A Phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors

Abstract

Background: Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients.  We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active.

Patients and Methods: Eligible patients with solid tumors received micronized CAI daily (150-250mg PO) and paclitaxel intravenously q3weeks (175-250mg/m2), sequentially escalating each drug.  CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. Patients were assessed for toxicity, pharmacokinetics, and disease outcome.

Results: Twenty-nine heavily pretreated patients (median 3 [0-7]) were enrolled on 5 dose levels. No additive or cumulative toxicity was observed, and grade 3 nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses.  The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m2 q3weeks.  Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p