Correlative trial of fenretinide against Glioblastomas

描述(申请人提供)：恶性胶质瘤，其中最常见的成人是多形性胶质母细胞瘤，具有严重的预后和高发病率和死亡率。手术、放疗和化疗在这些肿瘤的治疗中只有不大的价值。在针对胶质瘤的新化合物测试中，13顺式维甲酸作为单一药物或联合使用，在临床试验中显示出抗复发胶质瘤的活性。芬维甲素是一种相关的合成维甲酸，在体外可以诱导多种恶性肿瘤的细胞凋亡和抑制增殖，在人体内口服时耐受性良好。芬维奈德在3-5微米的浓度下通过诱导细胞凋亡来抑制胶质瘤细胞的增殖(Puduvalli等人，1999)。I期试验的数据表明，非维甲酸耐受性很好，每天两次1200 mg/m2的剂量可以达到大约10？M的浓度。基于这些数据，我们推测，在这个剂量下给予非维甲酸将导致足够的胶质瘤组织浓度来诱导细胞凋亡，并导致这种肿瘤类型的临床疗效。我们还假设，芬维甲素可以诱导分子和放射学变化，可以作为该药抗胶质瘤效果的替代标记。为了验证这些假设，我们提出了一项包含临床和相关终点的II期试验(安慰剂对照)。临床试验设计：将40例因手术而复发的胶质母细胞瘤患者随机分为两组，每组20例，在手术前7天口服非维甲酸或安慰剂，采集血清样本进行药代动力学研究。手术时，将同时采集切除的组织和血清样本进行相关研究。然后，所有40名患者都将继续接受开放式标签芬伦替尼治疗，直到肿瘤进展。目的：1)以6个月无进展生存期(临床终点)为指标，确定非维甲酸治疗复发性胶质母细胞瘤的疗效；2)测定脑胶质瘤组织中非维甲酸水平，并与血药浓度进行相关性分析。目的3)探讨芬维甲素是否诱导肿瘤组织细胞凋亡，以及细胞凋亡程度与血清和组织中4-HPR浓度及临床疗效的关系。目的4)利用维甲醇、视黄醇结合蛋白、视黄醇受体(RARGamma、RARbeta和RXRα)和胰岛素样生长因子-1(IGF-1)等与视黄醇信号转导相关的血清和组织标志物，确定Fenretinide对胶质瘤组织影响的放射学和分子替代标志物；b)肿瘤的多体素磁共振波谱(MRS)检测肿瘤细胞凋亡的变化，并将其与MRS靶向组织样本中的细胞凋亡相关联；c)寡核苷酸芯片以确定与胶质瘤相关的转录改变的分子，包括介导性侵袭、血管生成和细胞凋亡的分子。因此，来自这项研究的关于非维甲酸的组织效应的数据可以为在靶组织水平上的非维甲酸的作用机制提供新的见解。这些数据可能不仅与未来维甲酸治疗胶质瘤的试验有关，也可能与正在进行的非维甲酸治疗其他恶性肿瘤的试验有关。

DESCRIPTION (provided by applicant): Malignant gliomas, the most common of which in adults is glioblastoma multiforme, carry a grave prognosis with high morbidity and mortality. Surgery, radiotherapy and chemotherapy are only of modest value in the management of these tumors. Among novel compounds being tested against gliomas, 13 cis-retinoic acid, as single agent or in combination, has shown activity against recurrent gliomas in clinical trials. Fenretinide, a related synthetic retinoid, induces apoptosis & decreases proliferation in a variety of malignancies in vitro and is well tolerated on oral administration in humans. Fenretinide inhibits proliferation of glioma cells by induction of apoptosis at 3 - 5 muM concentration (Puduvalli et al 1999). Data from Phase I trials indicate that fenretinide is well tolerated and concentrations of approximately10?M are achievable at a dose of 1200 mg/m2 twice daily. Based on these data, we hypothesize that fenretinide administered at this dose will result in glioma tissue concentrations sufficient to induce apoptosis and result in clinical efficacy in this tumor type. We also hypothesize that fenretinide can induce molecular & radiological changes that can serve as surrogate markers for the effect of this agent against gliomas. To test these hypotheses, we propose a Phase II trial (placebo-controlled) with clinical & correlative endpoints. Clinical Trial Design: 40 patients with recurrent glioblastoma due to undergo surgery will be randomized in a blinded manner to receive fenretinide or placebo orally (20 patients each group) for 7 days prior to surgery with serum samples being collected for pharmacokinetic studies. At surgery, resected tissue will be collected with concurrent serum samples for correlative studies. All 40 patients will then continue on open label fenrentinide therapy until tumor progression. Specific Aims: Aim 1) To determine the efficacy of fenretinide against recurrent glioblastomas as measured by 6-month progression free survival (clinical endpoint) Aim 2) To determine the levels of fenretinide in glioma tissue and correlate it with serum concentrations. Aim 3) To determine whether fenretinide induces apoptosis in tumor tissue and correlate the degree of apoptosis with serum and tissue concentrations of 4-HPR and with clinical efficacy. Aim 4) To identify radiological and molecular surrogate markers of fenretinide effects on glioma tissue by utilizing - a) serum & tissue markers related to retinoid signaling such as retinol, retinol binding protein, retinoid receptors (RARgamma, RARbeta & RXR alpha) and IGF-1; b) Multivoxel MR Spectroscopy (MRS) of the tumor (before and after 7 day presurgery treatment with fenretinide) to detect changes indicative of apoptosis and correlate this with apoptosis seen in MRS-targeted tissue samples; c) Oligonucleotide microarrays to determine transcriptionally altered molecules relevant to gliomas including those that mediate invasion, angiogenesis and apoptosis. Data from this study about the tissue effects of fenretinide could hence provide new insights into the mechanism of action of fenretinide at the target tissue level. Such data could be relevant not only to future trials of retinoids in gliomas but also for ongoing trials of fenretinide in other malignancies.