Effects of the P-glycoprotein (Pgp) antagonist tariquidar (XR-9576; TQD) on Pgp function as well as the toxicity and efficacy of combined chemotherapy in patients with metastatic adrenocortical cancer (mACC).

2543 Background: ACC is a rare tumor optimally treated surgically. ACC expresses high levels of Pgp. We added TQD to a regimen of daily oral mitotane with infusional doxorubicin, vincristine, and etoposide (MAVE) to assess the efficacy of Pgp inhibition in mACC and whether the MAVE regimen could be improved.,46 pts with mACC received daily mitotane (mean 3.99 g/day) and 96-hour infusional doxorubicin (8 mg/m/day), etoposide (60 mg/m/day), and vincristine (0.24 mg/m/day). Six pts underwent surgery after achieving best chemotherapy response. Tc-sestamibi scans obtained before and after TQD administration and rhodamine efflux from CD56+ mononuclear cells were used to assess Pgp inhibition.,46 pts were enrolled and 44 are evaluable for response and toxicity. 54% had functional tumors. A total of 210 cycles were administered. The response rate was 8.7% with a median shrinkage of 13% in the 14% of pts with measurable shrinkage. Two pts have ongoing CRs over 3 years. Two pts had PR with mean duration of response of 15 weeks; 25 pts had stable disease. The median overall survival (OS) was 13.7 months. The predominant G3/4 toxicity was neutropenia in 80% of first cycles. Pegylated G-CSF was given in subsequent cycles. Fever occurred in only 4.7% of cycles. TQD inhibition of Pgp in vivo was marked and sustained as evidenced by Tc-sestamibi scans demonstrating inhibition of functional Pgp with a median increase accumulation of Tc-sestamibi of 133% (range 10-240%) and 179% (range 38-424%) in mACC lesions and normal liver, respectively, with only a 2% change in the heart. Rhodamine efflux from CD56+ cells was blocked with a median inhibition of 92% at 24 hours and 81% at 48 hours, demonstrating excellent Pgp inhibition in vivo.,TQD results in potent and sustained inhibition of Pgp. mACC expresses functional Pgp and this can be blocked by TQD. The myelotoxicity of this regimen was resolved by G-CSF administration. The addition of TQD does not appear to prolong OS in mACC. However, the safety of TQD and its sustained potency warrant its further investigation as a Pgp antagonist in future studies with cytotoxic and novel agents that are Pgp substrates. No significant financial relationships to disclose.