A PHASE I STUDY OF SAHA (NSC #701852) IN PEDIATRIC PATIENTS WITH RECURRENT OR

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。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。SAHA通过在酶的活性位点插入一个羟肟基团、大部分脂肪链和部分苯基氨基与HDAC结合。SAHA插入活性位点可阻止天然底物的结合并阻断酶促去乙酰化。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，影响细胞周期阻滞和诱导p53非依赖性凋亡。SAHA抗肿瘤作用的一个可能模型是抑制HDAC活性和随后乙酰化组蛋白的积累，激活表达诱导分化或凋亡的基因的转录，抑制肿瘤生长。暴露于SAHA后，不到2%的表达基因的表达受到调节。在体外和体内异种移植模型中，视黄酸受体与组蛋白去乙酰化酶抑制剂的组合已被证明在血液学和实体恶性肿瘤的治疗中具有协同活性。HL-60细胞暴露于Trichostatin A （TSA）和9-cis-RA可导致分化增加。同样，AML （M2和M4）患者的原代细胞暴露于TSA后，恢复了类视黄酮依赖的转录激活，并导致了终末分化。HDAC抑制剂CBHA与全反式RA联合在体外和体内异种移植模型中对神经母细胞瘤细胞系产生协同细胞毒性。初步研究表明，SAHA联合13顺式RA对神经母细胞瘤、横纹肌肉瘤、成神经管细胞瘤和原发性脑肿瘤细胞系等儿科转化细胞系具有协同作用。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。SAHA：已经在成人中进行了几项I/II期研究。在一项针对晚期实体和血液恶性肿瘤患者的SAHA I期试验中，评估了几种口服方案，包括每天200- 600mg或bid，300- 400mg bid，每周3天。62名患者参加了这项研究。成人的MTD和推荐II期剂量已确定为每日400mg， bid 200mg或bid 300mg x每周3天。在实体瘤和血液学恶性肿瘤患者中，剂量限制性毒性是非血液学的（厌食、脱水、腹泻和疲劳）。非剂量限制性血液学毒性包括贫血和血小板减少症，在药物中断后可迅速逆转。一项针对晚期白血病或骨髓增生异常综合征患者的I期试验正在进行中，剂量水平为100mg - 300mg tid，每21天连续14天。初始剂量为100mg tid，剂量以50mg tid递增。15例患者已接受治疗，毒性可评估。没有患者发生与SAHA相关的3级或4级毒性或死亡。基于这些数据，目前正在进行几项成人II期试验，推荐剂量为每日400mg。成人II期推荐剂量每日400mg已被用作本方案起始剂量的基础。13-顺式维甲酸：儿童研究一项针对13-顺式RA儿童患者的I期试验确定了MTD为160 mg/m2/天。在这项儿童I期试验中观察到13- cisRA的剂量限制性毒性包括皮疹和高钙血症。一项针对复发性或进行性神经母细胞瘤儿童患者的13-顺式RA的II期临床试验显示，剂量为100mg /m2/天的抗肿瘤活性微乎其微。然而，在巩固治疗后的6个月内，以160 mg/m2/天每日两次，每月2周的剂量给予13-cisRA，可提高3年无事件生存率，从对照组的29%提高到接受13-cisRA患者的45%。本试验中建议的类维生素a的剂量和时间表将与先前在III期儿科试验中使用的剂量和时间表相同。鉴于上述在接受RA的儿童中观察到的有限副作用，我们预计建议的13-顺式维甲酸和SAHA的组合将具有良好的耐受性。本研究的主要目的是：1。估计难治性或复发性实体瘤儿童每日口服一次SAHA，持续28天的最大耐受剂量（MTD）；2. 评估SAHA联合13顺式维甲酸对难治性或复发性神经母细胞瘤、髓母细胞瘤/中枢神经外胚层肿瘤（PNET）或非典型畸胎瘤样横纹肌样肿瘤（ATRT）患儿的最大耐受剂量（MTD），每日口服一次，持续28天；3. 评价MTD对复发性或难治性白血病患者的耐受性；4. 定义和描述SAHA单药和与13顺式维甲酸联合用药的毒性；和5。目的探讨SAHA在难治性癌症患儿中的药代动力学特征。次要目标是：1。初步确定SAHA单用和与13-顺式维甲酸联用的抗肿瘤活性；2. 通过检测外周单核细胞（PMNC）和肿瘤组织标本中组蛋白乙酰化状态来评估SAHA的生物活性；和3。目的：探讨遗传多态性（如UGT1A1）对药物动力学的影响

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. SAHA is an inhibitor of histone deacetylase (HDAC) that causes the arrest of cell cycle transition at G1 and G2M phases. SAHA binds to HDAC by inserting a hydroxamic group, most of the aliphatic chain and part of the phenyl amino group in the active site of the enzyme. The insertion of SAHA into the active site prevents the binding of the natural substrate and blocks enzymatic deacetylation. It has been reported to selectively induce expression of p21 waf/CIP1 cyclin dependent kinase inhibitor, to effect cell cycle arrest and to induce p53 independent apoptosis. A possible model for the antitumor action of SAHA is the inhibition of HDAC activity and subsequent accumulation of acetylated histones, and the activation of transcription of genes whose expression causes induction of differentiation or apoptosis and the inhibition of tumor growth. The expression of less than 2% of expressed genes is regulated following exposure to SAHA. The combination of a retinoid acid receptor with a histone deacetylase inhibitor has been shown to have synergistic activity in the treatment of hematological and solid malignancies in both in vitro and in vivo xenograft models. Exposure of HL-60 cells to Trichostatin A (TSA) and 9-cis-RA results in more than additive increase in differentiation. Similarly, the exposure of primary blasts from AML (M2 and M4) patients to TSA restored retinoid-dependent transcriptional activation and led to terminal differentiation. The combination of the HDAC inhibitor, CBHA, with all-trans RA led to synergistic cytotoxicity against neuroblastoma cell lines in vitro and xenograft in vivo models. Preliminary studies of SAHA combined with 13-cis RA have shown synergistic activity in pediatric transformed cell lines such as neuroblastoma, rhabdomyosarcoma and medulloblastoma and primary brain tumor cell lines (personal communication, Olson laboratory.) Retinoid acid receptors recruit co-regulatory complexes with HDAC activity in the absence of a ligand, which results in repression of gene transcription. SAHA: Several phase I/II studies have been conducted in adults. In a phase I trial of SAHA in patients with advanced solid and hematological malignancies, several oral schedules were evaluated including 200-600 mg daily or bid,300- 400 mg bid for 3 days each week. Sixty-two patients were enrolled on this study. The MTD and the recommended phase II dose in adults has been established at 400 mg daily, 200 mg bid or 300 mg bid x 3 days every week. The dose limiting toxicities were non-hematologic (anorexia, dehydration, diarrhea, and fatigue) in both solid tumor and hematological malignancy patients. Non-dose-limiting hematological toxicities included anemia and thrombocytopenia, which were rapidly reversible after drug interruption. A phase I trial in patients with advanced leukemia or myelodysplastic syndrome is ongoing, with dose levels starting at 100 mg-300 mg tid x 14 consecutive days every 21 days. The initial dose was 100 mg tid with dose escalation in increments of 50 mg tid. Fifteen patients have been treated and are evaluable for toxicity. No patient has experienced grade 3 or 4 toxicity or death related to SAHA. Based on these data, several phase II trials in adults are now ongoing at the recommended dose of 400 mg po daily. The adult phase II recommended dose of 400 mg daily has been used as a basis for the starting dose of this protocol. 13-cis Retinoic Acid: Pediatric Studies A Phase I trial of 13-cis RA in pediatric patients established the MTD of 160 mg/m2/day. Dose limiting toxicities of 13- cisRA observed in this pediatric phase I trial included rash and hypercalcemia. A Phase II clinical trial of 13-cis RA at 100 mg/m2/day administered to pediatric patients with recurrent or progressive neuroblastoma revealed minimal anti- tumor activity. However, administration of 13-cisRA at 160 mg/m2/day twice daily for 2 weeks monthly, over a period of six months following consolidation therapy improved event free survival at three years, from 29% in the control cohort to 45% in patients receiving 13-cisRA. The dose and schedule of retinoids proposed in this trial will be identical to that previously used in Phase III pediatric trials. Given the above noted limited side effects observed in children receiving RA, we anticipate that the proposed combination of 13-cis retinoic acid and SAHA will be well tolerated. The primary aims of this study are: 1. To estimate the maximum tolerated dose (MTD) of SAHA administered once daily orally for 28 days to children with refractory or recurrent solid tumors; 2. To estimate the maximum tolerated dose (MTD) of SAHA administered once daily orally for 28 days in combination with 13-cis retinoic acid to children with refractory or recurrent neuroblastoma, medulloblastoma/ CNS neuroectodermal tumor (PNET) or atypical teratoid rhabdoid tumor (ATRT); 3. To assess the tolerability of the solid tumor MTD in patients with recurrent or refractory leukemia; 4. To define and describe the toxicities of SAHA administered on this schedule as a single agent and in combination with 13 cis-retinoic acid; and 5. To characterize the pharmacokinetics of SAHA in children with refractory cancer. Secondary aims are: 1. To preliminarily define the antitumor activity of SAHA as a single agent and in combination with 13-cis retinoic acid within the confines of a Phase 1 study; 2. To assess the biologic activity of SAHA by measuring histone acetylation status in peripheral mononuclear cells (PMNC) and tumor tissue specimens; and 3. To explore the effect of genetic polymorphisms (e.g., UGT1A1) on the pharmacokinetics of