title: Phase I clinical trial combining imatinib mesylate and IL-2 in refractory cancer patients: IL-2 interferes with the pharmacokinetics of imatinib mesylate.
abstract: Imatinib mesylate (IM) is a small molecule inhibitor of protein tyrosine kinases. In addition to its direct effect on malignant cells, it has been suggested IM may activate of natural killer (NK) cells, hence exerting immunomodulatory functions. In preclinical settings, improved antitumor responses have been observed when IM and interleukin-2 (IL-2), a cytokine that enhances NK cells functions, were combined. The goals of this study were to determine the maximum tolerated dose (MTD) of IL-2 combined with IM at a constant dose of 400 mg, the pharmacokinetics of IM and IL-2, as well as toxicity and clinical efficacy of this immunotherapeutic regimen in patients affected by advanced tumors. The treatment consisted in 50 mg/day cyclophosphamide from 21 d before the initiation of IM throughout the first IM cycle (from D-21 to D14), 400 mg/day IM for 14 d (D1 to D14) combined with escalating doses of IL-2 (3, 6, 9 and 12 MIU/day) from days 10 to 14. This treatment was administered at three week intervals to 17 patients. Common side effects of the combination were mild to moderate, including fever, chills, fatigue, nausea and hepatic enzyme elevation. IL-2 dose level II, 6 MIU/day, was determined as the MTD with the following dose-limiting toxicities: systemic capillary leak syndrome, fatigue and anorexia. Pharmacokinetic studies revealed that the area under the curve and the maximum concentration of IM and its main metabolite CGP74588 increased significantly when IM was concomitantly administered with IL-2. In contrast, IM did not modulate IL-2 pharmacokinetics. No objective responses were observed. The best response obtained was stable disease in 8/17 (median duration: 12 weeks). Finally, IL-2 augmented the impregnation of IM and its metabolite. The combination of IM (400 mg/day) and IL-2 (6 MIU/day) in tumors that express IM targets warrants further investigation.
authors.affiliation: Département de Médecine; Institut de Cancérologie Gustave Roussy; Villejuif, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pautier
authors.forename: Clara
authors.initials: C
authors.lastname: Locher
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Alain
authors.initials: A
authors.lastname: Deroussent
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Annie
authors.initials: A
authors.lastname: Rey
authors.forename: Ratislav
authors.initials: R
authors.lastname: Bahleda
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
keywords: cancer; imatinib mesylate; interleukin-2; maximum tolerate dose; pharmacokinetics