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Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma
K Margolin1, F R Aronson, M Sznol
1City of Hope National Medical Center, Department of Medical Oncology, Duarte, California 91010-0269.
Abstract:
Interleukin (IL-4) is a pluripotent cytokine that stimulates proliferation of activated T-cells and has antineoplastic activity against human renal tumors in animal systems. In phase I trials, IL-4 could be tolerated at doses up to 20 micrograms/kg, with dose-limiting toxicities consisting of fever, fluid retention, nasal congestion, and mucositis. We report the results of two separate Phase II trials of IL-4 in 30 patients with metastatic malignant melanoma and 19 patients with advanced renal cancer. IL-4 was administered intravenously every 8 h for 14 doses in two 5-day courses separated by a 9-day interval. The first 27 patients were treated at a dose of 800 micrograms/m2, but after three of these patients developed cardiac toxicities, the dose was decreased to 600 micrograms/m2. One complete response occurred in a patient with metastatic melanoma (duration > or = 30 months). No responses were seen among the patients with renal cancer. The most frequent side effects were fever, nausea, malaise, nasal congestion, and diarrhea. Reversible hepatic and renal dysfunction were also common. Hypotension was infrequent, but transient weight gain due to fluid retention was common. The major life-threatening toxicities were cardiac and gastrointestinal. Suspected cardiac ischemia was observed in two patients, pericarditis in one, and arrhythmias in two. Three patients had major upper gastrointestinal bleeding without evidence of local tumor. We conclude that IL-4, when given as a single agent on this schedule at maximum tolerated dose, does not possess meaningful activity in renal cancer or melanoma.
Insights
Interleukin-4 (IL-4) showed limited efficacy in treating advanced melanoma and renal cancer. The cytokine was generally tolerated but caused significant side effects, including cardiac and gastrointestinal toxicities.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Interleukin-4 (IL-4) is a cytokine with demonstrated antineoplastic activity in preclinical models.
- Phase I trials established tolerability of IL-4 up to 20 micrograms/kg, with dose-limiting toxicities including fever and fluid retention.
Purpose of the Study:
- To evaluate the efficacy and safety of IL-4 as a single agent in patients with metastatic malignant melanoma and advanced renal cancer.
- To determine the maximum tolerated dose and dose-limiting toxicities of IL-4 in these patient populations.
Main Methods:
- Two Phase II trials were conducted involving 30 melanoma patients and 19 renal cancer patients.
- IL-4 was administered intravenously every 8 hours for 14 doses across two 5-day courses with a 9-day interval.
- Initial dose of 800 micrograms/m2 was reduced to 600 micrograms/m2 due to cardiac toxicities.
Main Results:
- One complete response was observed in a melanoma patient, lasting over 30 months.
- No responses were observed in patients with renal cancer.
- Common side effects included fever, nausea, malaise, nasal congestion, and diarrhea. Reversible hepatic and renal dysfunction were frequent.
- Serious toxicities included cardiac ischemia, pericarditis, arrhythmias, and major gastrointestinal bleeding.
Conclusions:
- IL-4, administered as a single agent on the tested schedule at the maximum tolerated dose, lacks meaningful clinical activity in advanced melanoma and renal cancer.
- The observed toxicities, particularly cardiac and gastrointestinal, limit the therapeutic potential of IL-4 in these indications.