Correlative trial of fenretinide against Glioblastomas

描述（申请人提供）：恶性胶质瘤，成人中最常见的是多形性胶质母细胞瘤，预后严重，发病率和死亡率高。手术、放疗和化疗对这些肿瘤的治疗价值不大。在治疗胶质瘤的新化合物中，13顺式维甲酸作为单一药物或联合药物，在临床试验中显示出对复发性胶质瘤的活性。芬维甲酸是一种相关的合成类维甲酸，在体外诱导多种恶性肿瘤细胞凋亡和减少细胞增殖，并在人体口服耐受良好。芬维啶在3 - 5mum浓度下通过诱导细胞凋亡抑制胶质瘤细胞增殖（Puduvalli et al . 1999）。I期试验数据表明，芬瑞啶耐受性良好，浓度约为10？每日两次，剂量为1200mg /m2。基于这些数据，我们假设以该剂量给药的芬维甲酸将导致胶质瘤组织浓度足以诱导细胞凋亡，并在该肿瘤类型中产生临床疗效。我们还假设芬维甲酸可以诱导分子和放射学变化，可以作为该药物对胶质瘤作用的替代标记物。为了验证这些假设，我们提出了一项具有临床和相关终点的II期试验（安慰剂对照）。临床试验设计：40例因手术而复发的胶质母细胞瘤患者将采用盲法随机分组，术前7天口服芬维甲酸或安慰剂（每组20例），并收集血清样本进行药代动力学研究。在手术中，切除的组织将与并发血清样本一起收集，用于相关研究。所有40名患者将继续接受开放标签芬伦替尼治疗，直到肿瘤进展。具体目的：目的1)通过6个月无进展生存期（临床终点）确定芬维啶对复发性胶质母细胞瘤的疗效（临床终点）目的2)确定胶质瘤组织中芬维啶的水平及其与血清浓度的相关性。目的3)研究芬维啶是否诱导肿瘤组织细胞凋亡，细胞凋亡程度与4-HPR在血清和组织中的浓度及临床疗效之间的关系。目的4)利用与类视黄醇、视黄醇结合蛋白、类视黄醇受体（RARgamma、rrbeta和RXR α）和IGF-1等类视黄醇信号相关的血清和组织标志物，鉴定芬维甲酸对胶质瘤组织影响的影像学和分子替代标志物；b)肿瘤的多体素磁共振光谱（MRS）（芬维啶术前和术后7天）检测指示细胞凋亡的变化，并将其与MRS靶向组织样本中的细胞凋亡相关联；c)寡核苷酸微阵列检测与胶质瘤相关的转录改变分子，包括介导侵袭、血管生成和凋亡的分子。本研究关于芬维甲酸的组织效应的数据可以为芬维甲酸在靶组织水平的作用机制提供新的见解。这些数据不仅与未来类维甲酸治疗胶质瘤的试验有关，也与正在进行的芬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.