Interleukin-2 With or Without Histamine Dihydrochloride in Treating Patients With Stage IV Melanoma Metastatic to the Liver

Study Overview
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Brief Summary
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RATIONALE: Interleukin-2 may stimulate a person's white blood cells to kill tumor cells. Histamine dihydrochloride may help interleukin-2 kill more tumor cells by making tumor cells more sensitive to the drug. It is not yet known if interleukin-2 is more effective with or without histamine dihydrochloride in treating stage IV melanoma that is metastatic to the liver. PURPOSE: Randomized phase III trial to compare the effectiveness of interleukin-2 with or without histamine dihydrochloride in treating patients who have stage IV melanoma that is metastatic to the liver.

Detailed Description
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OBJECTIVES: Compare the duration of survival in patients with stage IV melanoma with hepatic metastasis treated with interleukin-2 with or without histamine dihydrochloride. Compare the progression-free survival, response rate, response rate of hepatic tumors, and lack of disease progression in patients treated with these regimens. Determine the safety of these regimens, in terms of frequency, severity, and causal relationship of adverse events, in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center location (North America vs Europe), lactate dehydrogenase (less than ULN vs ULN or greater), and metastatic sites (liver only vs liver and other sites). Patients are randomized to one of two treatment arms. Arm I: Patients receive interleukin-2 (IL-2) subcutaneously (SC) twice daily on days 1 and 2 of weeks 1 and 3 and days 1-5 of weeks 2 and 4. Patients also receive histamine dihydrochloride SC over 10-30 minutes on days 1-5 of weeks 1-4. Arm II: Patients receive IL-2 as in arm I. In both arms, treatment repeats every 6 weeks for at least 8 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 3 years and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 224 patients (112 per treatment arm) will be accrued for this study.

Official Title
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A Phase III, Multi-Center Controlled Trial With Stratified Randomization Comparing The Efficacy Of Interleukin-2 (IL-2) Plus Histamine Dihydrochloride (HDC) Versus IL-2 Alone To Increase The Duration Of Survival In Patients With AJCC Stage IV Malignant Melanoma With Hepatic Metastasis

Conditions
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Melanoma (Skin), Metastatic Cancer

Intervention / Treatment
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* Biological: aldesleukin
* Drug: histamine dihydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed stage IV melanoma Must have radiological evidence of lesions in liver (target or non-target) At least 1 measurable lesion outside previously irradiated field At least 20 mm by contrast-enhanced CT scan, MRI, medical photography, or physical exam OR at least 10 mm by spiral CT scan No prior or concurrent clinical and/or objective evidence of brain metastasis PATIENT CHARACTERISTICS: Age: 18 and over Performance status: WHO 0-1 Life expectancy: At least 3 months Hematopoietic: Hemoglobin at least 9.5 g/dL WBC at least 3,000/mm^3 Granulocyte count at least 2,000/mm^3 Platelet count at least 100,000/mm^3 Hepatic: Bilirubin no greater than 2 times upper limit of normal (ULN) AST and ALT no greater than 4 times ULN Alkaline phosphatase no greater than 4 times ULN Hepatitis B and C negative Renal: Creatinine no greater than 1.7 mg/dL Calcium no greater than 11.5 mg/dL Cardiovascular: No abnormal thallium stress test No acute myocardial infarction within the past year No New York Heart Association class III or IV heart disease Pulmonary: No asthma requiring active treatment within the past 5 years Oxygen saturation by pulse oximeter at least 90% unless FEV_1 is greater than 2 L or at least 75% predicted Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative Concurrent medically-controlled (except with glyburide) or diet-controlled diabetes is allowed Concurrent medically-controlled thyroid dysfunction is allowed No other active malignancy within the past 5 years except carcinoma in situ of the cervix or localized squamous cell or basal cell skin cancer No serious non-malignant medical conditions, including psychiatric disability, that would preclude study compliance No active autoimmune disease (e.g., lupus, inflammatory bowel disease, or psoriasis) No active peptic and/or esophageal ulcer disease No hypersensitivity to histamine products or urticaria No active IV drug abuse PRIOR CONCURRENT THERAPY: Biologic therapy: No prior immunotherapy with high-dose IV interleukin-2 (IL-2) No prior combination immunotherapy with chemotherapy At least 1 year since prior low-dose adjuvant IL-2 as part of vaccine therapy or as therapy for stage II or III melanoma Chemotherapy: See Biologic therapy Endocrine therapy: No chronic systemic glucocorticoid steroids Asthma inhalers, topical creams, or intra-articular injections allowed Hormonal therapy for non-melanoma-related conditions allowed Radiotherapy: See Disease Characteristics Concurrent radiotherapy as palliative therapy for isolated non-target lesions (e.g., bone lesions) allowed Surgery: Not specified Other: At least 4 weeks since prior therapy directed at malignancy At least 4 weeks since prior investigational medications or therapies At least 2 weeks since prior parenteral antioxidants and/or vitamins At least 2 weeks since prior antibiotics for active illness At least 2 weeks since prior H2 antagonists, beta-blockers, antihypertensives, antimalarials, antitrypanosomals, neuromuscular-blocking agents, tricyclic antidepressants, or alprazolam At least 24 hours since prior antihistamines No prior enrollment in any Maxim Pharmaceuticals investigational trials No concurrent anticonvulsant therapy for seizure disorder No other concurrent investigational drug No concurrent H2 antagonists, tricyclic antidepressants, alprazolam, beta- blockers, antihypertensives, antitrypanosomals, antimalarials, or monoamine oxidase inhibitors No concurrent inhibitors of diamine oxidase, monoamine oxidase, or histamine N-methyltransferase No concurrent antihistamines

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: aldesleukin|nan|
|Drug: histamine dihydrochloride|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV melanoma, recurrent melanoma, liver metastases