A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor

Abstract

Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44-77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2-6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 - 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 - 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (19%), and peripheral edema (19%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7-19.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration: NCT02257541 .

Keywords: BGJ 398; FGFR inhibition; Gastrointestinal stromal tumor; Imatinib; Phase I.

Conflict of interest statement

Compliance with Ethical Standards

Conflict of Interest:

CMK: Declares that she has no conflict of interest

ANS: consulting or advisory role – Castle biosciences, Immunocore, Vaccinex; Research funding – Bristol Myers Squibb, Immunocore; Travel, Accommodation, Expenses – Bristol Myers Squibb.

LXQ: Declares that she has no conflict of interest

SPD: Consulting or Advisory Role – Amgen, EMD Serono, Nektar

MAD: Declares that he has no conflict of interest

MMG: Honoraria – Amgen, Daiichi Sankyo, Karyopharm Therapeutics, TRACON Pharma; Consulting or Advisory Role – Amgen, Daiichi Sankyo, Epizyme, Karyopharm Therapeutics; Speakers’ Bureau – Amgen; Travel, Accommodations, Expenses – Amgen, Daiichi Sankyo, Karyopharm Therapeutics.

MLK: Declares that she has no conflict of interestCM: Declares that she has no conflict of interest

AS: Declares that she has no conflict of interest

SS: Declares that he has no conflict of interest

RPD: Declares that he has no conflict of interest

SH: Declares that she has no conflict of interest

MHH: Declares that he has no conflict of interestJHF: Declares that she has no conflict of interest

CRA: Declares that she has no conflict of interest

PC: Honararia - Novartis

WDT: Consulting or Advisory Role – Adaptimmune, Daiichi Sankyo, Eisai, EMD Serono, Immune Design, Janssen, Lilly, Novartis, Plexxikon, TRACON Pharma

Figures

Figure 1. Consort Diagram

Abbreviations: N, number of study participants; Schedule A, BGJ 398 2 weeks on, 1 week off & imatinib 400mg once daily; Schedule B, BGJ 398 1 week on, 3 weeks off & imatinib 400mg once daily; DL, dose level; DLT, dose limiting toxicity. *Two patients experienced a DLT at DL1 on schedule A. The DLTs included a grade 3 non-ST elevation myocardial infarction together with grade 4 CPK elevation and a grade 3 elevation in alanine transaminase.

Figure 2.

Duration of time on study