Phase I trial of subcutaneous recombinant human interleukin-2 in patients with metastatic melanoma

BACKGROUND. Interleukin-2 (IL-2) has activity in metastatic melanoma when given in high doses by the intravenous (IV) route, but its side effects and effectiveness when given in intermediate to high doses by the subcutaneous (SC) route have not been studied adequately. This study sought to determine the maximum tolerated dose (MTD) of IL-2 administered once daily by the SC route. METHODS. Outpatients with progressive metastatic melanoma after chemotherapy were enrolled in a Phase I trial of IL-2 administered SC daily for 5 days per week for 4 consecutive weeks, repeated at 6-week intervals. Patients were instructed to drink at least 2 L of fluid daily. IL-2 pharmacokinetic studies were performed at the two highest dose levels. Toxicity was recorded weekly using the National Cancer Institute Common Toxicity Criteria. Response was assessed at 6-week intervals. RESULTS. Three patients, 6 patients, 6 patients, and 4 patients received a median of 2 courses of SC IL-2 at dose levels of 6 MIU/m(2), 9 MIU/m(2), 12 MIU/m(2), and 15 MIU/m', respectively. Failure to maintain adequate fluid intake was responsible for 2 episodes of syncope at the 9 MIU/m' dose level and for 2 incidents of reversible prerenal azotemia at the 15 MIU/m(2) dose level. IL-2 treatment was resumed in these patients without incident. At the 15 MIU/m(2) dose level, 2 patients had severe headaches, depression, and visual hallucinations requiring discontinuation of treatment. Cough and fluid retention at the end of the third and fourth weeks at the 15 MIU/m(2) dose level approximated the symptoms reported by inpatients treated by continuous IV infusion at 9 MIU/m(2) on the same schedule. There was a partial response and a complete response in subcutaneous disease at the 12 MIU/m' and 15 MIU/m(2) dose levels, respectively, each lasting < 2 months. Plasma IL-2 levels after SC injection of 1000-5000 pg/mL reached maximum by 3 hours and were detectable for up to 48 hours after administration. The half-lives for SC IL-2 absorbance and clearance were 1.6 hours and 5.2 hours, respectively, and the calculated area under the curve was 30,584 pg/mL X hour. CONCLUSIONS. SC IL-2 was well tolerated and had high sustained bioavailability at the higher doses studied. The MTD for a daily SC regimen was 12 MIU/m(2) and is recommended for future studies.