A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors.
A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors.
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DOI：
10.1007/s10637-014-0166-6
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发表时间：
2015-02
影响因子：
3.4
通讯作者：
Liu, Glenn
中科院分区：
文献类型：
--
作者：
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
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。先前的研究已表明，Notch信号通路的抑制可增强癌细胞对化疗的敏感性。开展这项I期研究是为了确定RO4929097和卡培他滨在晚期实体瘤中的最大耐受剂量（MTD）、毒性和疗效。
难治性实体瘤患者接受固定剂量为1000 mg/m²、每日两次的卡培他滨治疗，同时按照3 + 3设计在21天一个周期内逐步增加RO4929097的剂量。卡培他滨服用14天，RO4929097每日一次，每周3天，均以21天为一个周期。
30名患者接受了6个剂量水平（20至150 mg）的治疗。未达到最大耐受剂量。在3 - 6级的每个剂量水平均观察到一种剂量限制性毒性（低磷血症、疲劳以及恶心/呕吐）。观察到3例经确认的部分缓解：2例氟嘧啶耐药的结肠癌患者和1例宫颈癌患者。随着剂量水平和持续时间的增加，证实了RO4929097的自身诱导作用。
推荐的II期剂量为在第1 - 14天口服卡培他滨1000 mg/m²，每日两次，同时在第1 - 3天、8 - 10天和15 - 17天口服RO4929097 20 mg，每日一次，21天为一个周期。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，均观察到RO4929097的自身诱导作用。RO4929097的血浆浓度高于Notch抑制所需的浓度。
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 1000 mg/m2 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 1000 mg/m2 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.
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