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A multicenter phase I study of pazopanib in combination with paclitaxel in first-line treatment of patients with advanced solid tumors.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2015 Feb; Vol. 14 (2), pp. 461-9. Date of Electronic Publication: 2014 Dec 10. - Publication Year :
- 2015
-
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.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Antineoplastic Agents adverse effects
Antineoplastic Agents pharmacology
Antineoplastic Combined Chemotherapy Protocols adverse effects
Dose-Response Relationship, Drug
Female
Humans
Indazoles
Leukocyte Count
Male
Middle Aged
Neoplasm Staging
Neoplasms blood
Neoplasms pathology
Paclitaxel adverse effects
Paclitaxel pharmacokinetics
Paclitaxel pharmacology
Pyrimidines adverse effects
Pyrimidines pharmacology
Sulfonamides adverse effects
Sulfonamides pharmacology
Antineoplastic Agents therapeutic use
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Neoplasms drug therapy
Paclitaxel therapeutic use
Pyrimidines therapeutic use
Sulfonamides therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 14
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 25504632
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-14-0431