ADVL0919: A PHASE 1 STUDY OF RO4929097, AN ORAL SMALL MOLECULE INHIBITOR OF GAMM

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 Notch信号传导通过对细胞命运决定、干细胞更新、分化、存活和增殖的不同影响，在许多组织和细胞类型的正常发育中起关键作用。1 Notch信号传导与肿瘤发生有关。2通过配体结合激活后，Notch蛋白通过TNF α转化酶和？分泌酶复合物，释放称为细胞内Notch（ICN）的活性形式，调节关键增殖和 Notch信号传导在多种人类癌症中被异常激活，包括实体瘤和血液恶性肿瘤，特别是T细胞白血病（T-ALL）。与儿科癌症相关，在骨肉瘤、神经胶质瘤、髓母细胞瘤、室管膜瘤和血液恶性肿瘤中观察到改变的Notch信号传导。一种抑制Notch信号传导的新兴策略是使用β-分泌酶抑制剂（GSI），其防止Notch受体活化裂解。RO 4929097是口服给药的小分子，其是有效的和选择性的GSI。在临床前研究中，RO 4929097在间歇性或每日给药方案下显示出抗肿瘤活性。 本项I期研究将首先评价RO 4929097在复发性/难治性实体瘤（包括CNS肿瘤或淋巴瘤）儿童中口服给药的安全性和药代动力学（第1部分），给药方案为每周给药3天/停药4天，每日一次（方案A）和每周给药连续5天，每日一次（方案B）。方案A中RO 4929097的起始剂量（mg/m2）相当于方案A中成人的II期目标剂量（mg），方案B中的起始剂量相当于方案A的每周剂量（分5天）。一个周期将持续28天。在没有进行性疾病或不可接受的治疗相关毒性的情况下，患者可以继续治疗，最多总共24个周期。GSI临床开发的主要挑战之一是对胃肠道的潜在不良副作用。基于表明皮质类固醇可以改善胃肠道毒性的临床前数据（即，腹泻）和增加抗肿瘤活性，我们接下来将在儿童中评估至少一种伴随地塞米松的方案 实体瘤包括中枢神经系统肿瘤或淋巴瘤（第2部分）。确定RO 4929097联合地塞米松的MTD后，研究将开始招募复发性难治性T-ALL患者（第3部分），以获得RO 4929097联合地塞米松在该患者人群中的初步疗效数据。 此外，该研究还包括相关研究，以研究RO 4929097对PBMC和/或T-ALL母细胞中Notch信号通路组分的影响，检查存档肿瘤样本的靶分子表达或扩增，并使用FDG PET成像初步评估治疗后的变化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Notch signaling plays a key role in the normal development of many tissues and cell types through diverse effects on cell fate decision, stem cell renewal, differentiation, survival, and proliferation.1 Notch signaling has been implicated in tumorigenesis.2 After activation by ligand binding, the Notch proteins are proteolytically cleaved in two steps by TNFa-converting enzyme and ?-secretase complex, releasing the active form called intracellular Notch (ICN), which modulates the expression of key proliferationand differentiation-specific genes.Notch signaling is aberrantly activated in a variety of human cancers, including solid tumors and hematological malignancies, in particular T-cell leukemia (T-ALL). Relevant to pediatric cancer, altered Notch signaling is observed in osteosarcoma, gliomas, medulloblastomas,ependymoma, and hematological malignancies. One emerging strategy to inhibit Notch signaling is the use of -secretase inhibitors (GSIs), which prevent Notch receptor activation cleavage.RO4929097 is an orally administered small molecule that is a potent and selective GSI. In preclinical studies, RO4929097 showed antitumor activity on an intermittent or daily schedule. This Phase I study will first evaluate the safety and pharmacokinetics of RO4929097 administered orally to children with relapsed/refractory solid tumors including CNS tumors, or lymphoma (part 1) on 2 schedules: once daily on a 3 day on/4 day off weekly schedule (schedule A) and once daily for 5 consecutive days weekly schedule (schedule B). The starting dose of RO4929097 for schedule A will be the equivalent in mg/m2 of the target Phase 2 dose in mg for schedule A in adults, and for schedule B, the equivalent to the weekly dose of schedule A divided over 5 days. One cycle will be 28 days in duration. In absence of progressive disease or unacceptable treatment-related toxicity, patients may continue therapy up to a total of 24 cycles. One of the major challenges in clinical development of GSIs is the potential untoward side effects on the gastrointestinal tract. Based on preclinical data suggesting that corticosteroids may ameliorate gastrointestinal toxicity (i.e., diarrhea) and increase anti-tumor activity, we will next evaluate at least one of the schedules with concomitant dexamethasone in children with solid tumors including CNS tumors, or lymphoma (part 2). After the MTD of RO4929097 plus dexamethasone has been identified, the study will begin enrollment of patients with relapsed-refractory T-ALL (part 3) to obtain initial efficacy data on RO4929097 in combination with dexamethasone in this patient population. In addition, the study includes correlative studies to study the effect of RO4929097 on components of the Notch signaling pathway in PBMCs and/or T-ALL blasts, to examine archival tumor samples for expression or amplification of target molecules, and to preliminarily assess changes after treatment using FDG PET imaging.