Abstract 3527: A pharmacodynamic study of docetaxel in combination with the p-glycoprotein antagonist, tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer
Authors: Kelly Ronan J. , Robey Robert , Draper Deborah , Chen Clara , Venkatesan Aradhana M. , Figg William D. , Gardner Erin , Piekarz Richard , Balis Frank , Fojo Tito , Bates Susan E. 
Published: February 2011

Purpose: P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to demonstrate meaningful results. However, data highlighting Pgp-mediated drug efflux continues to be reported. A growing body of evidence suggests that sestamibi uptake in lung cancer correlates with disease response to chemotherapy and has been proposed as a pre-selection technique to identify tumors that will respond to chemotherapy. We report the results of a clinical trial using tariquidar (XR9576), a potent Pgp antagonist, in combination with docetaxel.

Experimental Design: Patients first received either 40 mg/m2 of docetaxel alone or 40 mg/m2 docetaxel administered in combination with 150 mg tariquidar. In the first cycle, the pharmacokinetics of docetaxel were monitored after the day 1 and day 8 doses with or without tariquidar. 99mTc-sestamibi scanning and rhodamine efflux from CD56+ mononuclear cells were performed to establish whether tariquidar modulates Pgp. In subsequent cycles, 75 mg/m2 of docetaxel was administered with 150mg of tariquidar every three weeks.

Results: Forty-eight patients were enrolled onto the trial. Twenty-nine percent of the patients (14/48) had previously treated metastatic non-small cell lung cancer (NSCLC). Three partial responses were seen in the NSCLC cohort, measuring 40%, 57% and 67% reduction in tumor size by RECIST. Two patients remained on study for 7 and 24 months, respectively. Non-hematologic grade 3/4 toxicities in 235 cycles included fatigue (6%), nausea (4%), and diarrhea (1%). Tariquidar blocked Pgp-mediated rhodamine efflux from CD56+ cells and reduced 99mTc-sestamibi clearance from the liver. Sestamibi results were available in 32 of the 48 patients, and an increased area under the curve for the liver was noted, ranging from 5.8% to 251% over the pre-tariquidar scan. A 12% to 25% increase in sestamibi uptake was noted in 8 of 10 patients with lung cancer with visible lesions. A pharmacokinetic analysis evaluating potential interaction between tariquidar and docetaxel will be presented; previous reports suggest minimal interaction with anticancer agents.

Conclusions: Tariquidar is a Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Surrogate studies show increased retention of the Pgp substrate sestamibi following tariquidar in imagable lung cancers. Although the percentage increase was less than 25%, we have previously noted that quantitation by planar sestamibi imaging tends to underestimate actual change in accumulation. While response in this trial was designed as an exploratory endpoint only, three responses among 14 in a heavily pretreated population with NSCLC are somewhat surprising and suggest that a follow-up phase II study may be worthwhile.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3527.