COG ADVL0416: A STUDY OF SAHA IN PEDIATRIC PATIENTS WTH RECURRENT SOLID TUMORS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这是一项用于治疗复发性或难治性实体瘤或白血病的儿童和青少年的亚酰苯胺羟肟酸（SAHA）的I期研究。SAHA是一种组蛋白去乙酰化酶（HDAC）抑制剂，导致细胞周期转变在G1和G2M期停滞。已有报道选择性诱导p21 waf/CIP1周期蛋白依赖性激酶抑制剂的表达，影响细胞周期阻滞1和诱导p53非依赖性凋亡。SAHA抗肿瘤作用的一种可能模型是抑制HDAC活性，从而激活表达迫使肿瘤分化、凋亡或抑制肿瘤生长的基因的转录。类视黄酸受体在缺乏配体的情况下招募具有HDAC活性的共调节复合物，从而导致基因转录的抑制。本研究将分为三个部分。在A部分，将通过标准I期剂量递增方案确定实体瘤患者的SAHA最大耐受剂量（MTD）。患有复发性或难治性实体瘤（包括淋巴瘤）的儿童和青少年患者如果血液学、肝脏、肾脏和肺部状况良好，将有资格参加单药SAHA剂量递增部分的研究。在研究的B部分，6例复发性或难治性白血病患者（每组3人）将被纳入实体瘤MTD，以评估复发性或难治性白血病患者对实体瘤MTD的耐受性。如果SAHA在实体肿瘤MTD中不能耐受，SAHA将在复发或难治性白血病患者中进行单独的I期试验。在该研究的C部分，将纳入一组神经母细胞瘤、髓母细胞瘤/中枢神经系统神经外胚层肿瘤（PNET）或非典型畸胎瘤样横纹肌样肿瘤（ATRT）患者，以确定SAHA与13-顺式维甲酸（13-顺式RA）联合使用的MTD，其剂量和时间表旨在提高神经母细胞瘤患者的无事件生存率。C部分将在a部分确定SAHA MTD后开始。参与者将每天口服一次SAHA，持续服用。一个疗程被认为是28天。研究的B部分和C部分的登记将在A部分完成后同时进行。可选的药代动力学研究、药物遗传学研究和评估外周血单个核细胞和肿瘤组织中的组蛋白乙酰化将同时进行。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a phase I study of suberoylanilide hydroxamic acid (SAHA) in children and adolescents with recurrent or refractory solid tumors or leukemia. SAHA is an inhibitor of histone deacetylase (HDAC) that causes the arrest of cell cycle transition at G1 and G2M phases. It has been reported to selectively induce expression of p21 waf/CIP1 cyclin-dependent kinase inhibitor, to effect cell cycle arrest1 and to induce p53 independent apoptosis. A possible model for the antitumor action of SAHA is the inhibition of HDAC activity causing the activation of transcription of genes whose expression force tumor differentiation, apoptosis or inhibit tumor growth. Retinoid acid receptors recruit co-regulatory complexes with HDAC activity in the absence of a ligand, which results in repression of gene transcription. This study will be done in 3 parts. In Part A, the SAHA maximum tolerated dose (MTD) will be determined for solid tumor patients by a standard Phase I dose escalation scheme. Pediatric and adolescent patients with recurrent or refractory solid tumors (including lymphomas) will be eligible for the single agent SAHA dose escalation part of the study if they have adequate hematologic, hepatic, renal, and pulmonary status. In Part B of the study, 6 patients with recurrent or refractory leukemia (in cohorts of 3) will be enrolled at the solid tumor MTD to assess the tolerability of the solid tumor MTD in patients with recurrent or refractory leukemia. If SAHA is not tolerated at the solid tumor MTD, SAHA will be studied in a separate phase I trial in patients with recurrent or refractory leukemia. In Part C of the study, a cohort of patients with neuroblastoma, medulloblastoma/ CNS neuroectodermal tumor (PNET) or atypical teratoid rhabdoid tumor (ATRT) will be enrolled to determine the MTD of SAHA when combined with 13-cis retinoic acid (13-cis RA) at the dose and schedule determined to improve event-free survival in neuroblastoma patients. Part C will start after the SAHA MTD has been determined in Part A. Participants will be given SAHA orally once daily, continuously. A course of therapy is considered to be 28 days. Enrollment to Parts B and C of the study will occur simultaneously after Part A is completed. Optional pharmacokinetic studies, pharmacogenetic studies and assessment of histone acetylation in peripheral blood mononuclear cells and tumor tissue will be performed concurrently.