Pediatric phase I trial and pharmacokinetic study of P-glycoprotein inhibitor, tariquidar, in combination with doxorubicin, vinorelbine or docetaxel

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8541 Background: P-glycoprotein (Pgp), an ATP-dependent membrane transporter present in normal tissues, confers multidrug resistance in cancer cells. Tariquidar (TQ) blocks Pgp by inhibiting ATP binding and hydrolysis. Objectives: Assess toxicity, optimal dose, pharmacokinetics (PK) and pharmacodynamics of TQ in children with solid tumors and assess toxicity and PK of anticancer drugs (AD) in combination with TQ. Methods: TQ (1 [n=4], 1.5 [n=6], or 2 [n=5] mg/kg IV) was given alone on d 1 and with doxorubicin (DOXO, 50 mg/m2, n=10), docetaxel (75 mg/m2, n=4), or vinorelbine (20 mg/m2 d 3 & 10, n=1) on d 3. Plasma PK samples from d 1 & 3 were assayed for TQ by LC/MS/MS and DOXO by LC-fluorescent detection. Pgp function in vivo was assessed pre & post TQ using rhodamine uptake in CD56+ blood cells 24 h post TQ by flow cytometry (n=12) and 99mTc-sestamibi scintigraphy (n=6) immediately ater TQ. Results: 15 children (age 2–18, median 13) with sarcoma (n=8), adrenocortical carcinoma (n=3) or other (n=4) were enrolled. TQ was well tolerated at all dose levels. Delayed neutrophil recovery (n=2), grade 3 thrombocytopenia from docetaxel (n=1) and grade 3 mucositis (n=3) were prominent AD toxicities. AD toxicities may be more severe at the 2 mg/kg TQ dose. PK parameters for TQ alone are presented below. DOXO clearance (CL, n=8) was 400±150 mL/min/m2 given with TQ. Inhibition of rhodamine efflux in CD56+ cells was 54, 62, and 79% of maximum at the 1, 1.5 and 2 mg/kg doses of TQ. Sestamibi uptake increased by 1.7- to 4.1-fold (median, 2.6-fold) in liver and 1.2 to 1.4-fold in tumor (n=2) after TQ. Conclusions: 2 mg/kg TQ is well tolerated in children. TQ CL may be dose dependent, and at 2 mg/kg TQ CL is comparable to CL in adults. DOXO CL was comparable to published results. Pgp function in CD56+ blood cells is inhibited for ≥24 h. TQ also enhanced retention of sestamibi in liver and in some tumors. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration QLT, Inc.; Xenova Group, plc QLT, Inc.; Xenova Group, plc Xenova Group, plc

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