Tariquidar (XR9576) is a potent and effective P-glycoprotein (Pgp) inhibitor that can be administered safely with chemotherapy

3093 Background: Inhibition of P-glycoprotein (Pgp) as a means to improve chemotherapeutic efficacy remains a valid but unproven hypothesis. Two recent trials in patients with lung cancer using the Pgp inhibitor, tariquidar (XR9576), closed prematurely due to toxicity concerns. We report our experience using tariquidar with chemotherapy. Methods: Patients with refractory or metastatic adrenocortical cancer (ACC) received tariquidar on days 1 & 3 with a 96-hour infusion of doxorubicin, vincristine, and etoposide with mitotane (X-MAVE) every 21 days. Patients with refractory ovarian, cervical & lung cancer received tariquidar with a docetaxel infusion every 21 days. Study participants had two 99mTc-sestamibi scans. Time-activity curves were generated and areas under the curve calculated to compare 99mTc-sestamibi accumulation at baseline to that 1 h after tariquidar. Rhodamine efflux from CD56+ cells was measured before and after tariquidar to assess Pgp inhibition. Results: To date, 15 patients with ACC have received 71 cycles of X-MAVE, and 16 patients with ovarian, cervical or lung cancer have received 66 cycles of docetaxel. Grade 3 non-hematologic toxicities (# of cycles) observed with X-MAVE include: abdominal pain/constipation (4), arthralgia (4), nausea/vomiting (2), diarrhea (1), esophagitis (1), fatigue (6), hand-foot reaction (1), and hyponatremia (3); those with docetaxel include: diarrhea (1), dyspnea (1) fatigue (6), hyponatremia (3), pain (3) and tearing (2). 99mTc-sestamibi accumulation increased 39 to 129%, compared to a mean increase of 106% in the liver, in 6 of 8 patients with ACC whose lesions could be visualized. Quantitation for the 10 such patients with ovarian, cervical or lung cancer is ongoing. Rhodamine efflux from CD56+ cells assayed in 30 patients was reduced by a mean of 85% after tariquidar and was sustained even after 48 h. Pharmacokinetic sampling before and after tariquidar has been performed. Conclusions: Tariquidar is a potent and highly effective Pgp inhibitor that can be administered safely with a combination of doxorubicin, etoposide and vincristine or with docet axel. The efficacy in patients with refractory cancers continues to be evaluated. No significant financial relationships to disclose.