COG ADVL0316: A PHASE I STUDY OF 17-AAG IN RELAPSED/REFRACTORY PEDIATRIC

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。本研究为I期临床试验艾滋病相关研究，多中心I期研究。这是一项涉及人类患者的研究。I期研究的目的是确定患者可以安全耐受的新药(PS-341，Bortezomib)的最高剂量。I期研究通常包括许多不同类型的白血病患者。参加I期研究的患者以前经常接受过几种治疗。一旦第一阶段研究确定了最高剂量，就可能进行另一项研究，称为第二阶段研究，以衡量疾病对新药的反应。这项I期研究测试了一种名为PS-341(或VELCADE或Bortezomib)的新药在难治性/复发性白血病患者中的安全性。(白血病是一种影响儿童血细胞的癌症，复发意味着疾病在治疗后复发，难治意味着这种疾病很难治疗。)使用PS-341进行的实验室实验表明，它通过阻止癌细胞的生长来杀死癌细胞。已经在成人和儿童实体瘤患者中发现了安全剂量的PS-341，但在白血病儿童中尚未发现安全剂量。这项研究的目的是测试PS-341的安全性，看看它们对儿童和儿童白血病有什么效果(好的和坏的)，并找到可以给白血病儿童服用而不会引起严重副作用的最高剂量。这项研究的其他目标是了解人体如何处理药物，并更好地了解癌细胞与健康细胞的不同之处。由于这一I期试验的主要目的是寻找PS-341可安全用于难治性/复发性白血病儿童的最大剂量，因此一些患者接受的剂量可能太小，对他们的疾病没有任何影响，也可能太高，导致不良副作用。目前尚不清楚这种药物在任何剂量下是否都能有效地治疗这项研究中接受治疗的儿童的白血病。这项研究是这样设计的，孩子们被分成几组。第一组儿童将在开始剂量时给予PS-341。如果起始剂量的副作用不是太严重，下一组儿童将被给予更高剂量的PS-341。这将继续下去，直到找到不会导致不可接受的副作用的最大剂量。PS-341的剂量不会在每个儿童身上增加。每个疗程将持续21天。在每个疗程中，患者将在每个疗程的第1、4、8和11天给予PS-341。PS-341将通过静脉给药。参加这项研究的儿童在治疗期间将接受标准的体检，如体检、蛋白质水平测试以及肝肾功能检查。在前三个疗程的每个疗程结束时，都会进行一项名为骨髓抽吸物的测试，以确定这种药物是否影响白血病，然后每隔一个疗程结束一次。除了这些测试外，患者还可以选择在第一个疗程的几天内采集血液样本进行称为药代动力学的测试。药代动力学测试发现药物在体内细胞中的行为方式。患者还可以选择参加其他涉及他们的骨髓和血液样本的特殊研究。由于使用PS-341治疗，一些儿童会出现一些副作用。患者将受到密切关注，如果出现严重的副作用，将停止治疗。在接受PS-341治疗的成人和儿童中，一些更常见的副作用包括疲倦、恶心、便秘、腹泻、呕吐、头晕、低血小板计数、头痛、发热、呼吸急促、腹痛、低血盐、食欲不振和关节疼痛。PS-341引起的副作用较少，包括皮疹、肺部积液、皮肤剥落和肠道刺激。罕见的副作用包括低血压、心率异常、肾功能障碍、精神状态改变和出血。

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. This study is a phase I clinical trial AIDS related study, multi-center Phase I study. This is a research study involving human patients. The purpose of a phase I study is to determine the highest dose of a new drug (PS-341, bortezomib) that patients can tolerate safely. Phase I studies usually include patients with many different kinds of Leukemia. Patients who enroll in phase I studies often have had several kinds of treatment before. Once the highest dose is determined by a phase I study, another study, called a phase II study, may be performed to measure the response of a disease to the new drug. This phase I study tests the safety of a new experimental drug called PS-341 (or Velcade or Bortezomib) in refractory/recurrent leukemia patients. (Leukemia is a type of cancer that affects a child's blood cells, recurrent means the disease came back after being treated, and refractory means that the disease is hard to treat.) Laboratory experiments performed with PS-341 showed that it kills cancer cells by stopping their growth. A safe dose of PS-341 has already been found in adults and in children with solid tumors, but a safe dose has not been found in children with leukemia. The goals of this study are to test the safety of PS-341, to see what effects (good and bad) they have on children and children's leukemia, and to find the highest dose of PS-341 that can be given to children with leukemia without causing severe side effects. Other goals of this study are to learn how the body handles the drug, and to better understand how cancer cells are different from healthy cells. Because the main purpose of this phase I trial is to find the maximum dose of PS-341 that can be given safely to children with refractory/recurrent leukemias, the dose that some patients receive may be too little to have any effect on their disease, or it may be too high and cause bad side effects. It is not known if this drug, at any dose, will be effective in treating the leukemia of children treated on this study. The study is designed such that the children are separated into groups. The first group of children will be given PS-341 at the starting dose. If the side effects at the starting dose are not too serious, the next group of children will be given a higher dose of PS-341. This will continue until the maximum dose is found that does not result in unacceptable side effects. The dose of PS-341 given will not be increased in each individual child. Each course of therapy will last 21 days. During each course, the patient will be given PS-341 on days 1, 4, 8 and 11 of each course. PS-341 will be given through a vein. Children on this study will be given standard medical exams during therapy, such as physical exams, protein level tests and tests to examine liver and kidney function. A test to find out whether or not the drug is affecting the leukemia, called a bone marrow aspirate, will be done at the end of every course for the first three courses, and then at the end of every other course. In addition to these tests, patients will be the given the option to have blood samples taken on a few days during the first course of therapy for tests called pharmacokinetics. Pharmacokinetic tests find out how the drug is behaving in cells in the body. Patients will also be given the option to participate in other special research studies involving their bone marrow and blood samples. As a result of treatment with PS-341, some side effects will be seen in some children. Patients will be watched carefully and treatment will be stopped if serious side effects develop. Some of the more common side effects that were seen in adults and children who were treated with PS-341 included tiredness, nausea, constipation, diarrhea, vomiting, dizziness, low platelet counts, headache, fever, shortness of breath, abdominal pain, low blood salts, loss of appetite, and joint pain. Less common side effects due to PS-341 included rash, fluid in lungs, skin flaking and gut irritation. Rarely seen side effects included low blood pressure, abnormal heart rate, kidney dysfunction, confusion, altered mental status and bleeding.