Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma.
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.
Pusztai
Lajos
L
Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. lpusztai@mdanderson.org
Wagner
Peter
P
Ibrahim
Nuhad
N
Rivera
Edgardo
E
Theriault
Richard
R
Booser
Daniel
D
Symmans
Fraser W
FW
Wong
Franklin
F
Blumenschein
George
G
Fleming
Donald R
DR
Rouzier
Roman
R
Boniface
Graeme
G
Hortobagyi
Gabriel N
GN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects*; D017256:Technetium Tc 99m Sestamibi; D014055:Tomography, Emission-Computed
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011804:Quinolines; D017256:Technetium Tc 99m Sestamibi; C402343:tariquidar