CLINICAL TRIAL: PK AND BIOL STUDY OF SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) IN P

临床试验：辛酰苯胺异羟肟酸（SAHA）在 P 中的 PK 和生物研究

• 批准号: 7718721
• 负责人: John Sarantopoulos
• 金额: $ 0.02万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718721
• 关键词: Acute Promyelocytic Leukemia; Adult; Adverse effects; Apoptosis; Binding; Biological; Biopsy; Breast Carcinoma; Caring; Cell Cycle Arrest; Clinical Trials; Colon Carcinoma; Computer Retrieval of Information on Scientific Projects Database; Daily; Disease regression; Disease remission; Dose; Enrollment; Enzymes; Female; Funding; G2 Phase; Genetic Transcription; Grant; Healthcare Systems; Histone Deacetylase; Histones; Human; Incidence; Institution; Interleukin-2; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Metastatic Renal Cell Cancer; Mus; Outcome; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Population; Prior Immunotherapy; Progression-Free Survivals; Prostate; Rate; Renal Cell Carcinoma; Research; Research Personnel; Resources; Safety; Secondary to; Source; South Texas; Survival Rate; Toxic effect; Transgenic Organisms; Tretinoin; Tumor Tissue; United States National Institutes of Health; Veterans; Vorinostat; Week; Xenograft procedure; angiogenesis; base; cell transformation; clinically relevant; day; indexing; inhibitor/antagonist; intraperitoneal; male; mouse model; response; therapy resistant; tumor; tumor growth

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. OBJECTIVES: Primary - To determine the antitumor activity of SAHA in patients with advanced renal cell carcinoma (RCC) who have failed up to 2 lines of prior immunotherapy and/or bilogical therapy or in previously untreated patients who are not appropriate candidates to receive IL-2 based treatment, as determined by objective response and progression rates. Secondary - To further evaluate the safety and tolerability of SAHA given at a dose of 300mg twice daily for 3 consecutive days every week in this patient population as determined by toxicity profile, incidence and rating according to NCI/CTC v3.0 criteria - To further evaluate the biologic activity of SAHA as determined by progression free survival, survival rate at 12 months after initiation of treatment and overall survival. - To characterize the pharmacodynamic relationships between the plasma steady state concentration of SAHA and the drug effect on expression of acetylated histones in peripheral blood mononuclear cells (PBMC) and tumor tissue where the tumor is accessible for biopsy. - To analyze the biologic effects of SAHA on apoptosis, angiogenesis and downstream targets and gene transcription. - To correlate changes in these biological measurements with indices of patient outcome. RESEARCH PLAN: Adult male and female patients with advanced renal cell carcinoma, metastatic or inoperable, are expected to participate in the study. METHODS: Potential patients eligible for care at the VA/GCRC will be treated with SAHA. Enrollment of about 5 patients is anticipated at the GCRC, located at the South Texas Veterans Health Care System, Audie Murphy Division. CLINICAL RELEVANCE: SAHA is a potent inhibitor of HDAC activity and binds directly to the catalytic pocket of HDAC enzymes. SAHA causes G1 or G2 phase cell-cycle arrest, apoptosis, or differentiation in cultured transformed cells. Intraperitoneal administration of SAHA causes significant tumor growth inhibition in human prostate cancer xenografts in mice; tumor regressions were observed at SAHA doses (50 mg/kg/day) that did not produce toxic side effects. Intraperitoneal administration of SAHA in combination with retinoic acid induced leukemic remission and prolonged survival in a therapy-resistant transgenic mouse model of acute promyelocytic leukemia (APL). Intraperitoneal administration of SAHA causes significant tumor growth inhibition in both human breast carcinoma and human colon carcinoma cancer xenografts in mice. Tumor growth inhibition was observed at SAHA doses (100 mg/kg/day) that do not produce toxic side effects.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 目标： 基本的 - 确定SAHA在晚期肾细胞癌（RCC）患者中的抗肿瘤活性，这些患者最多未能接受2行的先前免疫疗法和/或双毛治疗或以前未经治疗的患者，这些患者不适合接受基于IL-2的治疗，这是由客观反应和进展率确定的。 次要 - 进一步评估SAHA的安全性和耐受性，每周两次以300毫克的剂量在该患者人群中连续3天，根据NCI/CTC V3.0标准确定该患者人群的剂量，发病率和评级。 - 为了进一步评估SAHA的生物学活性，取决于无进展生存率，在治疗开始后12个月的生存率和总体存活率。 - 表征SAHA的血浆稳态浓度与药物对外周血单核细胞（PBMC）（PBMC）和肿瘤组织中乙酰化组蛋白表达的影响之间的药效学关系。 - 分析SAHA对凋亡，血管生成和下游靶标和基因转录的生物学作用。 - 将这些生物测量的变化与患者结局指数相关。 研究计划： 患有晚期肾细胞癌（转移性或无法手术）的成年男性和女性患者将参与研究。 方法： 有资格在VA/GCRC进行护理的潜在患者将接受SAHA治疗。 预计位于奥迪·墨菲（Audie Murphy）部门南德克萨斯州退伍军人卫生保健系统的GCRC预计将有大约5例患者入学。 临床相关性： SAHA是HDAC活性的有效抑制剂，直接与HDAC酶的催化口袋结合。 SAHA导致G1或G2相细胞周期停滞，凋亡或培养的转化细胞分化。 腹膜内给药SAHA会在小鼠的人类前列腺癌异种移植物中引起明显的肿瘤生长抑制作用。在没有产生有毒副作用的SAHA剂量（50 mg/kg/day）处观察到肿瘤回归。 腹膜内施用SAHA与视黄酸诱导的白血病缓解和长时间存活中的腹膜内给药，并在抗治疗的急性前临床细胞性白血病（APL）的耐药性转基因小鼠模型中（APL）。 腹膜内施用SAHA会导致人类乳腺癌和人类结肠癌癌症异种移植物的显着肿瘤生长抑制作用。 在不产生有毒副作用的SAHA剂量（100 mg/kg/天）处观察到肿瘤生长抑制。