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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究为艾滋病相关的I期临床试验，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，硼替佐米）的最高剂量。一期研究通常包括患有多种不同类型白血病的患者。参加I期研究的患者通常之前接受过几种治疗。一旦I期研究确定了最高剂量，就可以进行另一项称为II期研究的研究，以测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或硼替佐米）的新型实验性药物对难治性/复发性白血病患者的安全性。（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，难治性意味着疾病难以治疗。）用PS-341进行的实验室实验表明，它通过阻止癌细胞生长来杀死癌细胞。PS-341的安全剂量已经在成人和患有实体瘤的儿童中被发现，但在患有白血病的儿童中还没有发现安全剂量。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影响（好的和坏的），并找到给白血病儿童服用PS-341而不会产生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，以及更好地了解癌细胞与健康细胞的不同之处。由于这项I期试验的主要目的是找到可以安全给予难治性/复发性白血病儿童的PS-341的最大剂量，一些患者接受的剂量可能太少而对他们的疾病没有任何影响，或者可能太高而导致不良副作用。目前尚不清楚这种药物，在任何剂量下，是否会有效地治疗儿童白血病。这项研究的目的是把孩子们分成几组。第一组儿童将以起始剂量给予PS-341。如果开始剂量的副作用不太严重，下一组儿童将被给予更高剂量的PS-341。这一过程将持续到发现最大剂量不会产生不可接受的副作用为止。PS-341的剂量不会在每个儿童中增加。每个疗程21天。在每个疗程的第1、4、8、11天给予PS-341。PS-341将通过静脉注射。本研究的儿童在治疗期间将接受标准的医学检查，如体格检查、蛋白质水平检查和肝肾功能检查。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的测试，以确定药物是否对白血病有影响，然后在其他疗程结束时进行。除了这些测试之外，患者还可以选择在第一个疗程的几天内抽取血液样本进行药物动力学测试。药代动力学测试发现药物在体内细胞中的表现。患者还可以选择参与其他涉及其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。患者将被仔细观察，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劳、恶心、便秘、腹泻、呕吐、头晕、血小板计数低、头痛、发烧、呼吸急促、腹痛、低血盐、食欲不振和关节痛。PS-341不太常见的副作用包括皮疹、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、意识不清、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.