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A Phase I Trial of Carboxyamido-triazole and Paclitaxel for Relapsed Solid Tumors

Potential Efficacy of the Combination and Demonstration of Pharmacokinetic Interaction

Medicine Branch [E. C. K., E. R., G. A. S., L. M., K. S. B., F. B-B., E. F., A. T., M. N., W. D. F.], Laboratory of Pathology [E. C. K., V. K., L. A. L.], and Cancer Therapy Evaluation Program [J. P.], National Cancer Institute, and Warren G. Magnuson Clinical Center [B. G.], NIH, Bethesda, Maryland 20892

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.

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