Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma.

Abstract

BACKGROUND:

The primary objective of this study was to determine whether addition of the selective P-glycoprotein (P-gp) inhibitor tariquidar (XR9576) to chemotherapy could induce an objective tumor response in patients who previously were resistant to the same agents. The secondary objectives were to evaluate P-gp expression by immunohistochemistry (IHC), to determine functional activity of the P-gp transporter before and after administration of tariquidar with serial technetium-99m ((99m)Tc)-sestamibi scans, and to correlate those parameters with clinical response.

METHODS:

Seventeen women with Stage III-IV breast carcinoma were included in the study who progressed (n = 13 women) or had stable disease (n = 4 women) on doxorubicin-containing or taxane-containing chemotherapy regimens. During the study, the same chemotherapy was continued without dose modifications, but tariquidar (150 mg intravenously) was added to the treatment regimen.

RESULTS:

Thirty-six percent of patients had P-gp-positive tumors by IHC, and 5 patients (29%) experienced increases > or = 10% in sestamibi uptake (median increase, 40%; range, 10-63%) after the administration of tariquidar. There was one partial response in a patient who had the greatest increase in sestamibi uptake and who also showed inducible P-gp expression. There was one patient who experienced severe doxorubicin/docetaxel-related toxicity after tariquidar was added to her chemotherapy regimen.

CONCLUSIONS:

Tariquidar showed limited clinical activity to restore sensitivity to anthracycline or taxane chemotherapy. Functional imaging of the tumor with (99m)Tc-sestamibi scans before and after administration of multidrug-resistance inhibitor may be useful to identify the small subset of patients who could benefit from multidrug-resistance modulation in future trials.

• Authors: Lajos Pusztai, Peter Wagner, Nuhad Ibrahim, Edgardo Rivera, Richard Theriault, Daniel Booser, Fraser W Symmans, Franklin Wong, George Blumenschein, Donald R Fleming, Roman Rouzier, Graeme Boniface, Gabriel N Hortobagyi
• Journal: Cancer (Cancer) Vol. 104 Issue 4 Pg. 682-91 (Aug 15 2005) ISSN: 0008-543X [Print] United States
• PMID: 15986399 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Quinolines
• Technetium Tc 99m Sestamibi
• tariquidar

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, drug effects, metabolism)
• Adult
• Aged
• Antineoplastic Agents (therapeutic use)
• Breast Neoplasms (diagnostic imaging, drug therapy)
• Drug Resistance, Neoplasm
• Female
• Humans
• Immunohistochemistry
• Infusions, Intravenous
• Middle Aged
• Neoplasm Recurrence, Local (diagnostic imaging, drug therapy)
• Quinolines (administration & dosage, adverse effects)
• Technetium Tc 99m Sestamibi
• Tomography, Emission-Computed