A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor.
Alpelisib
GIST
Gastrointestinal stromal tumor
Imatinib
Regorafenib
Sunitinib
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
06 May 2022
06 May 2022
Historique:
received:
04
10
2021
accepted:
05
04
2022
entrez:
6
5
2022
pubmed:
7
5
2022
medline:
11
5
2022
Statut:
epublish
Résumé
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. 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. 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%). 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. ClinicalTrials.gov NCT01735968 (date of initial registration 28/11/2012).
Sections du résumé
BACKGROUND
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
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
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
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
BACKGROUND
ClinicalTrials.gov NCT01735968 (date of initial registration 28/11/2012).
Identifiants
pubmed: 35524239
doi: 10.1186/s12885-022-09610-4
pii: 10.1186/s12885-022-09610-4
pmc: PMC9078016
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Thiazoles
0
Alpelisib
08W5N2C97Q
Imatinib Mesylate
8A1O1M485B
Banques de données
ClinicalTrials.gov
['NCT01735968']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
511Subventions
Organisme : BLRD VA
ID : I01 BX000338
Pays : United States
Organisme : BLRD VA
ID : I01 BX005358
Pays : United States
Informations de copyright
© 2022. The Author(s).
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