Titre du document / Document title

A Phase I Pharmacokinetic and Pharmacodynamic Study of TK1258, an Oral, Multitargeted Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

Auteur(s) / Author(s)

SARKER Debashis ⁽¹⁾ ; MOLIFE Rhoda ⁽¹⁾ ; EVANS T. R. Jeffrey ⁽²⁾ ; HARDIE Maryon ⁽²⁾ ; MARRIOTT Cheryl ⁽¹⁾ ; BUTZBERGER-ZIMMERLI Priska ⁽²⁾ ; MORRISON Rosemary ⁽²⁾ ; FOX Judith A. ⁽³⁾ ; HEISE Carla ⁽³⁾ ; LOUIE Sharianne ⁽³⁾ ; AZIZ Natasha ⁽³⁾ ; GARZON Felix ⁽³⁾ ; MICHELSON Glenn ⁽³⁾ ; JUDSON Ian R. ⁽¹⁾ ; JADAYEL Dalal ⁽¹⁾ ; BRAENDLE Edgar ⁽³⁾ ; DE BONO Johann S. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Royal Marsden Hospital and Institute of Cancer Research, Sutton, ROYAUME-UNI
⁽²⁾ Beatson Oncology Centre, University of Glasgow, Glasgow, ROYAUME-UNI
⁽³⁾ Novartis Oncology, East Hanover, New Jersey, ETATS-UNIS

Résumé / Abstract

Purpose: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258). Experimental Design: A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule. Results: Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels. Conclusions: The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.

Revue / Journal Title

Clinical cancer research    ISSN  1078-0432   CODEN CCREF4 

Source / Source

2008, vol. 14, n^o7, pp. 2075-2081 [7 page(s) (article)] (15 ref.)

Langue / Language

Anglais

Editeur / Publisher

American Association for Cancer Research, Philadelphia, PA, ETATS-UNIS  (1995) (Revue)

Mots-clés anglais / English Keywords

Cancer

;

Malignant tumor

;

Enzyme

;

Transferases

;

Receptor tyrosine kinase

;

Solid tumor

;

Advanced stage

;

Human

;

Tyrosine kinase inhibitor

;

Protein-tyrosine kinase

;

Enzyme inhibitor

;

Oral administration

;

Pharmacokinetic pharmacodynamic relationship

;

Mots-clés français / French Keywords

Cancer

;

Tumeur maligne

;

Enzyme

;

Transferases

;

Récepteur tyrosine kinase

;

Tumeur solide

;

Stade avancé

;

Homme

;

Inhibiteur de la tyrosine kinase

;

Protein-tyrosine kinase

;

Inhibiteur enzyme

;

Voie orale

;

Relation pharmacocinétique pharmacodynamie

;

Mots-clés espagnols / Spanish Keywords

Cáncer

;

Tumor maligno

;

Enzima

;

Transferases

;

Tumor sólido

;

Estadio avanzado

;

Hombre

;

Inhibidor tyrosine kinase

;

Protein-tyrosine kinase

;

Inhibidor enzima

;

Vía oral

;

Relación farmacocinética farmacodinamia

;

Localisation / Location

INIST-CNRS, Cote INIST : 26073, 35400019584136.0200