A Feasibility Study of Organ-Sparing Marrow-Targeted Irradiation (OSMI) to Condition Patients With High-Risk Hematologic Malignancies Prior to Allogeneic Hematopoietic Stem Cell Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- TRM, defined as death occurring in a patient from causes other than disease relapse
研究概览
简要总结
This pilot clinical trial aims to assess feasibility and tolerability of using an LINAC based "organ-sparing marrow-targeted irradiation" to condition patients with high-risk hematological malignancies who are otherwise ineligible to undergo myeloablative Total body irradiation (TBI)-based conditioning prior to allogeneic stem cell transplant. The target patient populations are those with ALL, AML, MDS who are either elderly (>50 years of age) but healthy, or younger patients with worse medical comorbidities (HCT-Specific Comorbidity Index Score (HCT-CI) > 4). The goal is to have the patients benefit from potentially more efficacious myeloablative radiation based conditioning approach without the side effects associated with TBI.
详细描述
PRIMARY OBJECTIVES:
I. To assess feasibility and tolerability of OSMI based hematopoietic stem cell transplant (HSCT) as defined by transplant-related mortality (TRM) at day 30 as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days.
SECONDARY OBJECTIVES:
I. Day 100 transplant-related mortality (TRM). II. Donor chimerism assessment at day 100 (to assess failure of engraftment rate).
III. Incidence of acute graft-versus-host disease (aGVHD) by day 100. IV. Incidence of chronic GVHD at one year. V. Cumulative incidence of grade II organ toxicity through day 100. VI. Rate and kinetics of hematopoietic recovery. VII. Incidence of graft failure (primary and secondary). VIII. Rate of infectious complications. IX. Cumulative incidence of relapse, overall survival, and progression-free survival at 1 year.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndromes (MDS) with fewer than 10% myeloblasts or lymphoblasts in the bone marrow and no blasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen; if remission bone marrow is available beyond 30 days a new bone marrow evaluation is required to assess remission status
- •The diagnosis of AML, ALL, or MDS will be based on World Health Organization (WHO) criteria
- •Pre-transplant bone marrow sample must be evaluable for assessment of remission status (i.e. aspirate smear containing particles and/or evaluable bone marrow core biopsy)
- •Patients with leukemia infiltration in the central nervous system (CNS) are eligible if cerebrospinal fluid (CSF) cytospin is negative for myeloblasts or lymphoblasts at time of enrollment
- •If the patient has an intra-abdominal chloroma on presentation, and has a partial response or complete response to treatment (size reduction of chloroma and marrow blast < 10%), the patient is eligible; however the chloroma must be included as part of the treatment target
- •For patients receiving treatment of their AML, MDS or ALL prior to transplantation:
- •Interval between the start of a cycle of conventional cytotoxic chemotherapy and the start of conditioning regimen must be at least 30 days
- •Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and the start of conditioning regimen must be at least 10 days
- •Hematopoietic Cell Transplantation-Specific Comorbidity Index score (HCT-CI) =< 4 for patients in Cohort 1 and > 4 for Cohort 2
- •Patient must be able to lie still in full body cast for 45 minutes
- •Must have a suitable donor defined as a sibling matched at 5/6 or 6/6 antigens (human leukocyte antigen [HLA]-A, B, and DRB1) or an unrelated volunteer matched at 7/8 or 8/8 HLA alleles (HLA-A, B, C, and DRB1)
- •Signed informed consent
- •DONOR: "High resolution" typing at HLA-A, B, C and DRB1 alleles
- •Single antigen mismatch for siblings and single allele mismatch for volunteer unrelated donors is acceptable
- •Donors must be >= 17 years of age
排除标准
- •Circulating peripheral blood myeloblasts or lymphoblasts on morphologic analysis from time of last treatment to time of enrollment
- •Prior allograft or prior autograft
- •Active CNS disease as identified by positive CSF cytospin at time of enrollment
- •Karnofsky performance score < 70
- •Symptomatic uncontrolled coronary artery disease or ejection fraction < 40%
- •Total bilirubin >= 2 x the upper limit of normal
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >= 3 x the upper limit of normal
- •Diffusion capacity of the lung for carbon monoxide (DLCO) < 40%
- •Forced expiratory volume in one second (FEV1) < 50% (corrected for hemoglobin)
- •Receiving supplementary continuous oxygen
- •Creatinine clearance < 50 mL/min/1.73m^2
- •Patients with active uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms)
- •Patients seropositive for the human immunodeficiency virus (HIV)
- •Females who are pregnant or breastfeeding
- •Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment
- •Patients who had prior radiation to more than 20% bone marrow containing areas or to any areas exceeding 2000 cGy
- •Donors will be excluded if they are an identical twin of the recipient
- •Females who are pregnant (positive serum beta human chorionic gonadotropin beta [β HCG]) or uninterruptible breastfeeding
- •HIV seropositive
- •Donors receiving experimental therapy or investigational agents unless approved by the protocol chair
研究组 & 干预措施
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: radiation therapy (Radiation)
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: cyclophosphamide (Drug)
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: anti-thymocyte globulin (Biological)
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: tacrolimus (Drug)
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: methotrexate (Drug)
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: allogeneic bone marrow transplantation (Procedure)
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: allogeneic hematopoietic stem cell transplantation (Procedure)
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: peripheral blood stem cell transplantation (Procedure)
Treatment (OSMI, allogeneic transplant)
CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.
TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
TRM, defined as death occurring in a patient from causes other than disease relapse
时间窗: At day 30 post-transplant
Proportions will be derived for incidence of TRM divided by all evaluable patients along with corresponding 95% binomial confidence intervals.
Rate of grade II/III organ toxicity, defined by the Bearman Regimen-Related Toxicities Scale
时间窗: Up to 30 days
Toxicities will be tabulated by grade for each cohort, by type of toxicity, as well as the maximum grade overall. Toxicity frequencies will be described for the day +30, day +100, and one year time intervals as well as cumulative over time. Proportions will be derived for incidence of grade II/III organ toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals.
次要结局
- Incidence of chronic GVHD, scored according to the OSU BMT Program policy(At 1 year)
- Incidence of relapse(Time from start of conditioning to relapse, assessed at 1 year)
- Incidence of aGVHD, graded according to Ohio State University Bone Marrow Transplant (OSU BMT) Program policy(Up to day 100)
- Immune reconstitution(Up to 12 months post transplant)
- Cumulative incidence of grade II organ toxicity(Up to day 100)
- Incidence of hematopoietic recovery(Up to day 100)
- TRM(Day 100 post-transplant)
- Donor chimerism(Day 100)
- Incidence of graft failure(Up to 1 year post-transplant)
- Rate of infectious complications(Up to 12 months)
- Overall survival(Time from start of conditioning to death, loss to follow up, or end of study, whichever comes first, assessed at 1 year)
- Progression-free survival(Time from start of conditioning to relapse, progression, death, initiation of non-protocol therapy, loss to follow up or end of study, whichever comes first, assessed at 1 year)
研究者
Sumithira Vasu
Principal Investigator
Ohio State University Comprehensive Cancer Center