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Durable Complete Responses With High-Dose Bolus Interleukin-2 in Patients With Metastatic Melanoma Who Have Experienced Progression After Biochemotherapy

Ahmad A. Tarhini, John M. Kirkwood, William E. Gooding, Chao Cai, Sanjiv S. Agarwala

From the University of Pittsburgh Cancer Institute, Pittsburgh; and St Luke’s Hospital and Health Network, Bethlehem, PA

Address reprint requests to Sanjiv S. Agarwala, MD, St Luke's Medical Center, 801 Ostrum St, Bethlehem, PA 18015; e-mail: AgarwaS{at}slhn.edu

	ABSTRACT

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Purpose: We conducted a phase II trial of high-dose bolus (HDB) interleukin-2 (IL-2) in patients with metastatic melanoma who had experienced progression after biochemotherapy (BCT).

Patients and Methods: Eligible patients had experienced progression on or after BCT (cisplatin, vinblastine, dacarbazine, IL-2 9 MU/m²/d for 4 days, and interferon alfa-2b). HDB IL-2 was administered at 600,000 U/kg per dose for a maximum of 14 doses per cycle with a 1-week rest period between cycles. Stable or responding patients were offered an additional course (two cycles) after 6 to 8 weeks.

Results: Twenty-six patients (12 men and 14 women), age 28 to 70 years (median, 45 years), have been treated. All but three patients received at least two cycles of HDB IL-2; 10 patients received a second course of therapy. Disease stage was American Joint Committee on Cancer (AJCC) stage M1a (n = 5), M1b (n = 5), and M1c (n = 16). Grade 3 and 4 toxicities included hyperbilirubinemia (n = 10), thrombocytopenia (n = 6), oliguria (n = 3), diarrhea (n = 1), infection (n = 2), and neurologic toxicity (n = 2). Overall response rate was 19.2% (four complete responses, lasting 4, 4, 26+, and 41+ months; and one partial response, lasting 3 months). Five patients (19%) had stable disease lasting 1 to 3 months, but all eventually experienced progression. All four complete responders had AJCC stage M1a disease. At a median follow-up time of 10 months, median survival time was 42 weeks (95% CI, 19.1 to 86.6 weeks), and median progression-free survival time was 10 weeks (95% CI, 8 to 16.1 weeks). An initial response to BCT was not found to be predictive for response to HDB IL-2.

Conclusion: HDB IL-2 is active therapy for patients who experience progression on BCT. This observation has implications regarding the importance of dose-intensity for IL-2 therapy.

	INTRODUCTION

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Metastatic melanoma responds poorly to most forms of systemic therapy. Chemotherapy, using either single or multiple agents, induces short-lived responses in 10% to 40% of patients, but evidence for a significant impact on survival is lacking.¹ Dacarbazine has been found to induce response rates ranging between 6.8% and 20% and remains the only US Food and Drug Administration (FDA) –approved agent since 1976.

Immunotherapy with two agents, interferon (IFN) alpha and interleukin-2 (IL-2), has shown reproducible activity in metastatic melanoma on the order of 15% to 20%. Recombinant IL-2, a cytokine with a range of immunomodulatory effects, has been investigated for more than 20 years as therapy for melanoma. Reports from prospective clinical trials demonstrate a 16.3% response rate to IL-2 in patients with melanoma.² These data demonstrate that higher dose regimens are more likely to induce tumor regression than lower dose regimens, both for melanoma and for renal cell carcinoma. A retrospective analysis of 270 patients with metastatic melanoma treated with high-dose (HD) IL-2 between 1985 and 1993 has demonstrated objective response rates of 16%, including 6% complete responses (CRs). The median duration of response was 6.5 months, and 60% of complete responders remained progression free at 5 years.³ These data led to the FDA approval of the HD IL-2 regimen in patients with metastatic melanoma.

A major difference between the HD bolus (HDB) IL-2 regimen and other chemotherapeutic or chemoimmunotherapeutic regimens for melanoma lies in the duration and quality of responses obtained. Of 24 patients on HDB IL-2 regimens at the National Cancer Institute (NCI) who experienced complete regression, only five have experienced recurrence, and 19 remain in CR for 46 to 137+ months.⁴ These numbers, albeit small, are the first evidence for potential cure in metastatic melanoma with an immunologic form of treatment.

Several investigators have studied combinations of IL-2 and chemotherapy in metastatic melanoma. Composite results of biochemotherapy (BCT) regimens applied to more than 400 patients show a response rate of approximately 50% (CRs, 10% to 20%), a median response duration of 6 to 8 months, and a median survival time of 11 to 12 months. Legha and Buzaid⁵ tested combinations of chemotherapy with cisplatin, vinblastine, and dacarbazine with IL-2 administered by continuous infusion (9 MU/m²) and IFN- in various schedules. Concurrent administration of these drugs was found to be most practical and effective, with a response rate of 62% and median response duration of 6 months. A study of a slightly modified version of this regimen was reported to be less toxic, equally efficacious, and amenable to application in the community hospital setting.⁶ This regimen has been tested in a high-priority intergroup randomized trial against combination chemotherapy alone (E3695).⁷ This phase III trial failed to show significantly better response rates, progression-free survival, overall survival, or durable CRs relative to chemotherapy alone. In addition, toxicity, particularly grade 4 toxicity, was greater for BCT.⁷

Although randomized trials have not been conducted, it seems that HDB IL-2 (600,000 to 720,000 U/kg intravenous [IV] every 8 hours for 15 doses) as administered in the original NCI studies, is superior to IL-2 administered by continuous IV infusion.⁸ Although response rates may be comparable, responses tend to be of shorter duration. Continuous infusion of IL-2 at intermediate dosage is a critical component of BCT regimens, and it is unknown whether patients who have been treated with BCT and have experienced either treatment failure or progression will respond to the HDB regimen. Because options for treatment for patients who have been treated with BCT are limited, we conducted a phase II trial to determine the role of conventional HDB IL-2 in patients with metastatic melanoma who have experienced treatment failure or progression after treatment with BCT. The hypothesis on which we undertook this trial was that HDB IL-2 has dose-dependent clinical activity that would be evident after failure of aggressive combinations using lower dosages of IL-2 as have been incorporated into regimens of BCT.

	PATIENTS AND METHODS

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Patients
Patients were eligible if they had histologically confirmed metastatic melanoma (American Joint Committee on Cancer [AJCC] stage IV). Patients were required to have been previously treated with BCT (cisplatin, vinblastine, dacarbazine, IL-2, and IFN--2b) as evaluated in the Eastern Cooperative Oncology Group (ECOG) protocol E3695 or as therapy off protocol using this same regimen. Eligible patients were also required to have met the following criteria: age 18 years; ECOG performance status of 0 or 1; life expectancy of 3 months or longer; and adequate hematologic values (absolute neutrophil count 1,500 cells/µL, hemoglobin 10 g/dL, and platelet count 100,000/µL), hepatic function (serum bilirubin 2x the upper limit of normal and serum ALT and serum AST 3x the upper limit of normal), and renal function (serum creatinine < 2 mg/dL or calculated clearance > 60 mL/min).

All patients more than 45 years of age or as clinically indicated underwent a cardiac stress test and pulmonary function tests within 8 weeks before registration. Patients were eligible if they had no significant abnormality on cardiac stress testing and a forced expiratory volume in 1 second of more than 2 L or more than 75% of predicted.

Patients were permitted to have previously received additional treatment regimens including those containing subcutaneous IL-2. Other previous therapies, including hormonal therapy, gene therapy, IFN, vaccines, and other immunologic agents, as part of adjuvant therapy or therapy for metastatic disease were allowed. At least 4 weeks must have elapsed since prior therapy (6 weeks for mitomycin or nitrosoureas) for patients to be enrolled.

Patients with brain metastases were eligible only after definitive treatment, which could include surgical resection, stereotactic radiosurgery, whole-brain radiation therapy, or combinations thereof. At the time of protocol enrollment, all brain lesions met the following criteria: they were not symptomatic; they were all less than 1.5 cm in diameter; there was no significant edema; and they did not require corticosteroids. Patients who had received whole-brain radiation therapy were eligible 2 weeks after completion of radiation. Patients who received stereotactic radiosurgery were eligible 48 hours after completion of the procedure.

Patients were ineligible if they had any of the following: organ allografts; systemic corticosteroid requirement; a significant other medical or psychological condition that could interfere with protocol treatment; concomitant second malignancy except for basal cell carcinoma and squamous cell carcinoma in situ of the skin or cervix (patients with previous malignancies of other sites were eligible provided they had been disease free continuously for at least 5 years); and pregnancy. All acute toxicities from previous therapies must have resolved. All patients provided written informed consent.

Study Design and Treatment
This was a phase II, single-arm study carried out in a specialized inpatient oncology unit (not an intensive care unit) at the University of Pittsburgh Medical Center. Eligible patients received HD IL-2 (Chiron, Emeryville, CA) 600,000 to 720,000 U/kg as a 15-minute IV infusion every 8 hours for up to 14 doses (cycle 1) followed by a rest period of 1 to 2 weeks and readmission for a second HD IL-2 treatment (cycle 2) for up to 14 doses. This constitutes one course of treatment (two cycles; Table 1). NCI guidelines for the administration of HDB IL-2 were followed.

Toxicity and Response Assessments
The NCI Common Toxicity Criteria version 3.0 were used for grading toxicities. Patients were monitored for toxicity on days 1 to 5 of each treatment cycle, with a complete history and physical examination, vital signs, and a laboratory assessment (including CBCs, serum chemistry, and urinalysis). The same assessment was repeated on day 10 of each treatment cycle.

Systemic computed tomography scans and gadolinium magnetic resonance imaging of the brain were performed at baseline. Computed tomography scans were repeated at the completion of every even-numbered treatment cycle to assess response. Radiologic studies were reviewed and confirmed independently by a central radiology facility, which was blinded to patient characteristics.

The following criteria were used to determine the levels of response. A CR was defined as the complete disappearance of all clinically detectable malignant disease. A partial response (PR) was defined, for bidimensionally measurable disease, as a decrease by at least 50% of the sum of the products of the largest perpendicular diameters of all measurable lesions, and for unidimensionally measurable disease, as a decrease by at least 50% in the sum of the largest diameters. SD was defined as either no change in the size of tumor lesions or an increase or decrease of less than 25% and the absence of any new lesions. Levels of response were determined separately at two consecutive examinations at least 4 weeks apart and were valid only in the absence of the development of new CNS lesions.

Dose Modifications
Established guidelines for administration of HDB IL-2 were followed. Patients were continuously assessed, and a decision to administer a dose of IL-2 or not was made at each 8-hour time point. No dose modifications were made; either the entire dose was administered, or it was held based on the presence or absence of relative and absolute criteria as per the published guidelines. If a dose was held as per protocol, the decision regarding the administration of the next dose was made at the next established 8-hour time point.

Statistical Methods
This was a single-arm, nonrandomized, phase II clinical trial. A two-stage Simon-type phase II study design⁹ was used to minimize the expected sample size if the response rate was low. The primary data analysis was estimation with 95% CIs of the objective response rate. The response rates were calculated for patients with measurable disease. For the analysis of secondary objectives, toxicities were summarized by grade, frequency, and duration. Time to disease progression and survival time were estimated using the Kaplan-Meier method.¹⁰

	RESULTS

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Patient Characteristics
A total of 26 patients with AJCC stage IV melanoma were enrolled between June 2000 and August 2003, and all patients met protocol eligibility requirements. Among these patients, 12 were men, and 14 were women, and the age range was 28 to 70 years (median, 45 years). Five patients had AJCC disease stage M1a, five had stage M1b, and 16 had stage M1c.¹¹ All patients had been previously treated with the BCT regimen followed by disease progression. In addition and before BCT, nine patients had been treated with chemotherapy, and nine patients had received radiation therapy. Seventeen patients had an ECOG performance status of 0 (normal), and nine patients had a performance status of 1 (ambulatory). Baseline patient and disease characteristics are listed in Table 2.

Safety
Table 5 lists the most frequently reported adverse events by severity. The most frequently reported adverse events were fever (100%), chills (96%), weight gain (81%), edema (96%), nausea (96%), vomiting (85%), diarrhea (77%), oliguria (96%), and high bilirubin (81%). Hematologic grade 3 or 4 adverse events included anemia (four patients, 15%), leukopenia (three patients, 12%), and thrombocytopenia (seven patients, 27%). The most frequent nonhematologic grade 3 or 4 adverse events were high bilirubin in 13 patients (50%), tachycardia in five patients (19%), hypotension in four patients (15%), and oliguria in three patients (12%).

	DISCUSSION

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Stage IV melanoma has an ominous prognosis and is associated with a median survival time of only 6 to 12 months.¹² Chemotherapy with single-agent dacarbazine is the only FDA–approved chemotherapy agent for metastatic melanoma. As tested in the ECOG-led intergroup phase III trial E3695 in patients with metastatic melanoma, BCT failed to produce significantly better response rates, progression-free survival, overall survival, or durable CR compared with the chemotherapy regimen on which it was based administered alone. In addition, toxicity, particularly grade 4 toxicity, was greater for BCT.⁷ HDB IL-2 received FDA approval for patients with metastatic melanoma based on phase II data showing durable responses in some patients with metastatic melanoma.³ Although randomized trials have not been conducted, it seems that administration of HDB IL-2 (600,000 to 720,000 U/kg IV every 8 hours for 15 doses), as administered in the original NCI studies, is superior to IL-2 administered by continuous IV infusion.⁸ Although response rates may be comparable, they tend to be of shorter duration. Continuous infusion of IL-2 at intermediate dosage is a critical component of BCT regimens, and it was previously unknown whether patients treated with BCT and who did not achieve a response or who responded and then experienced progression are capable of subsequently responding and benefiting clinically from the original HDB regimen.¹³

The objective responses noted in this study, which achieved an overall response rate of 19.2%, included four patients with CR, of whom two are still in CR at 26+ and 41+ months. This suggests that HDB IL-2 is active in patients who have either experienced treatment failure or progression after being treated with BCT. It also supports the hypothesis that HDB IL-2 is superior to continuous infusion of IL-2 at the intermediate dosage used in the BCT regimen as tested in ECOG E3695. Although no randomized clinical trials were conducted in melanoma, a randomized phase III trial in patients with metastatic renal cell carcinoma has shown that HDB IL-2 is superior to low-dose IL-2 and IFN--2b.¹⁴ These findings have potential applications in the design of future BCT regimens.

In an attempt to dissect the outcome results of this study, we divided our patients into those who were BCT refractory during primary therapy and those who had some response to BCT and then demonstrated progression. We then evaluated patients in terms of response to subsequent HDB IL-2 therapy. These results are listed in Table 6. Given these findings, we conclude that an initial response to BCT therapy, as tested in E3695, does not predict response to HDB IL-2. All four patients who developed a CR and the patient who developed a PR with HDB IL-2 were primarily refractory to BCT. In addition, all patients who had either a CR or PR with BCT did not respond to HDB IL-2.

Autoimmunity associated with immunotherapy has been correlated with improved outcome in patients with melanoma and renal cell carcinoma.^15-22 HD IL-2 has been shown to achieve its benefit on progression-free and overall survival of melanoma patients in association with the development of autoimmune responses and, in particular, in patients who have developed autoimmune thyroiditis.^15-22 Recent studies of immunotherapy for melanoma with anti-CTLA4 antibody have demonstrated a correlation of antitumor effects and a broad array of autoimmune phenomena including thyroiditis, hypophysitis, enteritis, hepatitis, and dermatitis.^23-26 Gogas et al²⁷ have recently shown that high-risk melanoma patients participating in a trial evaluating 4 weeks versus 52 weeks of a modified HD IFN--2b regimen who developed serologic or clinical manifestations of autoimmunity after treatment had dramatically improved clinical outcomes measured in terms of time to progression or time to death compared with patients who did not develop these manifestations of autoimmunity. To define baseline characteristics of patients who may have a propensity toward developing autoimmunity and for whom immunotherapy may be considered beneficial, certain immunogenetic markers may have a predictive role. These may include the HLA genotype, polymorphisms in the CTLA4 gene, and mutations in the FOXP3 transcription factor gene. In one study, a correlation was noted between the presence of HLA-DR3 and HLA-DR4 alleles and decreased tolerance to IL-2, whereas homozygosity for HLA-DR decreased the chance of response.²⁸ In another study, a significant association was shown between the expression of HLA-DQ1 and clinical response and prolonged survival.²⁹

HDB IL-2 is superior to continuous infusion of IL-2 at intermediate dosage used in the BCT regimen as tested in ECOG E3695. An initial response to BCT, as tested in E3695, does not predict response to HDB IL-2. In fact, patients who are BCT primarily refractory seem to have a better chance of responding to HDB IL-2. Future IL-2–based BCT regimens must consider the importance of dose-intensity with IL-2 therapy. These studies should consider investigating the association between induced autoimmunity and clinical benefit in an effort to identify subgroups of patients who are more likely to benefit from immunotherapy.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Sanjiv S. Agarwala, Schering Plough Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Collection and assembly of data: William E. Gooding, Chao Cai

Data analysis and interpretation: William E. Gooding, Chao Cai

Manuscript writing: Ahmad A. Tarhini, John M. Kirkwood, Sanjiv S. Agarwala

Final approval of manuscript: Ahmad A. Tarhini, John M. Kirkwood, Sanjiv S. Agarwala

	NOTES

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

	REFERENCES

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Submitted January 6, 2007; accepted March 14, 2007.

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