A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).
A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).
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DOI：
10.1007/s10637-013-9965-4
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发表时间：
2014-04
影响因子：
3.4
通讯作者：
McWhirter E
中科院分区：
文献类型：
--
作者：
Richter S;Bedard PL;Chen EX;Clarke BA;Tran B;Hotte SJ;Stathis A;Hirte HW;Razak AR;Reedijk M;Chen Z;Cohen B;Zhang WJ;Wang L;Ivy SP;Moore MJ;Oza AM;Siu LL;McWhirter E
目的确定口服γ-分泌酶抑制剂RO 4929097（RO）联合吉西他滨的II期推荐剂量;次要目的包括评价安全性、耐受性、药代动力学、Notch信号传导生物标志物和初步抗肿瘤活性。方法将晚期实体瘤患者纳入不断增加的RO剂量水平（DL）队列。测试的RO DL为20 mg、30 mg、45 mg和90 mg。在第1-3、8-10、15-17、22-24天口服RO，每日一次。吉西他滨1,000 mg/m2，第1、8和15天给药，28天为1个周期。根据CTCAE v4评估剂量限制性毒性（DLT）。采集连续血浆用于RO（总血浆和未结合血浆）和吉西他滨药代动力学分析。通过免疫组织化学在存档组织中评估Notch信号传导的生物标志物。评价抗肿瘤活性（RECIST 1.1）。结果共纳入18例患者，以确定推荐的II期剂量。其中，3例患者接受20 mg RO，7例患者接受30 mg RO，6例患者接受45 mg RO，2例患者接受90 mg RO。DLT为3级transaminitis（30 mg RO）、3级transaminitis和斑丘疹（45 mg RO）以及3级transaminitis和继发于长期中性粒细胞减少症（90 mg）的75%计划RO剂量失败;所有这些都是可逆的。在90 mg RO时超过了最大耐受剂量。总RO和游离RO的药代动力学分析证实了在45和90 mg时存在自诱导。接受少于4个周期的个体中Notch 3染色的中位水平较高（p = 0.029）。循环血管生成因子水平与疾病进展时间或≥ 3级不良事件无关。最佳反应（RECIST 1.1）为部分反应（鼻咽癌），3例患者（胰腺、气管和乳腺原发性癌症）观察到疾病稳定> 4个月。结论RO与吉西他滨联合应用是安全的。RO的推荐II期剂量为30 mg，联合吉西他滨1，000 mg/m2。尽管RO暴露量受到自身诱导的限制，但达到的RO水平超过了使用每日给药的临床前模型中预测疗效的0-24 h浓度-时间曲线下面积（AUC 0 -24）。确定了临床抗肿瘤活性和疾病长期稳定的证据。
Purpose To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1–3, 8–10, 15–17, 22–24. Gemcitabine was administered at 1,000 mg/m2 on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). Results A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). Conclusions RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m2. Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0–24 h (AUC0–24) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.
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DOI：
10.1073/pnas.0603371103
发表时间：
2006-06-13
影响因子：
11.1
作者：
Klinakis, Apostolos;Szaboics, Matthias;Efstratiadis, Argiris
通讯作者：
Efstratiadis, Argiris
DOI：
10.1016/j.ejca.2012.02.056
发表时间：
2012-05
期刊：
European journal of cancer (Oxford, England : 1990)
影响因子：
--
作者：
Strosberg JR;Yeatman T;Weber J;Coppola D;Schell MJ;Han G;Almhanna K;Kim R;Valone T;Jump H;Sullivan D
通讯作者：
Sullivan D
影响因子：
6.6
作者：
He, Wei;Luistro, Leopoldo;Boylan, John F.
通讯作者：
Boylan, John F.
影响因子：
5.3
作者：
Jarriault, S;Le Bail, O;Israël, A
通讯作者：
Israël, A
具有体内功效和药效特性的有效γ-分泌酶抑制剂靶向Notch信号的临床前谱。
影响因子：
11.2
作者：
Luistro L;He W;Smith M;Packman K;Vilenchik M;Carvajal D;Roberts J;Cai J;Berkofsky-Fessler W;Hilton H;Linn M;Flohr A;Jakob-Røtne R;Jacobsen H;Glenn K;Heimbrook D;Boylan JF
通讯作者：
Boylan JF