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

Abstract

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).

• Authors: Maria A Pantaleo, Michael C Heinrich, Antoine Italiano, Claudia Valverde, Patrick Schöffski, Giovanni Grignani, Anna K L Reyners, Sebastian Bauer, Peter Reichardt, Daniel Stark, Ghimja Berhanu, Ulrike Brandt, Tommaso Stefanelli, Hans Gelderblom
• Journal: BMC cancer (BMC Cancer) Vol. 22 Issue 1 Pg. 511 (May 06 2022) ISSN: 1471-2407 [Electronic] England
• PMID: 35524239 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: © 2022. The Author(s).

Chemical References

• Protein Kinase Inhibitors
• Thiazoles
• Alpelisib
• Imatinib Mesylate

Topics

• Gastrointestinal Stromal Tumors (pathology)
• Humans
• Imatinib Mesylate (therapeutic use)
• Protein Kinase Inhibitors (therapeutic use)
• Thiazoles
• Treatment Outcome