Two formulations of orally administered CAI have completed phase I clinical trial and have had manuscripts submitted. A total of 49 patients have been treated on the two formulations, liquid and gelatin capsule. Disease stabilization was observed in patients with a variety of solid tumors (60% of 40 evaluable patients), lasting up to 7 months. CAI was well tolerated in both formulations, however, escalation of the gelcap to 125 mg/m2/d resulted in compliance- limiting nausea and vomiting (grade II). The liquid formulation caused compliance-limiting gastrointestinal complaints (grade II) at 150 - 175 mg/m2/d. Neutropenia was observed in 1 patient (2%) and reversible peripheral neuropathy in 4 (grade II, 3 [6%]; grade III, 1 [2%]). Patients are currently receiving the micronized powder formulation at 250 mg/m2/d with escalation proceeding. We have demonstrated a relative bioavailability of 50% with the micronized formulation compared with the liquid CAI. Two prominent metabolite peaks have been isolated and are undergoing biochemical and biological characterization. The first metabolite is an isolated tail group with retained chloride groups. This compound is inactive in signaling or proliferation assays. The second metabolite is undergoing functional characterization presently. In follow-up of laboratory observations that CAI exposure prior to paclitaxel treatment resulted in an additive effect for human breast and ovarian cancer cell lines, a clinical trial has been developed and approved for use. The protocol uses CAI for one week to attain optimal plasma levels and is followed by a 3 hr infusion of paclitaxel. The cycles are given every 21 days. A total of 3 patients have been accrued to the first level, CAI 50 mg/m2/d liq x 8 days and paclitaxel 110 mg/m2 infusion. It has been well tolerated. Chemoprevention preclinical studies are continuing.
