TY - JOUR
T1 - Phase I clinical trial combining imatinib mesylate and IL-2 in refractory cancer patients
T2 - IL-2 interferes with the pharmacokinetics of imatinib mesylate
AU - Pautier, Patricia
AU - Locher, Clara
AU - Robert, Caroline
AU - Deroussent, Alain
AU - Flament, Caroline
AU - Le Cesne, Axel
AU - Rey, Annie
AU - Bahleda, Ratislav
AU - Ribrag, Vincent
AU - Soria, Jean Charles
AU - Vassal, Gilles
AU - Eggermont, Alexander
AU - Zitvogel, Laurence
AU - Chaput, Nathalie
AU - Paci, Angelo
N1 - Funding Information:
This work was supported by Novartis SA, Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labelisée, L.Z.), l’Association pour la Recherche sur le Cancer (A.R.C.), Fondation pour la Recherche Médicale and Fondation de France. We acknowledge Novartis for providing chemicals used for pharmacokinetic analyses, i.e., [d8]-imatinib and N-desmethyl-imatinib (CGP74588). The authors thank Lorna Saint Ange (Institut Gustave Roussy) for editing.
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Cancer
KW - Imatinib mesylate
KW - Interleukin-2
KW - Maximum tolerate dose
KW - Pharmacokinetics
UR - https://www.scopus.com/pages/publications/84886943675
U2 - 10.4161/onci.23079
DO - 10.4161/onci.23079
M3 - Article
AN - SCOPUS:84886943675
SN - 2162-4011
VL - 2
JO - OncoImmunology
JF - OncoImmunology
IS - 2
M1 - e23079
ER -