A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor.
A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor.
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DOI：
10.1007/s10637-018-0648-z
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发表时间：
2019-04
影响因子：
3.4
通讯作者：
Tap WD
中科院分区：
文献类型：
--
作者：
Kelly CM;Shoushtari AN;Qin LX;D'Angelo SP;Dickson MA;Gounder MM;Keohan ML;Mcfadyen C;Sjoberg A;Singer S;DeMatteo RP;Hwang S;Heinemann MH;Francis JH;Antonescu CR;Chi P;Tap WD
临床前研究表明，胃肠道间质瘤 (GIST) 中的伊马替尼耐药性可以通过成纤维细胞生长因子 (FGF) 信号传导通过 MAP 激酶激活来介导。在 FGF 刺激的 GIST 细胞系中，BGJ398（一种泛 FGFR 激酶抑制剂）与伊马替尼联合使用具有细胞毒性，并且优于单独使用伊马替尼疗法。在 FGF 依赖性 GIST 中，BGJ398 和伊马替尼的组合可能提供克服伊马替尼耐药性的机制。 BGJ398 和伊马替尼的这项 Ib 期研究是在伊马替尼难治性晚期 GIST 患者中进行的。采用标准 3+3 给药方案来确定推荐的 II 期剂量 (RP2D)。评估了两种治疗方案，每天服用伊马替尼 400 毫克，并结合 (A) 每日 BGJ398，连续 3 周，停药 1 周；或 (B) BGJ398，每天服用 1 周，停药 3 周。 16 名患者入组。中位年龄为 54 岁（范围：44-77），81% 为男性，既往治疗的中位线数为 4 次 [范围：2-6，13 名患者既往接受过 3 次以上治疗]。 12 名患者接受方案 A 治疗 [BGJ398 剂量范围：25 – 75mg]：2 名患者按照方案 A（BGJ398 75mg）经历剂量限制性毒性（DLT）（n=1，心肌梗死和 (G)4 级 CPK 升高；n=1，G3 ALT 升高），未观察到显着的高磷酸盐血症，即中靶效应，这意味着最大耐受剂量低于治疗剂量。方案修订后，4 名患者按照时间表 B 入组 [BGJ398 剂量范围：75–100mg]：未观察到 DLT。 >15% 的患者中最常见的治疗相关不良事件包括 CPK 升高 (50%)、脂肪酶升高 (44%)、高磷血症 (24%)、贫血 (19%) 和外周水肿 (19%)。在 12 名可评估的患者中，根据 RECIST v1.1，7 名患者和 CHOI 9 名患者观察到疾病稳定 (SD) 是最佳缓解。 3 名患者 (25%) 观察到病情稳定≥ 32 周。中位无进展生存期为 12.1 周（95% CI 4.7 – 19.5 周）。 BGJ398 和伊马替尼联合治疗出现了毒性。由于赞助商撤回支持。该研究在 RP2D 或联合治疗的给药方案确定之前结束。在经过大量预先治疗的患者中，12 名可评估患者中有 3 名观察到病情稳定≥ 32 周。临床试验信息： .
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. 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 400mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. 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 – 75mg]: 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 75mg), 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: 75–100mg]: 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). 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. Clinical trial information: .
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
45.3
作者：
Choi, Haesun;Charnsangavej, Chuslip;Benjamin, Robert S.
通讯作者：
Benjamin, Robert S.
影响因子：
45.3
作者：
Blanke, Charles D.;Rankin, Cathryn;Borden, Ernest C.
通讯作者：
Borden, Ernest C.
DOI：
10.1016/s0140-6736(12)61857-1
发表时间：
2013-01-26
期刊：
Lancet (London, England)
影响因子：
--
作者：
Demetri GD;Reichardt P;Kang YK;Blay JY;Rutkowski P;Gelderblom H;Hohenberger P;Leahy M;von Mehren M;Joensuu H;Badalamenti G;Blackstein M;Le Cesne A;Schöffski P;Maki RG;Bauer S;Nguyen BB;Xu J;Nishida T;Chung J;Kappeler C;Kuss I;Laurent D;Casali PG;GRID study investigators
通讯作者：
GRID study investigators
影响因子：
168.9
作者：
Verweij, J;Casali, PG;Judson, I
通讯作者：
Judson, I