A phase Ib study of BGJ398 in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST).

Abstract

11039 Background: Preclinical studies suggest that imatinib resistance (IR) in GIST can be mediated by MAP-kinase activation via FGF signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR inhibitor in combination with imatinib, is cytotoxic and superior to imatinib alone, or imatinib in combination with MEK-inhibition. In GIST with FGF signaling, the combination of BGJ398 and imatinib may provide a mechanism to overcome IR. Methods: This phase Ib study of BGJ398 in combination with imatinib was performed in patients (pts) with imatinib resistant advanced GIST. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose. Two treatment schedules were evaluated incorporating imatinib 400mg daily continuously in combination with (A) BGJ daily 3 wks on, 1 wk off or (B) BGJ daily 1 wk on, 3 wks off. Response was evaluated by RECIST and CHOI every 8 wks x4 and then every 12 wks. Results: 16 pts enrolled. Median age 54 (range: 44-77), 81% male, median prior therapy 4 [range: 2-6, 13/16 pts had ≥ 3 prior therapies (81%)]. 12 pts received treatment on schedule A [dose level (DL)1 (BGJ 75mg), n = 6; DL-1 (BGJ 50mg), n = 3; DL-2 (BGJ 25mg), n = 3]: 3 DLTs (myocardial infarction, grade (G)4 CPK elevation, G3 ALT elevation) were observed on schedule A at DL1, hyperphosphatemia (on target effect) was not observed raising concern for therapeutic efficacy at the maximum tolerated dose. Following protocol amendment that allowed an alternative dosing schedule, 4 pts enrolled on schedule B [DL1 (BGJ 75mg), n = 3; DL2 (BGJ 100mg), n = 1]: one DLT occurred (G3 intra-abdominal hemorrhage) at DL2. The most common non-DLT G3/4 toxicity was HTN (2/16pts) and G2 toxicity was prolonged QTc interval (3/16pts). Of the 12 pts with evaluable CT scans, stable disease (SD) was the best response observed in 7 pts by RECIST and 9 pts by CHOI. 3pts achieved SD for > 6 months. 2 pts remain on study at data cut-off (range: 1 – 67 wks). Median progression free survival is 8 weeks. Pharmacokinetic analysis of imatinib and BGJ is forthcoming. Conclusions: In heavily pre-treated pts, durable disease control was observed in 3/16 pts. This signal of efficacy suggests that further evaluation of FGF signaling in the development of IR is warranted. Clinical trial information: NCT02257541.