title: A multicenter phase I study of pazopanib in combination with paclitaxel in first-line treatment of patients with advanced solid tumors.
abstract: This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed. Twenty-eight patients received treatment. One patient at DL1 had dose-limiting toxicity (DLT) of elevated hepatic enzymes. After pazopanib discontinuation, liver enzyme concentrations remained high until a concurrent medication, simvastatin, was discontinued. This patient had the defective CYP2C8*3*3 genotype. At DL2, 1 patient had DLT of elevated hepatic enzymes with rash and 1 patient had DLT of rash. The MTR was paclitaxel 150 mg/m(2) plus pazopanib 800 mg. The most common toxicities were alopecia, fatigue, hypertension, nausea, diarrhea, dysgeusia, neutropenia, myalgia, hair color changes, and peripheral neuropathy. Coadministration of pazopanib and paclitaxel resulted in a 38% increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the MTR. Of the 28 patients treated with the combination, 10 achieved a partial response and 10 achieved stable disease of ≥12 weeks. Pazopanib 800 mg daily plus paclitaxel 150 mg/m(2) every 3 weeks was the recommended phase II dose, with a manageable safety profile, and with clinical activity in both melanoma and non-small cell lung cancer that suggest further evaluation of this combination is warranted.
authors.affiliation: Division of Medical Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States. Kari.Kendra@osumc.edu.
authors.forename: Kari L
authors.initials: KL
authors.lastname: Kendra
authors.affiliation: Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.affiliation: University of Chicago, Chicago, Illinois.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Department of Medicine, Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Mary E R
authors.initials: ME
authors.lastname: O'Brien
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Paul
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: A Benjamin
authors.initials: AB
authors.lastname: Suttle
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: Natalie
authors.initials: N
authors.lastname: Compton
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: Lone H
authors.initials: LH
authors.lastname: Ottesen
authors.affiliation: Division of Medical Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007191:Indazoles; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D017239:Paclitaxel