A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor.

Autor: Pantaleo MA; Division in Medical Oncology, IRCSS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. maria.pantaleo@unibo.it., Heinrich MC; Portland VA Health Care System and Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon, USA., Italiano A; Institut Bergonie, Bordeaux, France., Valverde C; Hospital Universitario Vall D Hebron, Medical Oncology, Barcelona, Spain., Schöffski P; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium., Grignani G; Division of Medical Oncology, Candiolo Cancer Institute, FPO - IRCCS, St. Provinciale 142, Km 3.95 - 10060, Candiolo, TO, Italy., Reyners AKL; Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Bauer S; Department of Medical Oncology, Sarcoma Center, West German Cancer Center and German Consortium for Translational Cancer Research (DKTK), University Hospital Essen, Essen, Germany., Reichardt P; Department of Oncology and Palliative Care Helios Klinikum Berlin Buch, Berlin, Germany., Stark D; Leeds Institute for Medical Research, St James's University Hospital, Leeds, UK., Berhanu G; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA., Brandt U; Novartis Pharma AG, Basel, Switzerland., Stefanelli T; Novartis Pharma AG, Basel, Switzerland., Gelderblom H; Department of Medical Oncology, Leiden University, Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2022 May 06; Vol. 22 (1), pp. 511. Date of Electronic Publication: 2022 May 06.
DOI: 10.1186/s12885-022-09610-4
Abstrakt: Background: Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib.
Methods: This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion.
Results: Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8-4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%).
Conclusions: The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing.
Trial Registration: ClinicalTrials.gov NCT01735968 (date of initial registration 28/11/2012).
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje