A Pilot Study of the Safety and Activity of Escalating Doses of ON 01910.Na in Patients With RAEB-1 AND RAEB-2 Myelodysplastic Syndrome (MDS) and AML With Trisomy 8
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 14
- 试验地点
- 2
- 主要终点
- The toxicity profile at each dose level.
研究概览
简要总结
This study will determine the highest dose of the experimental drug ON 01910.Na that can safely be given to patients with the bone marrow disorder myelodysplasia (MDS) and patients with refractory AML with trisomy 8. In this disease, the bone marrow can make some blood cells, but very few of these cells are released into the blood for use in the body. ON 01910.Na is an experimental drug that inhibits a protein called cyclinD1that is important for keeping MDS cells alive. In laboratory experiments, ON 01910.Na has acted against cyclinD1, causing MDS cells to die. The study will also evaluate how the body handles ON 01910.Na, the effect of the drug on MDS and AML and its side effects.
Patients 18 to 85 years old with MDS or AML who do not have a suitable sibling donor for a marrow transplant or who are not willing to have a transplant may be eligible for this study.
Participants receive ON 01910.Na in 2-week treatment cycles, with 3 to 5 days of drug infusion through a vein followed by 9 to 11 days of observation. To find the highest safe dose of ON 01910.Na, the first person enrolled in the study is given the smallest study dose of the drug for 3 days, followed 2 weeks later with a second dose for 3 days. If these doses are found safe, the next two people receive the same dose. If these subjects do well, the next group of patients receives the next higher dose level. The dose continues to be increased in groups of 3 to 6 subjects until the fourth and highest dose level is reached. Patients who do well on the treatment may receive an additional six cycles of ON 01910.Na (3 to 5 days of infusion once every other week for 12 weeks).
Before, during and after the treatment period, patients are periodically evaluated and monitored with the following tests and procedures:
- Physical examination and review of medical and medication history.
- Blood and urine tests.
- Pregnancy test for women of childbearing age.
- Electrocardiogram (EKG) and chest X-ray.
- Bone marrow biopsy.
详细描述
The myelodysplastic syndromes (MDS) and acute myelogenous leukemias (AML) are a group of heterogeneous diseases with wide variation in clinical presentation and disease severity. Typically patients are older adults with co-morbidities. AML and MDS are characterized by variable degrees of cytopenias (anemia, neutropenia, thrombocytopenia) due to ineffective hematopoiesis and dysplastic bone marrow morphology or hematological malignancy.
Treatment of MDS is unsatisfactory: chemotherapy has a limited role in the management of leukemic progression; autologous stem cell transplantation does not prolong relapse-free survival and stem cell transplantation is poorly tolerated in older individuals. Some MDS patients have been shown to respond to a wide variety of immunosuppressive agents ranging from corticosteroids to cyclosporine (CsA) and horse antithymocyte globulin (h-ATG). However, the overall response rate is less than 30% and relapse continues to be a problem. Few treatments appear to change the natural history of MDS however, growth factors, decitabine, and lenalidomide can improve cytopenias, and 5-azacytidine, can reduce transfusion requirements, and improve quality of life when compared to supportive care. In addition most MDS patients are older and tolerate aggressive therapies poorly.
Some AML patients can be cured with chemotherapy or by allogeneic stem cell transplantation. However standard treatment approaches are not effective for patients who become refractory to chemotherapy, elderly patients, and those who relapse after transplantation.
The management of MDS and relapsed/refractory AML patients therefore remains unsatisfactory and targeted therapies are needed. One such investigational drug, ON 01910.Na, is a potent inhibitor of cyclin D1 and mitosis. ON01910.Na shows activity against a broad spectrum of tumor cell lines. Animal model studies show little toxicity with a high therapeutic index in these tumors. In addition, the fact that MDS bone marrow (particularly trisomy 8) and patients with AML with the trisomy 8 abnormality (Sloand, unpublished data) over-express cyclin D1 and in vitro studies have demonstrated activity against cytogenetically abnormal cells and blasts despite minimal inhibition of normal hematopoiesis provides a rationale for its use in select patients with MDS or AML.
We therefore propose a non-randomized, pilot, dose escalating Phase I study of ON 01910.Na in MDS and patients with refractory AML with trisomy 8.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
The toxicity profile at each dose level.
次要结局
- Plasma pharmacokinetics, pharmacodynamics, and biological effects of hematologic improvement at each dose level.