals in 1960 to one in 74 individuals in 2000.^1,2 The incidence varies in different countries, from high rates of approximately 50 per 100,000 individuals in Australia, to 15 per 100,000 in Germany, and to less than one per 100,000 in China and Japan.^1,2 Melanoma risk is associated with intrinsic factors such as family history, hair color, and number of nevi, as well as environmental factors such as history of sunburn and exposure to ultraviolet radiation.^3-5

The prognosis is linked to the thickness of the primary tumor, presence of ulceration, involvement of lymph nodes, and presence of distant metastases.⁶ Thicker tumors indicate a poorer prognosis, and 5-year survival ranges from 45% to 95% for lymph node–negative disease and from 27% to 70% with regional lymph node involvement, but decreases to 10% to 19% for individuals with distant metastases.⁷ Although there have been significant improvements in recent years in the diagnosis and treatment of early melanoma, there has been little progress in improving the prognosis of patients with metastatic stage IV disease, with 1-year survival rates of 41% to 59%.⁷

No standard treatment has been defined for metastatic melanoma, most probably because no treatment has yet been shown to improve survival rates significantly in randomized controlled trials.^8,9 Surgical resection of metastases may be considered, and radiotherapy and dacarbazine may give palliative relief; entry onto a clinical trial of novel agents is encouraged.^8,9 The low response rates and short duration of response with systemic treatments such as single-agent chemotherapy or cytokines are slightly improved by polychemotherapy, but no improvement in survival is seen.¹⁰ Immunotherapeutic approaches have been of limited use, with few sustainable responses evident.¹⁰ Biochemotherapy (a combination of immunotherapy and cytotoxic chemotherapy) has also failed to increase survival in several prospective, randomized, phase III trials.^10-13

Interferons have been proven to have antitumor activity in a variety of neoplastic diseases, including stage IV metastatic melanoma, as single agents or in combination with cytostatics or interleukin-2.^13-15 However, complete tumor responses (CRs) are infrequent and often unsustainable. Interferon (IFN) therapy is associated with a dose-dependent toxicity and its administration is further complicated by its short half-life, which requires subcutaneous administration at least three times per week. Each postinjection peak in serum concentrations causes acute influenza-like symptoms (including fever, chills, myalgia, headache, and arthralgia). Repeated injections may induce liver abnormalities, hematologic toxicities and, most commonly, fatigue, which can hamper long-term treatment.¹⁶ These adverse effects are often severe enough to prompt dose reductions, resulting in patients receiving less than the target dose. Recombinant type I IFNs as well as natural IFNs can be immunogenic, resulting in the formation of neutralizing antibodies that reduce the clinical response^17-19 and may, in rare cases, cause fatal shock.²⁰ Clearly, better treatments are still required.

Recombinant human peginterferon alfa-2a (PEG-IFN-2a; Pegasys; Hoffman-La Roche Inc, Nutley, ND) is a form of IFN-2a modified by the covalent attachment of a branched 40-kd methoxypolyethylene glycol moiety. Already licensed for use in chronic hepatitis C, studies in this population found that PEG-IFN-2a has superior efficacy to nonpegylated IFN; the long half-life of PEG-IFN-2a allows a more convenient once-weekly dosing regimen with improved tolerability.^21,22 Formation of binding or neutralizing antibodies against PEG-IFN-2a is rare, and occurs in 6% or 2% of patients, respectively.²³ Phase I and II clinical studies have been conducted with PEG-IFN-2a in renal cell carcinoma^24,25 and chronic myelogenous leukemia.^26,27

This open-label, randomized, phase II, multicenter, dose-finding study aimed to evaluate the safety, tolerability, and efficacy of PEG-IFN-2a in patients with stage IV metastatic malignant melanoma.

	PATIENTS AND METHODS

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Study Design
The study consisted of a 24-week treatment phase, followed by 8 weeks of treatment-free follow-up or, for patients who had not experienced disease progression after 24 weeks of treatment, the possibility of continuing in a maintenance phase at the same dose until progression.

Outpatients with confirmed metastatic melanoma (American Joint Committee on Cancer stage IV⁷) were recruited from US and European centers. The target for enrolment was 135 patients, with the intention that a minimum of 120 assessable patients would complete the study. The sample size was not determined based on any statistical power for comparisons between treatment groups. Because this was the first clinical study with PEG-IFN-2a in metastatic melanoma patients, the sample size was chosen based on practical feasibility to evaluate the three doses of the PEG-IFN-2a in a descriptive manner. All participants were required to have a Karnofsky performance status of 80%, at least one bidimensionally measurable lesion according to WHO criteria, and a minimum indicator lesion (liver, soft tissue, or other mass) of diameter 10 mm. Other inclusion criteria were age 18 to 75 years, no previous chemotherapy or immunotherapy with interleukin-2 or IFN for stage IV melanoma, or progression to stage IV melanoma while receiving IFN therapy. Ethical approval was obtained from the local ethics committee for each center. Written informed consent was obtained from each patient.

Previous experience with PEG-IFN-2a in patients with hepatitis C,^21,22 renal cell carcinoma,^24,25 and chronic myeloid leukemia^26,27 determined a dose-limiting toxicity at 540 µg/wk, and effective dosing at 180 µg/wk. The doses chosen for this study were based on these findings. After baseline clinical and laboratory screening, patients were randomly assigned to receive a subcutaneous injection of PEG-IFN-2a at a dose of 180, 360, or 450 µg once weekly for 24 weeks. Patients were randomly assigned centrally to one of the treatment groups in the order of screening. Region of the study centers (North America, Western Europe), previous therapy with interferon (yes v no), lactate dehydrogenase status ( 1.5x v > 1.5x the upper limit of normal of the center) were used as stratification criteria to ensure comparable patient characteristics among the dose groups and avoid imbalance.

Up to two dose reductions, each of a 90-µg decrement, were permitted in patients who were unable to tolerate the randomly assigned dose. Patients could withdraw from the study at any time.

If patients showed no evidence of progression at 24 weeks, they could continue treatment at their randomized dose in the maintenance phase of the study until progression, at the investigator's discretion. Complete responders continued treatment for at least an additional 8 weeks. Those who did not enter maintenance treatment began an 8-week period of treatment-free follow-up.

Assessment of Efficacy and Safety
Marker lesions were identified at baseline by computed tomography scans. The primary efficacy variable was the proportion of patients with either a CR or partial tumor response (PR) during 24 weeks of PEG-IFN-2a treatment. CR was defined as the disappearance of all clinically detectable disease, determined by two consecutive observations not less than 4 weeks apart; PR was defined as 50% decrease in total tumor size of the marker lesions by two consecutive observations not less than 4 weeks apart, and no new lesions or progression in any lesion. Secondary efficacy variables included the duration of CR or PR, time to tumor response event, disease progression, or death as a result of any reason, and survival rate at 12 and 24 months.

Tolerability was assessed primarily by the frequency of dose reductions and withdrawals due to adverse events (AEs). The incidence and intensity of AEs or laboratory abnormalities were also recorded. The intensity of clinical AEs was graded according to the National Cancer Institute Common Toxicity Criteria grading system. Adverse events not listed on the National Cancer Institute Common Toxicity Criteria grading system were graded on a 4-point scale: mild (discomfort noticed but no disruption of normal daily activity); moderate (discomfort sufficient to reduce or affect daily activity); severe (inability to work or perform normal daily activity); and life threatening (represents an immediate threat to life).

Statistical Analysis
All randomly assigned patients were included in the data analysis, and patient characteristics, efficacy, and safety data were all summarized descriptively. Tumor response rates were assessed based on the best overall response, which was defined as the best response recorded from the start of trial medication. Response rates were calculated by dividing the number of specified responses during the entire study period (including maintenance phase) by the total number of randomly assigned patients in the respective treatment group. The rates of major response were compared among the three groups using Cochran-Mantel-Haenszel test, using the geographic region of the study sites as a stratification factor.

Overall survival time (time to death) was defined as days between the first study medication dose and the day of death, irrespective of the cause of death. Median time to death and the corresponding two-sided 95% CIs and survival rates at 12 and 24 months were calculated using the Kaplan-Meier approach for each treatment group. The log-rank test was used to compare among the three groups. All P values presented are without adjustment for multiple comparisons.

	RESULTS

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Patient Characteristics
In total, 150 patients were randomly assigned to the study, commencing treatment between January 2000 and May 2001. All randomly assigned patients received at least one dose of study medication, and all had at least one postbaseline assessment. Thus, all randomly assigned patients were included in safety and efficacy data analyses. Patient demographics were comparable among the three treatment groups (Table 1), although the 450-µg group had fewer patients with metastases at three or more sites compared with the other two dose groups. Approximately 20% of the patients had used IFN previously, all in the adjuvant setting. All patients received the dose to which they were randomly assigned. Median follow-up periods were 218 days (range, 18 to 976 days) for the 180-µg group, 319 days (range, 18 to 899 days) for the 360-µg group, and 304 days (range, 28 to 1,183 days) for the 450-µg group. Two patients who were randomly assigned to receive PEG-IFN-2a treatment (one in the 360-µg group and the other in the 450-µg group) were identified subsequently as not having metastatic disease (Table 1). However, data from both patients were included in all efficacy and safety analyses to include all randomly assigned patients in the efficacy analyses and all patients treated with PEG-IFN-2a in the safety analyses.

View this table: [in this window] [in a new window]   Table 2. Tumor Responses During the Entire Study, by PEG-IFN-2a Dose

View larger version (14K): [in this window] [in a new window]   Fig 1. Overall survival rates by peginterferon alfa-2a (PEG-IFN-2a) dose, based on Kaplan-Meier estimates.

Reductions or withholding of doses due to AEs or laboratory abnormalities occurred in 23% (n = 11), 51% (n = 27), and 41% (n = 20) of patients in the 180-, 360-, and 450-µg groups, respectively. In all dose groups, the majority of dose adjustments occurred in the first 3 months of the study.

During the entire study period, 96% of patients in the 180-µg group and 100% of patients in the 360- and 450-µg groups experienced at least one AE, but 88% of events were mild or moderate in nature. Fatigue was the most frequently reported AE, with the most frequently reported severe intensity. The most commonly reported AEs (occurring in 15% of patients) are listed in Table 4. Study withdrawal due to AEs or intercurrent illness during treatment or maintenance phases generally was infrequent, and was lowest in the 180-µg group (6%) compared with the 360-µg group (19%) and the 450-µg group (16%). There were no withdrawals because of laboratory abnormalities.

View this table: [in this window] [in a new window]   Table 4. Nature and Intensity of Frequently Occurring ( 15% in any dose group) Adverse Events During Treatment and Maintenance Phases

	DISCUSSION

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More patients in the two higher dose groups withdrew from the study due to AEs than those taking 180 µg/wk, but the withdrawal rate due to AEs was similar to that seen with high-dose IFN.^21,28 There were no meaningful differences in AEs recorded for the three doses. Therefore, it does not seem that there is an increase in toxicity with increasing doses up to 450 µg/wk. Similar AE rates between PEG-IFN-2a and standard IFN have been shown in other groups of patients, such as those with chronic hepatitis C.²² In most studies of high-dose IFN in patients with melanoma, about one third of patients experience severe toxicity (grade 3 and 4),²⁹ but in the present study, 51% of patients reported severe or life-threatening AEs. However, it should be noted that the nature of the AE was not serious clinically. The most frequently reported severe/life-threatening AE was fatigue (14% in the 450-µg group). Two percent, 11%, and 4% of patients in the 180-, 360-, and 450-µg groups, respectively, reported serious AEs related to the study drug.

There was no significant dose dependence of tumor response across the doses used in this trial, although the highest response rate was produced by the 450 µg/wk dose. However, this group seemed to have a slightly better prognostic profile (fewer patients with at least three metastatic sites), which may have contributed to the higher response rate and the improved survival. Additional study is required to determine whether a patient's prognosis could be improved by application of the American Joint Committee on Cancer staging system for metastases in melanoma. If this were the case, such data would support similar tumor responses with 180 to 450 µg/wk of PEG-IFN-2a. The response rate and the incidence of stable disease are comparable with those seen with conventional recombinant IFN but without its toxicity.^14,30,31 The lack of a dose-response relationship with PEG-IFN-2a perhaps is not surprising, given that the response to natural IFN appears to be only minimally affected by the dose used.³² Studies with large patient populations would be required to establish whether there is a true dose-response relationship with this drug. With the currently available data, there is no one dose of PEG-IFN-2a that can be recommended definitively, but considering that dose reductions and AEs tended to be more frequent with higher doses, a lower dose may be appropriate.

The overall tumor response rate with the three doses of PEG-IFN-2a was 8.7%, with a complete response rate of 2.7%. On first glance, this seems to be lower than the results reported for the most commonly used cytostatic drug, dacarbazine.³³ However, the largest clinical trial performed to date in metastatic melanoma comparing dacarbazine alone versus dacarbazine in combination with a bcl-2 antisense molecule has indicated an overall response rate of 6.8%, with a complete response rate of 0.5%.³⁴ Another trial comparing dacarbazine versus vaccination using peptide-pulsed dendritic cells has shown an overall response rate of 5.5% for dacarbazine.³⁵ These recent well-controlled trials illustrate that the response rate of 15% to 25% for single-agent dacarbazine indicated in earlier publications³³ was actually overestimated.

Our study was a closely monitored, multicenter trial, and the results obtained with the PEG-IFN in this study are in a similar range to the results that can be obtained by monochemotherapy, using the standard drug dacarbazine, or temozolomide, which is structurally related to dacarbazine. It is likewise interesting that survival benefit seemed to be greater with the higher doses of PEG-IFN-2a. This, together with the favorable tolerability and advantageous once-weekly dosing regimen of PEG-IFN-2a, may make it an attractive alternative to IFN for the treatment of metastatic melanoma patients who did not experience disease progression during adjuvant interferon therapy. More data would be required to clarify the optimal dose and whether it brings additional benefits as an adjuvant therapy. Additional information on the mechanism of action of IFNs may help to define patient subgroups that will obtain the greatest benefit.

Many studies have used conventional IFNs combined with chemotherapy, preferentially dacarbazine. A meta-analysis of 3,273 patients from 20 randomized trials suggests that the IFN plus dacarbazine combination produces a 53% greater response rate than dacarbazine alone.³³ Therefore, it is reasonable to propose that dacarbazine should be studied with the newer PEG-IFNs in metastatic melanoma in the near future.

In conclusion, when delivered subcutaneously, PEG-IFN-2a was well tolerated up to a once-weekly dose of 450 µg in patients with metastatic malignant melanoma, and demonstrated similar efficacy to that seen with standard IFN. The altered pharmacokinetic profile and sustained half-life provided by pegylation of IFN allows a more convenient once-weekly dosing regimen than that of IFN, and may facilitate compliance.

	Authors' Disclosures of Potential Conflicts of Interest and Author Contributions

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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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Reinhard Dummer Hoffmann-LaRoche (A) Claus Garbe Hoffmann-LaRoche (B) Hoffmann-LaRoche (A) Hoffmann-LaRoche (B) Kisook Yoo Hoffmann-LaRoche (N/R) Bengt Bergstrom Hoffmann-LaRoche (N/R)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Reinhard Dummer, Claus Garbe, John A. Thompson Financial support: Bengt Bergstrom Administrative support: Bengt Bergstrom, Tanja Meier Provision of study materials or patients: Reinhard Dummer, Claus Garbe, John A. Thompson, Bengt Bergstrom, Tanja Meier Collection and assembly of data: Reinhard Dummer, Bengt Bergstrom, Tanja Meier Data analysis and interpretation: Claus Garbe, John A. Thompson, Kisook Yoo, Bengt Bergstrom Manuscript writing: Reinhard Dummer, Claus Garbe, John A. Thompson, Alexander M. Eggermont, Bengt Bergstrom Final approval of manuscript: Reinhard Dummer, Claus Garbe, John A. Thompson, Alexander M. Eggermont, Bengt Bergstrom

 

	Acknowledgment

 
The authors wish to thank all the contributing centers (Prof Axel Hauschild, Kiel, Germany; Prof Dirk Schadendorf, Mannheim, Germany; Prof Hubert Pehamberger, Vienna, Austria, et al) for their input and the recruitment of patients.

	NOTES

 
Supported in part by the Swiss National Science Foundation (Grant No. 3100A0-103671-1 to R.D.) and by the Gottfried und Julia Bangerter-Rhyner Stiftung (R.D.).

Presented in part at the European Cancer Conference, Copenhagen, Denmark, September 19-25, 2003, the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL; and 9th World Congress on Cancers of the Skin, Seville, Spain, May 7-11, 2003.

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

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted September 21, 2005; accepted December 14, 2005.

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