A Dose Escalation Study of Intensity Modulated Total Marrow Irradiation (IMRT-TMI) With Fludarabine as a Myeloablative Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed and Refractory Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Maximum-tolerated dose (MTD) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine-Phase I only
研究概览
简要总结
This is a phase I/II clinical trial on the use of total marrow irradiation (TMI) given concurrently with fludarabine, a chemotherapy drug commonly used to treat leukemia, as a myeloablative therapy for patients undergoing Allo-HSCT. TMI is a targeted technique to deliver radiation to the bone marrow while minimizing dose to other normal organs in the body. In phase I of the clinical study, the dose of radiation to the bone marrow will be incrementally increased to determine the highest tolerated TMI dose. In phase II, the effectiveness of the TMI-fludarabine conditioning regimen utilizing that dose of radiation will be studied. Acute and long-term toxicity data as well as quality of life data will also be studied.
*Stopping criteria was met during the first dose level cohort in Phase l. The trial will not continue into Phase II as originally planned.
详细描述
This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of intensity modulated radiation therapy based total marrow irradiation (TMI) concurrent with fludarabine as a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (Allo-HSCT), as well as to determine the efficacy of the regimen in patients with high-risk and relapsed or refractory leukemia and myelodysplasia. TMI, which allows for conformal dosing of target bone marrow tissue while giving lower doses to organs at risk, is considered by many to be a superior alternative to conventional total body irradiation (TBI)
Primary Objectives:
Phase I:
Determine the MTD of TMI given concurrently with fludarabine (fixed at 150 mg/m2) as a conditioning regimen for Allo-HSCT for patients with high risk (relapsed/refractory) acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelogenous leukemia (CML).
Phase II:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must be diagnosed with one of the following conditions:
- •Acute Myeloid Leukemia (AML) who are not in complete remission, and who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:
- •Duration of first CR < 6 months (if previously in CR)
- •Poor risk karyotype including any of the following: complex karyotype with ≥3 clonal abnormalities, 5q-/-5, 7q-/-7, 11q23 abnormalities, inv(3q), 20q or 21q abnormalities, t(6;9), t(9;22), 17p abnormalities [or TP53 mutations] or monosomal karyotype. Molecular typing (except for TP53 mutation) will not be used for eligibility criteria determination.
- •Circulating peripheral blood blasts at time of enrollment
- •Karnofsky performance status <90%
- •Acute Lymphocytic Leukemia (ALL) who are not in complete remission, and who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:
- •First refractory relapse. Patients in second or subsequent relapse are excluded.
- •Donor is CMV seropositive
- •Bone marrow blasts >25% (within 30 days of admission)
- •Age >40 years
- •Myelodysplasia with a Revised International Prognostic Score (IPSS-R) of greater than 4.5 (i.e., high- or very-high risk).
- •Chronic Myelogenous Leukemia (CML) in either
- •Accelerated phase, defined by any of the following:
- •10-19% blasts in peripheral blood white cells or bone marrow
- •Peripheral blood basophils at least 20%
- •Persistent thrombocytopenia (<100 x 109/l) unrelated to therapy, or persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy
- •Increasing spleen size and increasing white blood cell (WBC) count unresponsive to therapy
- •Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase)
- •Chronic phase provided a complete hematologic remission was not achieved by 3 months or a complete cytogenetic remission by 18 months and the patient had received at least 2 tyrosine kinase inhibitors.
- •Patient age 18-65 years old at time of consent
- •Availability of a consenting human leukocyte antigens(HLA) -matched donor
- •Karnofsky Performance Status 70% or higher
- •Required baseline laboratory values:
- •Estimated creatinine clearance ≥ 60 ml/min
- •Aspartate aminotransferase and alanine aminotransferease ≤ 2.5 x upper limit of normal value
- •Bilirubin ≤ 1.5 x upper limit of normal value
- •Required baseline cardiac function of left ventricular ejection fraction (LVEF) > 45
- •corrected
- •Required baseline pulmonary function of lung diffusing capacity (DLCO) > 45 % predicted (corrected for hemoglobin)
- •Patient must be capable of understanding the investigational nature of this study, potential risks and benefits of the study, and be able to provide a valid informed consent.
排除标准
- •Patients with ALL who are in second or subsequent relapse
- •HIV seropositive patients.
- •Pregnant or nursing females are excluded from this study.
- •Prior radiation therapy
- •Patients who have had a prior autologous or allogeneic bone marrow or stem cell transplantation
研究组 & 干预措施
Fludarabine + Total Marrow Irradiation
干预措施: Fludarabine (Drug)
Fludarabine + Total Marrow Irradiation
干预措施: Total Marrow Irradiation (TMI) (Radiation)
结局指标
主要结局
Maximum-tolerated dose (MTD) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine-Phase I only
时间窗: Day -7 of conditioning regimen through 30 days post transplant (37 days)
Overall survival (OS) rate 1 year post transplant-Phase II only
时间窗: 1 year
Dose limiting toxicity (DLT) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine- Phase I only
时间窗: Day -7 of conditioning regimen through 30 days post transplant (37 days)
次要结局
- Incidence of sinusoidal obstruction syndrome (SOS)(100 days)
- Incidence of pneumonitis(100 days)
- Time to engraftment of neutrophils(from date of transplant to the first of three consecutive days after transplantation during which the absolute neutrophil count (ANC) is greater than or equal to 0.5 x 10^9/liter)
- Incidence of non-relapse mortality(1 year)
- Incidence of infection(100 days)
- Type of infections(100 days)
- Incidence of chronic graft versus host disease (GvHD)(2 years)
- Frequency of non hematologic toxicities(100 days)
- Incidence of graft versus host disease (GvHD)(100 days)
- Incidence of mucositis(100 days)
- Disease response rate(Day 30 after transplant (30 days))
- Mean Quality of Life (QOL) as measured by Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) version 4(Screening (at simulation), day +180, day +365, + 2 years from transplant (approximately 2 years))
- Time to engraftment of platelets(from date of transplant until he first of seven consecutive days after transplantation during which the platelet count is greater than or equal to 20 x10^9/liters without transfusion.)
- Incidence of relapse mortality(1 year)
- Disease-Free Survival(2 years)
研究者
Naoyuki G. Saito, M.D., Ph.D.
Assistant Professor of Radiation Oncology
Indiana University School of Medicine