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

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 Notch 信号传导通过对细胞命运决定、干细胞更新、分化、存活和增殖产生多种影响，在许多组织和细胞类型的正常发育中发挥着关键作用。1 Notch 信号传导与肿瘤发生有关。2 通过配体结合激活后，Notch 蛋白被 TNFa 转换酶和 β-分泌酶复合物分两步进行蛋白水解裂解，释放出称为细胞内 Notch (ICN) 的活性形式，该形式调节关键增殖和增殖的表达。 分化特异性基因。Notch 信号传导在多种人类癌症中异常激活，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 Notch 信号传导的改变。抑制 Notch 信号传导的一种新兴策略是使用 β-分泌酶抑制剂 (GSI)，它可以防止 Notch 受体激活裂解。RO4929097 是一种口服小分子，是一种有效的选择性 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 I 期研究将首先评估 RO4929097 按 2 个时间表口服给患有复发/难治性实体瘤（包括 CNS 肿瘤或淋巴瘤）的儿童（第 1 部分）的安全性和药代动力学：每周给药 3 天/休息 4 天，每天一次（时间表 A），以及每周连续 5 天每天一次（时间表 B）。 RO4929097对于附表A的起始剂量将相当于成人附表A的目标2期剂量（以mg为单位），对于附表B，相当于附表A的每周剂量除以5天。一个周期的持续时间为 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多 24 个周期。 GSI 临床开发的主要挑战之一是对胃肠道潜在的不良副作用。基于临床前数据表明皮质类固醇可以改善胃肠道毒性（即腹泻）并增加抗肿瘤活性，我们接下来将评估至少一种与地塞米松联合治疗儿童的方案 实体瘤，包括中枢神经系统肿瘤或淋巴瘤（第 2 部分）。在确定 RO4929097 加地塞米松的 MTD 后，该研究将开始招募复发难治性 T-ALL 患者（第 3 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原始细胞中Notch信号通路成分的影响，检查档案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.