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

Purpose: 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 (IFN alpha) to inhibit tumor cell growth in vitro, A phase I trial of 13-cis-retinoic acid (CRA), IFN alpha, 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 IFN alpha could modulate bcl-2 expression in vitro and in patients. Patients and Methods: Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFN alpha and escalating doses of TAX. The effect of CRA/IFN alpha on TAX pharmacokinetics was analyzed in hath patients and human liver microsomes, the effect of CRA/IFN alpha on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting, Results: CRA 1 mg/kg on days 1 to 4, IFN alpha 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/IFN alpha caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-rime curve valves 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/IFN alpha decreased bcl-2 expression in vitro and in PBMCs. Conclusion: CRA/IFN alpha and TAX is a well-tolerated regimen. CRA/IFN alpha increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFN alpha can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFN alpha/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response, (C) 1999 by American Society of Clinical Oncology.