Phase I-II Trial of Interferon-α_2b by Continuous Subcutaneous Infusion over 28 Days

Interferon-α_2b (IFN-α) was administered by continuous subcutaneous (s.c.) infusion to 23 patients with hematologic malignancies or metastatic solid tumors: 5 patients with multiple myeloma, 3 with malignant melanoma, 2 with chronic myelogenous leukemia (CML), 10 patients with renal cell cancer, and 3 patients with other solid tumors. Drug was delivered by continuous s.c. infusion for 28 days (1 cycle) at daily dose levels of 0.7, 1.4, 2.5, 3.6, or 5.0 × 10⁶ IU/m² to 3, 3, 3, 8, and 6 patients, respectively. At the highest dose level, a severe flu-like syndrome was seen in 3 patients and severe gastrointestinal toxicity in 2 patients. The maximally tolerated dose (MTD) was 3.6 × 10⁶ IU/m² · day and the principal toxicity was a mild to moderate flu-like syndrome. Local skin reactions were occasionally noted at all dose levels if the s.c. needle site was not rotated every 3-4 days. At dose levels of 2.5-3.6 × 10⁶ IU/m² · day, IFN-α serum levels at steady state ranged from 19 to 61 IU/ml. The time to achieve steady-state conditions ranged from 40 to 72 h and at steady state, 24 h area under the concentration time curve (AUC₂₄ h) ranged from 480 to 1,464 IU/ml · h. Objective responses-were seen 3 of 17 evaluable patients: 1/7 in renal cell cancer (14%); 1/2 in CML and in one patient with ependymoma. Remissions lasted 4, 8, and 15 months in renal cell, CML, and ependymoma, respectively. Continuous s.c. IFN-α produces objective responses and higher cumulative serum drug exposures than bolus methods of drug administration, with an MTD for the continuous s.c. route being half that of daily bolus s.c. dosing. The recommended dose for phase II studies is 2.5 × 10⁶ IU/m² · day for 28 days.