Richter Suzanne, Bedard Philippe L, Chen Eric Xueyu, Clarke Blaise A, Tran Ben, Hotte Sebastien J, Stathis Anastasios, Hirte Hal W, Razak Albiruni R A, Reedijk Michael, Chen Zhuo, Cohen Brenda, Zhang Wen-Jiang, Wang Lisa, Ivy S Percy, Moore Malcolm J, Oza Amit M, Siu Lillian L, McWhirter Elaine
Princess Margaret Cancer Centre, Drug Development Program, 610 University Avenue, Toronto, Canada, M5G 2M9.
Invest New Drugs. 2014 Apr;32(2):243-9. doi: 10.1007/s10637-013-9965-4. Epub 2013 May 5.
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.
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/m(2) 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).
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).
RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). 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 (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.
确定口服γ-分泌酶抑制剂RO4929097（RO）与吉西他滨联合使用时的推荐II期剂量；次要目标包括评估安全性、耐受性、药代动力学、Notch信号通路生物标志物以及初步抗肿瘤活性。
晚期实体瘤患者入组递增RO剂量水平（剂量组）队列。测试的RO剂量组为20mg、30mg、45mg和90mg。RO口服给药，在第1 - 3天、8 - 10天、15 - 17天、22 - 24天每日一次。吉西他滨在第1、8和15天以1000mg/m²给药，每28天为一个周期。通过CTCAE v4评估剂量限制性毒性（DLT）。收集系列血浆用于RO（总药和游离药）及吉西他滨的药代动力学分析。通过对存档组织进行免疫组织化学评估Notch信号通路生物标志物。评估抗肿瘤活性（RECIST 1.1）。
共入组18例患者以确定推荐的II期剂量。其中，3例患者接受20mg RO，7例患者接受30mg RO，6例患者接受45mg RO，2例患者接受90mg RO。DLT包括3级转氨酶升高（30mg RO）、3级转氨酶升高和斑丘疹（45mg RO）以及3级转氨酶升高和因长期中性粒细胞减少未能接受75%计划RO剂量（90mg）；所有均为可逆性。90mg RO时超过了最大耐受剂量。总RO和游离RO的药代动力学分析均证实45mg和90mg时存在自身诱导现象。接受少于4个周期治疗的个体中Notch3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）为部分缓解（鼻咽癌），3例患者（胰腺癌、气管癌和原发性乳腺癌）观察到疾病稳定>4个月。
RO与吉西他滨可安全联合使用。RO与吉西他滨1000mg/m²联合使用时的推荐II期剂量为30mg。尽管RO暴露因自身诱导现象而受限，但所达到的RO水平超过了临床前模型中每日给药预测的0 - 24小时浓度 - 时间曲线下面积（AUC(0 - 24)）以达到疗效。已确定临床抗肿瘤活性及疾病长期稳定的证据。
