Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PTK787/ZK 222584 Administered Twice Daily in Patients With Advanced Cancer

• Published in: Journal of clinical oncology Vol. 23; no. 18; pp. 4162 - 4171
• Main Authors: THOMAS, Anne L, MORGAN, Bruno, HORSFIELD, Mark A, HIGGINSON, Anthony, KAY, Andrea, LEE, Lucy, MASSON, Eric, PUCCIO-PICK, Marie, LAURENT, Dirk, STEWARD, William P
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 20-06-2005; Lippincott Williams & Wilkins
• Subjects: Administration, Oral; Adult; Aged; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - pharmacology; Area Under Curve; Biological and medical sciences; Chi-Square Distribution; Chromatography, High Pressure Liquid; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Phthalazines - administration & dosage; Phthalazines - pharmacokinetics; Phthalazines - pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Pyridines - pharmacology; Statistics, Nonparametric; Treatment Outcome; Tumors; Human; Cancerology; Treatment; Toxicity; Phase I trial; Malignant tumor; Pharmacokinetics
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2005.09.034

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling.
Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response.
At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (K(i)) at day 2 predicted for nonprogression of disease.
The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK >/= 1,000 mg total daily dose is the biologically active dose.