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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 Notch信号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发挥关键作用。1 Notch信号与肿瘤的发生有关。2被配体结合激活后，Notch蛋白被TNFa转换酶和β-分泌酶复合体分两步降解，释放出被称为细胞内Notch(ICN)的活性形式，后者调节关键的增殖和转录因子的表达。 分化特异性基因：Notch信号在多种人类癌症中异常激活，包括实体瘤和血液系统恶性肿瘤，特别是T细胞白血病(T-ALL)。与儿科癌症相关，Notch信号改变可见于骨肉瘤、神经胶质瘤、髓母细胞瘤、室管膜瘤和血液系统恶性肿瘤。一种新出现的抑制Notch信号的策略是使用分泌酶抑制剂(GSI)，它可以防止Notch受体的激活和切割。RO4929097是一种口服的小分子，是一种有效和选择性的GSI。在临床前研究中，RO4929097显示出间歇性或每日的抗肿瘤活性。 这项第一阶段研究将首先评估RO4929097口服给患有包括中枢神经系统肿瘤或淋巴瘤(第1部分)在内的复发/难治性实体肿瘤的儿童的安全性和药代动力学，分两个计划：每天一次，每周三天，每周四天(计划A)和每天一次，每周连续五天(计划B)。计划A的RO4929097起始剂量将等同于成人计划A的目标第二阶段剂量的毫克/平方米，而计划B的起始剂量将相当于计划A的每周剂量除以5天。一个周期为28天。在没有进展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，最长可达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。根据临床前数据显示，皮质类固醇可以改善胃肠道毒性(即腹泻)并增强抗肿瘤活性，接下来我们将评估至少一个与地塞米松联合应用于儿童的方案。 实体瘤包括中枢神经系统肿瘤或淋巴瘤(第二部分)。在确定RO4929097联合地塞米松的MTD后，这项研究将开始招募复发难治性T-ALL患者(第三部分)，以获得RO4929097联合地塞米松在该患者群体中的初步疗效数据。 此外，该研究还包括相关研究，以研究RO4929097对PBMC和/或T-ALL母细胞中Notch信号通路成分的影响，检查归档肿瘤样本中靶分子的表达或扩增，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.