Campath® [Alemtuzumab] Dose Escalation, Low-Dose TBI and Fludarabine Followed by HLA Class I Mismatched Donor Stem Cell Transplantation for Patients With Hematologic Malignancies - A Multi-Center Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 7
- 主要终点
- Evaluate the Risk of Transplant Related Mortality.
研究概览
简要总结
This phase II trial studies the side effects and the best dose of alemtuzumab when given together with fludarabine phosphate and low-dose total body irradiation (TBI) and how well it works before donor stem cell transplant in treating patients with hematological malignancies. Giving chemotherapy and low-dose TBI before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. Also, monoclonal antibodies, such as alemtuzumab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine (CSP) and mycophenolate mofetil (MMF) after transplant may stop this from happening.
详细描述
PRIMARY OBJECTIVES:
I. To determine whether stable allogeneic engraftment from related and unrelated human leukocyte antigen (HLA)-mismatched stem cell donors can be safely established using a non-myeloablative conditioning regimen plus escalating doses of the anti-CD52 monoclonal antibody (mAb) Campath (alemtuzumab) in patients with hematologic malignancies.
SECONDARY OBJECTIVES:
I. Evaluate the risk of occurrence of acute and chronic graft-vs-host disease (GVHD).
II. Evaluate the risk/incidence of infections.
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
- — 至 74 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must be not eligible for conventional transplants and must have disease expected to be stable for at least 100 days without chemotherapy; patients with hematologic malignancies treatable with hematopoietic stem cell transplant (HSCT) or with a B cell malignancy except those treatable with autologous transplant will be included
- •Aggressive non-Hodgkin lymphomas (NHLs) and Other Histologies Such as Diffuse large B cell NHL
- •Patients with primary refractory or relapsed disease not eligible for an autologous transplant
- •Patients are eligible following an autologous transplant in remission or in relapse
- •Planned tandem transplant is allowed for patients at high risk of relapse
- •Low grade NHL with < 6 months duration of complete remission (CR) between courses of conventional therapy
- •Mantle Cell NHL may be treated in first CR
- •Chronic lymphocytic leukemia (CLL) - Must have failed 2 lines of conventional therapy and be refractory to fludarabine
- •Hodgkin disease (HD) - Must have received and failed frontline therapy; patients must have had a prior autologous transplant or were not eligible for autologous transplant; planned tandem transplants are allowed for patients at high risk of relapse
- •Multiple myeloma (MM) - Must have received prior chemotherapy and a prior autologous transplant, unless autologous transplant was not possible; planned tandem transplants are allowed for patients at high risk of relapse
- •Acute myeloid leukemia (AML) - Must have < 5% marrow blasts at the time of transplant
- •Acute lymphocytic leukemia (ALL) - Must have < 5% blasts at the time of transplant
- •Chronic myeloid leukemia (CML) - Patients will be accepted beyond chronic phase 1 (CP1) if they have received previous myelosuppressive chemotherapy or HSCT, and have < 5% marrow blasts at time of transplant
- •Myelodysplastic (MDS)/Myeloproliferative disorders - Must have failed previous myelosuppressive chemotherapy or HSCT, and have < 5% marrow blasts at time of transplant
- •Waldenstrom's Macroglobulinemia - Must have failed 2 courses of therapy
- •Patients < 12 years old must be approved by the Fred Hutchinson Cancer Research Center (FHCRC) principal investigator (PI)
- •Patients who refuse to be treated on a conventional transplant protocol; for this inclusion, criteria transplants must be approved by both the participating institution´s patient review committee such as the Patient Care Conference (PCC) at the FHCRC and the FHCRC principal investigator
- •Patients with related or unrelated donors for whom
- •The best available match is a HLA class II DRB1 and DQB1 matched donor incompatible for any single serologically detectable class I HLA-A, -B, -C mismatch; one additional allele level class I mismatch is allowed OR any combination of 2 allele level mismatches (if typed at the molecular level)
- •There is a likelihood of rapid disease progression while HLA typing and results of a preliminary search and the donor pool suggests that a 10/10 HLA-A, B, C, DRB1 and DQB1 matched unrelated donor will not be found
- •There is no HLA-A, -B or -C one locus allelic mismatched related donor available
- •There is no indication for an autologous transplantation as a treatment option
- •DONOR: Related or unrelated donors who are matched for HLA-DRB1 and DQB1 alleles (must be defined by high resolution typing), and who are mismatched for:
- •Any single serologically detectable HLA-A or B or C antigen +/- 1 allele or
- •Any combination of two HLA-A, -B, or -C alleles (if prospectively typed at molecular level)
排除标准
- •Patients who are homozygous at the mismatched major histocompatibility complex (MHC) class I locus
- •A positive cross-match exists between the donor and recipient
- •Patients with rapidly progressive intermediate or high grade NHL
- •Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
- •Life expectancy severely limited by diseases other than malignancy
- •Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
- •Fertile men or women unwilling to use contraceptives during and for up to 12 months post treatment
- •Female patients who are pregnant or breast-feeding
- •Human immunodeficiency virus (HIV) positive patients
- •Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
- •Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
- •Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
- •Patients with active bacterial or fungal infections unresponsive to medical therapy
- •Patients with the following organ dysfunction symptomatic coronary artery disease or ejection fraction < 35% or other cardiac failure requiring therapy; ejection fraction is required if the patient is > 50 years of age, or history of cardiac disease or anthracycline exposure
- •Diffusion capacity of carbon monoxide (DLCO) < 35%; total lung capacity (TLC) < 35%; or forced expiratory volume in one second (FEV1) < 35% and/or receiving supplementary continuous oxygen
- •Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure; cirrhosis of the liver with evidence of portal hypertension; alcoholic hepatitis; esophageal varices; a history of bleeding esophageal varices; hepatic encephalopathy; uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time; ascites related to portal hypertension; bacterial or fungal liver abscess; biliary obstruction; chronic viral hepatitis with total serum bilirubin >3 mg/dL; or symptomatic biliary disease
- •Patients with poorly controlled hypertension on multiple antihypertensives
- •Karnofsky score < 70 for adult patients
- •Lansky-Play Performance Score < 50 for pediatric patients
- •DONOR: Bone marrow (BM) donors
- •DONOR: Donors who are HIV-positive and/or, medical conditions that would result in increased risk for granulocyte colony-stimulating factor (G-CSF) mobilization and harvest of peripheral blood stem cell (PBSC)
- •DONOR: Donors < 12 years of age
研究组 & 干预措施
Treatment (dose-escalation of alemtuzumab, HSCT)
CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 2 hours on days -8 to -5 and fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0.
HSCT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
IMMUNOSUPPRESSION: Patients receive CSP IV or PO BID on days -3 to 180 with taper to day 365 and MMF PO TID on days 0-100, with taper to day 156.
干预措施: alemtuzumab (Biological)
Treatment (dose-escalation of alemtuzumab, HSCT)
CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 2 hours on days -8 to -5 and fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0.
HSCT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
IMMUNOSUPPRESSION: Patients receive CSP IV or PO BID on days -3 to 180 with taper to day 365 and MMF PO TID on days 0-100, with taper to day 156.
干预措施: fludarabine phosphate (Drug)
Treatment (dose-escalation of alemtuzumab, HSCT)
CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 2 hours on days -8 to -5 and fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0.
HSCT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
IMMUNOSUPPRESSION: Patients receive CSP IV or PO BID on days -3 to 180 with taper to day 365 and MMF PO TID on days 0-100, with taper to day 156.
干预措施: total-body irradiation (Radiation)
Treatment (dose-escalation of alemtuzumab, HSCT)
CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 2 hours on days -8 to -5 and fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0.
HSCT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
IMMUNOSUPPRESSION: Patients receive CSP IV or PO BID on days -3 to 180 with taper to day 365 and MMF PO TID on days 0-100, with taper to day 156.
干预措施: allogeneic hematopoietic stem cell transplantation (Procedure)
Treatment (dose-escalation of alemtuzumab, HSCT)
CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 2 hours on days -8 to -5 and fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0.
HSCT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
IMMUNOSUPPRESSION: Patients receive CSP IV or PO BID on days -3 to 180 with taper to day 365 and MMF PO TID on days 0-100, with taper to day 156.
干预措施: peripheral blood stem cell transplantation (Procedure)
Treatment (dose-escalation of alemtuzumab, HSCT)
CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 2 hours on days -8 to -5 and fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0.
HSCT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
IMMUNOSUPPRESSION: Patients receive CSP IV or PO BID on days -3 to 180 with taper to day 365 and MMF PO TID on days 0-100, with taper to day 156.
干预措施: mycophenolate mofetil (Drug)
Treatment (dose-escalation of alemtuzumab, HSCT)
CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 2 hours on days -8 to -5 and fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0.
HSCT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
IMMUNOSUPPRESSION: Patients receive CSP IV or PO BID on days -3 to 180 with taper to day 365 and MMF PO TID on days 0-100, with taper to day 156.
干预措施: cyclosporine (Drug)
结局指标
主要结局
Evaluate the Risk of Transplant Related Mortality.
时间窗: 100 days after transplant
Percentage patients with Day 100 transplant related mortality.
Evaluate the Risk of Occurrence of Acute and Chronic GVHD
时间窗: 1 year after transplant
Percentage patients who developed acute/chronic GVHD. aGVHD Stages Skin: 1. a maculopapular eruption involving \< 25% BSA 2. a maculopapular eruption involving 25 - 50% BSA 3. generalized erythroderma 4. generalized erythroderma with bullous formation and often with desquamation Liver: 1. bilirubin 2.0 - 3.0 mg/100 mL 2. bilirubin 3 - 5.9 mg/100 mL 3. bilirubin 6 - 14.9 mg/100 mL 4. bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade III: Stage 2 - 4 gastrointestinal involvement and/or +2 to +4 liver involvement, with or without a rash Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death
Determine Whether Engraftment Can be Maintained With a Single Dose Fludarabine, DLI and Continued MMF/CSP, Defined as Rejection Rate < 20%.
时间窗: 100 days after transplant
Mixed chimerism will be defined as the detection of donor T cells (CD3+) and granulocytes (CD 33+), as a proportion of the total T cell and granulocyte population, respectively, of greater than 5% and less than 95% in the peripheral blood. Full donor chimerism is defined as \> 95% donor CD3+ T cells.
次要结局
- Evaluate the Risk for Disease Progression and Relapse(1 year after transplant)
- Evaluate the Risk/Incidence of Infections(100 days after transplant)
研究者
Brenda Sandmaier
Principal Investigator
Fred Hutchinson Cancer Center