A phase I trial of carboxyamido-triazole and paclitaxel for relapsed solid tumors: Potential efficacy of the combination and demonstration of pharmacokinetic interaction

Elise C. Kohn, Eddie Reed, Gisele A. Sarosy, Lori Minasian, Kenneth S. Bauer, Frieda Bostick-Bruton, Vyta Kulpa, Eichi Fuse, Anne Tompkins, Marianne Noone, Barry Goldspiel, James Pluda, William D. Figg, Lance A. Liotta

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53 Scopus citations

Abstract

Purpose: Preclinical and clinical investigation of the combination of the antiangiogenesis/anti-invasion agent carboxyamido-triazole (CAI) administered with the cytotoxic agent paclitaxel (PAX). Experimental Design: Colony-forming assays were used to test the activity of CAI plus PAX on A2780 human ovarian cancer. The sequence of CAI followed by PAX (CAI>Pax) was modeled in nude mice to test for potential additive toxicity. The Phase I clinical dose escalation schema tested p.o. administered CAI in PEG-400 (50-100 mg/m2) or micronized CAI (250 mg/m2) for 8 days followed by a 3-h infusion of PAX (110-250 mg/m2) every 21 days. Patients were assessed for toxicity, pharmacokinetics of CAI and PAX, and disease outcome. Results: In preclinical studies, CAI>Pax was additive in A2780 human ovarian cancer cell lines when CAI (1 or 5 μM) preceded subtherapeutic doses of PAX. CAI did not reverse PAX resistance and collateral resistance to CAI was documented in PAX-resistant cells. CAI>PAX administration had no overt additive toxicity in nude mice. Thirty-nine patients were treated on a dose-escalation Phase I trial using daily oral CAI for 8 days followed by the PAX infusion. Pharmacokinetic analysis revealed that PAX caused an acute increase in circulating CAI concentrations in a dose-dependent fashion. No additive or cumulative toxicity was observed, and grade 3 nonhematological toxicity was rare. Three partial responses and two minor responses were observed. Conclusions: The sequential combination of CAI and PAX is well tolerated, and the activity observed suggests that further study of the combination is warranted.

Original languageEnglish
Pages (from-to)1600-1609
Number of pages10
JournalClinical Cancer Research
Volume7
Issue number6
StatePublished - 2001
Externally publishedYes

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