Hematopoietic Bone Marrow Transplantation for Patients With High-risk Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) Using Related HLA-Mismatched Donors: A Trial Using Radiolabeled Anti-CD45 Antibody Combined With Immunosuppression Before and After Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Number of Participants With Dose-limiting Toxicities (DLT) 30 Days After Transplant
研究概览
简要总结
This phase I trial studies the side effects and best dose of iodine I 131monoclonal antibody BC8 when given together with fludarabine phosphate, cyclophosphamide, total-body irradiation, and donor bone marrow transplant, and to see how well they work in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia that has spread to nearby or other places in the body (advanced), or high-risk myelodysplastic syndrome. Giving chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer or abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. Also, radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody BC8, can find cancer cells and carry 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 make an immune response against the body's normal cells. Giving cyclophosphamide together with mycophenolate mofetil and tacrolimus after the transplant may stop this from happening. Giving a radiolabeled monoclonal antibody together with donor stem cell transplant, fludarabine phosphate, cyclophosphamide, mycophenolate mofetil, and tacrolimus may be an effective treatment for advanced acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes.
详细描述
PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated dose of radiation delivered via 131 I-BC8 antibody (iodine I 131 monoclonal antibody BC8) when combined with pre- and post-transplant cyclophosphamide (CY), fludarabine phosphate (FLU), 2 Gy total-body irradiation (TBI), tacrolimus, mycophenolate mofetil (MMF), and a haploidentical allogeneic hematopoietic marrow transplant in patients who have advanced acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high risk myelodysplastic syndromes (MDS).
II. To estimate rates of immune reconstitution, engraftment, and donor chimerism resulting from this combined preparative regimen.
III. To determine rates of disease relapse, acute graft-versus-host disease (GVHD), and day 100 disease-free survival in patients receiving 131 I-BC8 antibody (Ab) combined with CY, FLU, 2 Gy TBI, tacrolimus, MMF, and human leukocyte antigen (HLA)-haploidentical allogeneic hematopoietic cell transplant (HCT).
OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with advanced AML or ALL defined as beyond first remission, primary refractory disease, or evolved from myelodysplastic or myeloproliferative syndromes; or patients with MDS expressed as refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML)
- •Patients not in remission must have cluster of differentiation (CD)45-expressing leukemic blasts; patients in remission do not require phenotyping and may have leukemia previously documented to be CD45 negative (because in remission patients, virtually all antibody binding is to non-malignant cells which make up >= 95% of nucleated cells in the marrow)
- •Patients should have a circulating blast count of less than 10,000/mm^3 (control with hydroxyurea or similar agent is allowed)
- •Patients must have a creatinine clearance greater than 50/ml per minute by the following formula (test must be performed within 28 days prior to registration):
- •Creatinine clearance (CrCl) = (140-age) (Wt in Kg) x 0.85 (female) OR 1.0 (male)/72 x serum Cr
- •Bilirubin < 2 times the upper limit of normal
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 times the upper limit of normal
- •Karnofsky score >= 70 or Eastern Cooperative Oncology Group (ECOG) =< 2
- •Patients must have an expected survival of > 60 days and must be free of active infection
- •Patients must have a related donor who is identical for one human leukocyte antigen (HLA) haplotype and mismatched at the HLA-A, -B or class II, DR beta 1 (DRB1) loci of the unshared haplotype with the exception of single HLA-A, -B or DRB1 mismatches
- •DONOR: Related donor who is identical for one HLA haplotype and mismatched at the HLA-A, -B, or DRB1 loci of the unshared haplotype with the exception of single HLA-A, -B, or DRB1 mismatches
排除标准
- •Circulating antibody against mouse immunoglobulin (HAMA)
- •Prior radiation to maximally tolerated levels to any critical normal organ
- •Cross-match positive with donor
- •Patients may not have symptomatic coronary artery disease and may not be on cardiac medications for anti-arrhythmic or inotropic effects
- •Left ventricular ejection fraction < 35%
- •Corrected diffusion capacity of carbon monoxide (DLCO) < 35% and/or receiving supplemental continuous oxygen
- •Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis, or symptomatic biliary disease
- •Patients who are known seropositive for human immunodeficiency virus (HIV)
- •Perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation
- •Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy and/or standard cranial-spinal radiotherapy
- •Women of childbearing potential who are pregnant (beta-human chorionic gonadotropin positive [b-HCG+]) or breast feeding
- •Fertile men and women unwilling to use contraceptives during and for 12 months post-transplant
- •Inability to understand or give an informed consent
研究组 & 干预措施
Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
干预措施: Allogeneic Bone Marrow Transplantation (Procedure)
Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
干预措施: Cyclophosphamide (Drug)
Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
干预措施: Fludarabine Phosphate (Drug)
Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
干预措施: Iodine I 131 Monoclonal Antibody BC8 (Radiation)
Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
干预措施: Mycophenolate Mofetil (Drug)
Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
干预措施: Tacrolimus (Drug)
Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
干预措施: Total-Body Irradiation (Radiation)
结局指标
主要结局
Number of Participants With Dose-limiting Toxicities (DLT) 30 Days After Transplant
时间窗: Up to 30 days post-transplant
The criteria of Grade III/IV regimen-related toxicity (Bearman) or dose-limiting toxicity (DLT) are as follows: Grade 1 Development of transient chemical abnormalities which are not of major clinical consequence and which reverse without requiring major medical interventions. In general, the intent of this toxicity scale is to observe transient target organ toxicity which is reversible. Grade 2 Development of chemical or laboratory abnormalities that are persistent and which may represent target organ damage that may not be readily reversed. It is anticipated that at this dose of the drug, the toxicity obtained would be manageable by clinical methods but may interfere with other therapies. Grade 3 Development of major clinical, chemical or laboratory abnormalities which represent maximum toxicities without being fatal. This grade of toxicity is designed to be the dose-limiting toxicity. Grade 4 Fatal
次要结局
- Number of Participants With 100% Donor Chimerism at Day 84(Day 84 after transplant)
- Number of Participants With Transplant-Related Mortality Within 100 Days After Transplant(Up to 100 days post-transplant)
- Participant Disease Response Within 90 Days After Transplant(Up to 90 days after transplant)
- Severity of Acute GVHD in Patients Who Completed the Study Treatment(100 days after transplant)
- Two-Year Disease-free Survival of Study Participants Who Completed the Study Regimen(2 years post-transplant)
研究者
Johnnie Orozco
Associate Professor
Fred Hutchinson Cancer Center