Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

Study Overview
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Brief Summary
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This phase II trial studies the side effects and best dose of iodine I 131 monoclonal antibody BC8 when given together with fludarabine phosphate, total-body irradiation, and donor stem cell transplant followed by cyclosporine and mycophenolate mofetil in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. Giving chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell 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 fludarabine phosphate and total-body irradiation before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Giving a radiolabeled monoclonal antibody together with donor stem cell transplant, cyclosporine, and mycophenolate mofetil may be an effective treatment for advanced acute myeloid leukemia or myelodysplastic syndromes.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the maximum tolerated dose (MTD) and the transplant-related mortality (TRM) and toxicity of delivering 131I-BC8 (iodine I 131 monoclonal antibody BC8) (anti-cluster of differentiation [CD]45 antibody) at a starting dose of 22 Gy to the normal organ receiving the highest dose in combination with the non-myeloablative regimen of fludarabine (fludarabine phosphate) (FLU), 2 Gy total body irradiation (TBI), cyclosporine (CSP), mycophenolate mofetil (MMF), and human leukocyte antigen (HLA)-matched related or unrelated allogeneic hematopoietic stem cell transplant (HSCT) in patients 16 to 50 years old who have advanced acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS). II. To estimate rates of donor chimerism resulting from this combined preparative regimen and to correlate level of donor chimerism with estimated radiation doses delivered to hematopoietic tissues via antibody. III. To determine rates of disease relapse, graft vs. host disease, and 2-year disease-free survival in patients receiving 131I-BC8 antibody combined with FLU, 2 Gy TBI, CSP, MMF, and HLA-matched related or unrelated allogeneic HSCT. OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8. RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 intravenously (IV) on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or orally (PO) twice daily (BID) on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO thrice daily (TID) on days 0 to 40 followed by a taper to day 96. After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24 months and then annually thereafter.

Official Title
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A Phase II Trial Combining Radiolabeled BC8 (Anti-CD45) Antibody With Fludarabine and Low Dose TBI Followed by Related or Unrelated PBSC Infusion and Post-Transplant Immunosuppression for Patients With Advanced AML or High Risk Myelodysplastic Syndrome

Conditions
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Secondary Acute Myeloid Leukemia, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Childhood Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Excess Blasts in Transformation, Refractory Anemia With Ringed Sideroblasts, Refractory Cytopenia With Multilineage Dysplasia, Secondary Myelodysplastic Syndromes

Intervention / Treatment
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* Radiation: iodine I 131 monoclonal antibody BC8
* Drug: fludarabine phosphate
* Radiation: total-body irradiation
* Procedure: allogeneic hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation
* Drug: cyclosporine
* Drug: mycophenolate mofetil
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with advanced AML 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 anemia with excess blasts in transformation (RAEBT), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML) Patients not in remission must have CD45-expressing leukemic blasts or myelodysplastic cells; 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 an estimated creatinine clearance greater than 50/ml per minute (serum creatinine value must be within 28 days prior to registration) 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 an HLA-identical sibling donor or an HLA-matched unrelated donor who meets standard Seattle Cancer Care Alliance (SCCA) and/or National Marrow Donor Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC) donation; related donors should be matched by molecular methods at the intermediate resolution level at HLA-A, B, C, and developmentally regulated RNA binding protein 1 (DRB1) according to Fred Hutchinson Cancer Research Center (FHCRC) Standard Practice Guidelines and to the allele level at DQB1; unrelated donors should be identified using matching criteria that follows the FHCRC Standard Practice Guidelines limiting the study to eligible donors that are allele matched for HLA-A, B, C, DRB1, and DQB1 (grade 1), and accepting up to one allele mismatch as per Standard Practice grade 2.1 for HLA-A, B, or C DONOR: Donors must meet HLA matching criteria as well as standard SCCA and/or NMDP or other donor center criteria for PBSC donation Exclusion Criteria: Circulating antibody against mouse immunoglobulin (human anti-mouse antibody [HAMA]) Prior radiation to maximally tolerated levels to any normal organ Patients may not have symptomatic coronary artery disease and may not be on cardiac medications for anti-arrhythmic or inotropic effects Inability to understand or give an informed consent Patients who are seropositive for human immunodeficiency virus (HIV) Perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation Patients who have previously undergone autologous or allogeneic HSCT

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This study will assess the feasibility and safety of patients with advanced AML or high-risk MDS treated with Iodine-131 BC8 antibody at a starting dose of 22 Gy delivered to the normal organ receiving the highest dose combined with fludarabine and 2 Gy total body irradiation (TBI), plus cyclosporine (CSP)/mycophenolate mofetil (MMF), followed by matched related or unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Determination of the maximum tolerated dose (MTD) will be the major study endpoint. Dose-escalation/de-escalation of radiolabeled BC8 antibody (I-131-BC8) is conducted using a two-stage approach. Under this plan, dose levels during the first stage are increased (or decreased) for individual patients until a dose-limiting toxicity (DLT) is observed, at which point the second stage proceeds with each dose level administered to a cohort of four patients.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1: 12 Gy iodine-131 monoclonal antibody BC8<br>RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. | Radiation: iodine I 131 monoclonal antibody BC8<br>* Given IV<br>* Other names: iodine I 131 MOAB BC8;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Undergo TBI<br>* Other names: TBI;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Undergo PBSC transplantation<br>Procedure: peripheral blood stem cell transplantation<br>* Undergo PBSC transplantation<br>* Other names: transplantation, peripheral blood stem cell;Drug: cyclosporine<br>* Given IV or PO<br>* Other names: Sandimmune;Drug: mycophenolate mofetil<br>* Given PO<br>* Other names: MMF;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Dose Level 7: 22 Gy iodine-131 monoclonal antibody BC8<br>RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. | Radiation: iodine I 131 monoclonal antibody BC8<br>* Given IV<br>* Other names: iodine I 131 MOAB BC8;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Undergo TBI<br>* Other names: TBI;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Undergo PBSC transplantation<br>Procedure: peripheral blood stem cell transplantation<br>* Undergo PBSC transplantation<br>* Other names: transplantation, peripheral blood stem cell;Drug: cyclosporine<br>* Given IV or PO<br>* Other names: Sandimmune;Drug: mycophenolate mofetil<br>* Given PO<br>* Other names: MMF;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Dose Level 8: 24 Gy iodine-131 monoclonal antibody BC8<br>RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. | Radiation: iodine I 131 monoclonal antibody BC8<br>* Given IV<br>* Other names: iodine I 131 MOAB BC8;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Undergo TBI<br>* Other names: TBI;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Undergo PBSC transplantation<br>Procedure: peripheral blood stem cell transplantation<br>* Undergo PBSC transplantation<br>* Other names: transplantation, peripheral blood stem cell;Drug: cyclosporine<br>* Given IV or PO<br>* Other names: Sandimmune;Drug: mycophenolate mofetil<br>* Given PO<br>* Other names: MMF;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Dose Level 9: 26 Gy iodine-131 monoclonal antibody BC8<br>RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. | Radiation: iodine I 131 monoclonal antibody BC8<br>* Given IV<br>* Other names: iodine I 131 MOAB BC8;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Undergo TBI<br>* Other names: TBI;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Undergo PBSC transplantation<br>Procedure: peripheral blood stem cell transplantation<br>* Undergo PBSC transplantation<br>* Other names: transplantation, peripheral blood stem cell;Drug: cyclosporine<br>* Given IV or PO<br>* Other names: Sandimmune;Drug: mycophenolate mofetil<br>* Given PO<br>* Other names: MMF;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Dose Level 10: 28 Gy iodine-131 monoclonal antibody BC8<br>RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. | Radiation: iodine I 131 monoclonal antibody BC8<br>* Given IV<br>* Other names: iodine I 131 MOAB BC8;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Undergo TBI<br>* Other names: TBI;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Undergo PBSC transplantation<br>Procedure: peripheral blood stem cell transplantation<br>* Undergo PBSC transplantation<br>* Other names: transplantation, peripheral blood stem cell;Drug: cyclosporine<br>* Given IV or PO<br>* Other names: Sandimmune;Drug: mycophenolate mofetil<br>* Given PO<br>* Other names: MMF;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLT) 100 Days After 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. | Up to 100 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Transplant Related Mortality Within 100 Days After Transplant | Number of participants that received and completed study treatment who died within 100 days after transplant | Up to 100 days post-transplant | 
| Participant Disease Response Within 4 Weeks After Transplant | The number of participants that are in complete remission (CR) or relapsed within 4 weeks after transplant. Complete Remission is defined as complete resolution of all signs of leukemia for at least four weeks with all of the following: Normal bone marrow with blasts <5% with normal cellularity, normal megakarypoiesis, more than 15% erythropoiesis and more than 25% granulocytopoiesis. Normalization of blood counts (no blasts, platelets >100,000/mm3, granulocytes >1,500/mm3). No extramedullary disease. Relapse is measured as follows: After CR: >5% blasts in the bone marrow and/or peripheral blood. Confirmation of relapse by bone marrow analysis with more than 10% blasts. Extramedullary disease confirmed cytologically or histologically. | 4 weeks after transplant | 
| Severity of Acute GVHD in Patients Who Completed the Study Treatment | The severity of acute GVHD is measured based on Graft-vs-Host Disease: Severity of GVHD Grade I +1 to +2 skin rash No gut or liver involvement Grade II +3 skin rash or 1 gastrointestinal involvement and/or +1 liver involvement Grade III +2 to +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 | 100 days after transplant | 
| Number of Participants With 100% Donor Chimerism at Day 28 and Day 84 | Post-transplant bone marrow samples were collected on day 28 and day 84 after transplant for DNA Chimerism Analysis | Day 28 and Day 80 after transplant | 
| Two-year Disease-free Survival of Study Participants Who Completed the Study Regimen | Survival and complete resolution of all signs of leukemia for 2 years after transplant with all of the following: Normal bone marrow with blasts <5% with normal cellularity, normal megakarypoiesis, more than 15% erythropoiesis and more than 25% granulocytopoiesis. Normalization of blood counts (no blasts, platelets >100,000/mm3, granulocytes >1,500/mm3). No extramedullary disease. | 2 years post transplant |