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Clinical Trial
. 2022 May 6;22(1):511.
doi: 10.1186/s12885-022-09610-4.

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

Maria A Pantaleo  1 , Michael C Heinrich  2 , Antoine Italiano  3 , Claudia Valverde  4 , Patrick Schöffski  5 , Giovanni Grignani  6 , Anna K L Reyners  7 , Sebastian Bauer  8 , Peter Reichardt  9 , Daniel Stark  10 , Ghimja Berhanu  11 , Ulrike Brandt  12 , Tommaso Stefanelli  12 , Hans Gelderblom  13
Affiliations
Clinical Trial

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

Maria A Pantaleo et al. BMC Cancer. .

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).

Keywords: Alpelisib; GIST; Gastrointestinal stromal tumor; Imatinib; Regorafenib; Sunitinib.

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Conflict of interest statement

MAP, PS, AKLR, DS, and HG had nothing to disclose. MCH reported personal fees and expert testimony from Novartis; grants and personal fees from Deciphera Pharmaceuticals and Blueprint Medicines; personal fees and equity interest from Molecular MD, outside the submitted work. In addition, MCH also reported a patent ‘Treatment of Gastrointestinal Stromal Tumors’ with royalties paid and partial salary support from a Veterans Affairs Merit Review Grant (I01 BX000338). AI reported grants and personal fees from Bayer; grants from Merck, MSD, Novartis, Chugai, and Astra Zeneca; and personal fees from Springworks, outside the submitted work. CV reported personal fees, advisory board, and travel expenses from Bayer, Pfizer, PharmaMar, and Lilly; and advisory board from Mundipharma and GSK, outside the submitted work. GG reported grants and personal fees from Novartis, Bayer, and PharmaMar; personal fees from Pfizer, Merck, EISAI, and Lilly; and travel support from Tesaro, outside the submitted work. SB reported grant from Incyte, Blueprint Medicines, and Novartis; personal fees from Deciphera, Blueprint Medicines, Lilly, Novartis, Daichii-Sankyo, Plexxikon, Exelixis, and Bayer; and CME from Pfizer, during the conduct of the study. In addition, SB also reported personal fees from PharmaMar, Lilly, Roche, and GSK, outside the submitted work. PR reported personal fees from Bayer, Clinigen, BMS, Roche, MSD, Deciphera, Novartis, Pfizer, PharmaMar, Lilly, and Amgen, outside the submitted work. GB, UB, and TS are Novartis employees. The authors declare no conflict of interest regarding the content discussed in the manuscript.

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