Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis

描述（由申请人提供）：Dana-Farber/哈佛癌症中心（DF/HCC）的U 01申请的总体目标是提供临床和科学经验以及患者资源，以进行I期单药临床试验 * I期药物联合临床试验、有限的II期临床试验和新型抗癌药物的试点临床试验。这些研究将由DF/HCC I期肿瘤学小组进行，该小组由参与研究的Dana-Farber癌症研究所（DFCI）、布里格姆妇女医院（BWH）、马萨诸塞州综合医院（MGH）和贝斯以色列女执事医疗中心（BIDMC）研究中心的研究者组成。DF/HCC I期肿瘤组在过去15年（1992-2007）中相互作用，进行了70多项研究性新细胞毒性剂、血管生成抑制剂、信号转导/细胞周期抑制剂、分化剂和抗癌疫苗的I期、I-II期药代动力学和药效学临床试验。在过去4年（2003-2006年，前一个资助期）进行的试验包括来自NCI临床试验评估计划（CTEP）的10种药物。DF/HCC I期肿瘤学组在2003-2006年期间的10项CTEP试验中累积了219例患者，平均每年累积55例患者。这些试验已与药代动力学、生物化学、病理学、免疫学、分子和成像研究相结合，这些研究将药物对其靶点的影响相关联。DF/HCC申请的具体目的是：1）对NCI CTEP IND产品组合中的新型药物进行I期、有限II期和试点临床试验，这些药物靶向参与细胞存活、增殖、凋亡、分化和血管生成调节的相关癌细胞信号传导途径; 2）评估这些药物单独或联合给药时的药代动力学，并建立剂量、时间表、暴露和效应之间的关系; 3）在适当的情况下采用新的设计进行这些试验，包括加速滴定和其他先进的设计方案; 4）为癌症患者建立安全和生物活性的治疗方案，包括那些患有肝和/或肾功能不全的患者; 5）获得针对新分子靶点的新药物的机理原理证明数据;和6）评价由这些试剂调节的分子靶和下游效应物的表达和/或活性的翻译终点。这项工作对公共卫生的重要性是通过需要为大量癌症患者提供更多和更好的治疗选择来实现的，这些癌症患者由于疾病对现有治疗无反应而成为新的研究药物的候选人。U 01协议中提出的研究重点是加速这些癌症患者获得新的治疗策略。

DESCRIPTION (provided by applicant): The overall objective of this U01 application from the Dana-Farber/Harvard Cancer Center (DF/HCC) is to provide clinical and scientific experience and patient resources to perform Phase I single agent clinical trials* Phase I agent combination clinical trials, limited Phase II clinical trials, and pilot clinical trials of novel anti- cancer agents. These studies will be performed by the DF/HCC Phase I Oncology Group consisting of investigators at the participating Dana-Farber Cancer Institute (DFCI), Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH) and the Beth Israel Deaconess Medical Center (BIDMC) sites. The DF/HCC Phase I Oncology Group has interacted over the past 15 years (1992-2007) in the conduct of more than 70 Phase I, l-ll pharmacokinetic and pharmacodynamic clinical trials of investigational new cytotoxic agents, angiogenesis inhibitors, signal transduction/cell cycle inhibitors, differentiating agents and anti-cancer vaccines. Trials performed over the past 4 years (2003-2006, prior funding period) include 10 agents from the NCI Clinical Trials Evaluation Program (CTEP). The DF/HCC Phase I Oncology Group has accrued 219 patients to the 10 CTEP trials during 2003-2006 with an average accrual of 55 patients annually. These trials have been integrated with pharmacokinetic, biochemical, pathological, immunological, molecular and imaging studies that correlate effects of the agents on their targets. The Specific Aims of the DF/HCC application are 1) To perform Phase I, limited Phase II and pilot clinical trials of novel agents in the NCI CTEP IND portfolio that target relevant cancer cell signaling pathways involved in the regulation of cell survival, proliferation, apoptosis, differentiation and angiogenesis; 2) To assess pharmacokinetics of these agents when administered alone or in combination and establish relationships between dose, schedule, exposure and effect; 3) To perform these trials with novel designs where appropriate, including accelerated titration and other advanced design schemes; 4) To establish safe and biologically active treatment schedules for patients with cancer, including those with hepatic and/or renal dysfunction; 5) To obtain mechanistic proof-of-principle data for new agents directed at novel molecular targets; and 6) To evaluate translational endpoints of expression and/or activity of molecular targets and downstream effectors that are regulated by these agents. The importance of this work to the public health is realized by the need for more and better treatment options for the substantial number of cancer patients who, because of disease unresponsive to existing treatments, become candidates for new investigational agents. The research proposed in this U01 agreement is focused on accelerating access of these cancer patients to new treatment strategies.