LoConte Noelle K, Razak Albiruni R A, Ivy Percy, Tevaarwerk Amye, Leverence Rachael, Kolesar Jill, Siu Lillian, Lubner Sam J, Mulkerin Daniel L, Schelman William R, Deming Dustin A, Holen Kyle D, Carmichael Lakeesha, Eickhoff Jens, Liu Glenn
University of Wisconsin Carbone Cancer Center, 600 Highland Ave, CSC K4/548, Madison, WI, 53792, USA,
Invest New Drugs. 2015 Feb;33(1):169-76. doi: 10.1007/s10637-014-0166-6. Epub 2014 Oct 17.
RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors.
Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle.
Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration.
The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.
RO4929097是一种γ-分泌酶的口服抑制剂，可导致Notch信号通路受到抑制。先前的研究表明，Notch信号通路抑制可增强癌细胞对化疗的敏感性。本I期研究旨在确定RO4929097与卡培他滨联合用于晚期实体瘤的最大耐受剂量（MTD）、毒性及疗效。
难治性实体瘤患者接受卡培他滨治疗，固定剂量为1000mg/m²，每日两次，同时在21天周期内采用3+3设计递增剂量的RO4929097。卡培他滨给药14天，RO49029097每日一次，每周3天，均为21天周期。
30例患者接受了六个剂量水平（20至150mg）的治疗。未达到最大耐受剂量。在3至6级剂量水平各观察到1例剂量限制性毒性（低磷血症、疲劳和恶心/呕吐）。观察到3例确诊的部分缓解：2例氟嘧啶难治性结肠癌患者和1例宫颈癌患者。随着剂量水平和用药时间的增加，RO4929097出现自身诱导现象。
推荐的II期剂量为卡培他滨1000mg/m²，第1至14天口服，每日两次，RO4929097 20mg，第1-3天、8-10天和15-17天口服，每日一次，2天周期。在宫颈癌和结肠癌中观察到临床获益。随着周期数增加和剂量增加，均出现RO4929097自身诱导现象。RO4929097的血浆浓度高于Notch抑制所需浓度。
