Phase I clinical and pharmacologic study of 13-cis-retinoic acid, interferon alfa, and paclitaxel in patients with prostate cancer and other advanced malignancies.

Abstract

Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFNalpha) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFNalpha, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFNalpha could modulate bcl-2 expression in vitro and in patients. Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFNalpha and escalating doses of TAX. The effect of CRA/IFNalpha on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFNalpha on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting. CRA 1 mg/kg on days 1 to 4, IFNalpha 6 MU/m(2) subcutaneously on days 1 to 4, and TAX 175 mg/m(2) on day 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFNalpha caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFNalpha decreased bcl-2 expression in vitro and in PBMCs. CRA/IFNalpha and TAX is a well-tolerated regimen. CRA/IFNalpha increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFNalpha can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFNalpha/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.