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.
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