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

Clin Cancer Res. 2001 Jun;7(6):1600-9.


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/m(2)) or micronized CAI (250 mg/m(2)) for 8 days followed by a 3-h infusion of PAX (110-250 mg/m(2)) 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 microM) 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Dose-Response Relationship, Drug
  • Drug Interactions*
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neovascularization, Pathologic
  • Ovarian Neoplasms / drug therapy
  • Paclitaxel / administration & dosage*
  • Paclitaxel / therapeutic use*
  • Recurrence*
  • Time Factors
  • Treatment Outcome
  • Triazoles / administration & dosage*
  • Triazoles / therapeutic use*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Triazoles
  • carboxyamido-triazole
  • Paclitaxel