A phase I trial of carboxyamido-triazole and paclitaxel for relapsed solid tumors: potential efficacy of the combination and demonstration of pharmacokinetic interaction.
OBJECTIVE
Preclinical and clinical investigation of the combination of the antiangiogenesis/anti-invasion agent carboxyamido-triazole (CAI) administered with the cytotoxic agent paclitaxel (PAX).


METHODS
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.
Kohn
E C
EC
Medicine Branch, National Cancer Institute, and Warren G. Magnuson Clinical Center, NIH, Bethesda, Maryland 20892, USA. eckohn@helix.nih.gov
Reed
E
E
Sarosy
G A
GA
Minasian
L
L
Bauer
K S
KS
Bostick-Bruton
F
F
Kulpa
V
V
Fuse
E
E
Tompkins
A
A
Noone
M
M
Goldspiel
B
B
Pluda
J
J
Figg
W D
WD
Liotta
L A
LA
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use*; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014230:Triazoles; C062058:carboxyamido-triazole; D017239:Paclitaxel