A phase I, pharmacokinetic and pharmacodynamic dose escalation trial of weekly paclitaxel with interferon-α2b in patients with solid tumors

Abstract

Paclitaxel and interferon have demonstrated anti-angiogenic activity in vitro and in vivo. The toxicity, pharmacokinetics, and pharmacodynamics of paclitaxel with interferon-alpha2b (IFN-alpha2b) were assessed in patients with solid tumors to assess the feasibility of this novel anti-angiogenic regimen. IFN-alpha2b (1 million units) was administered twice daily by subcutaneous injection. Paclitaxel was given weekly over 1 h starting at 30 mg/m2 and increased to 50 mg/m2. Cycles were repeated every 4 weeks. Nineteen patients with a variety of solid tumors were enrolled. Dose-limiting toxicity in cycle 1 was observed at 50 mg/m2. Eleven patients were treated at 40 mg/m2 with no undue toxicity. Pharmacokinetic parameter comparison studies were completed in 11 patients who received days 1 and 29 paclitaxel. Mean paclitaxel clearance and area under the curve (0-infinity) were not statistically different from days 1 to 29. There was a 50% increase in the average Cmax from days 1 to 29. There was also a 73% decrease of matrix metalloproteinase-9 (MMP-9) levels in these 11 patients from days 1 to 29 (p < 0.0005). All three patients with cutaneous angiosarcomas experienced clinically meaningful remissions. In addition, minor responses were observed in one patient with heavily pretreated ovarian cancer and another with adrenocortical carcinoma. This trial details the inability to dose escalate to the maximum tolerated dose of weekly paclitaxel when combined with low-dose interferon. However, this low-dose regimen caused a significant decrease in MMP-9 and demonstrated anti-cancer activity in cutaneous angiosarcomas.