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Radiolabeled Monoclonal Antibody Therapy, Fludarabine Phosphate, and Low-Dose Total-Body Irradiation Followed by Donor Stem Cell Transplant and Immunosuppression Therapy in Treating Older Patients With Advanced Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

Primary Purpose

Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q)

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
iodine I 131 monoclonal antibody BC8
total-body irradiation
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation
fludarabine phosphate
cyclosporine
mycophenolate mofetil
laboratory biomarker analysis
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia in Remission

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 [Note: classification removed under current World Health Organization [WHO] classification system]), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML) Patients in relapse must have documented cluster of differentiation (CD)45 expression by their myelodysplastic or leukemic cells to be studied and treated with 131I-labeled BC8 antibody; patients in remission do not require phenotyping and may have leukemia previously documented to be CD45 negative Patients should have a circulating blast count of less than 10,000/mm^3 (control with hydroxyurea or similar agent is allowed) Patients must undergo a 24-hour urine collection with documented creatinine clearance > 50 ml/min 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 human leukocyte antigen (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) 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 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; PBSC is the only permitted hematopoietic stem cell (HSC) source DONOR: Donors must meet HLA matching criteria as outlined above as well as standard Seattle Cancer Care Alliance (SCCA) and/or NMDP 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 marrow or PBSC transplantation

Sites / Locations

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment ( I 131 BC8, chemotherapy, TBI, PBSCT, CSP, MMF)

Arm Description

CONDITIONING REGIMEN: Patients receive iodine I 131 monoclonal antibody BC8 IV on day -12 and fludarabine phosphate IV on days -4 to -2. Patients undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV BID on days -3 to 56 with taper to day 80 (for patients with a related donor) OR days -3 to 100 with taper to day 177 (for patients with an unrelated donor) in the absence of GVHD. Patients also receive mycophenolate mofetil PO or IV TID on days 0 to 27 (for patients with a related donor) OR on days 0 to 40 with taper to day 96 (for patients with an unrelated donor) in the absence of GVHD.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of radiation delivered via 131I-BC8 antibody when combined with the nonmyeloablative regimen of fludarabine phosphate, TBI, and CSP/MMF
Rates of donor chimerism resulting from this combined preparative regimen
Correlated with estimated radiation doses delivered to hematopoietic tissues via antibody.
Disease response
Duration of remission
incidence of DLT at the estimated MTD of 131I-BC8

Secondary Outcome Measures

Full Information

First Posted
January 6, 2001
Last Updated
November 8, 2019
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00008177
Brief Title
Radiolabeled Monoclonal Antibody Therapy, Fludarabine Phosphate, and Low-Dose Total-Body Irradiation Followed by Donor Stem Cell Transplant and Immunosuppression Therapy in Treating Older Patients With Advanced Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes
Official Title
A Phase I Study Combining Escalating Doses of Radiolabeled BC8 (Anti-CD45) Antibody With Fludarabine, Low Dose TBI, PBSC Infusion and Post-Transplant Immunosuppression With Cyclosporine and Mycophenolate Mofetil to Establish Mixed or Full Donor Chimerism for Elderly Patients With Advanced Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
July 27, 1999 (Actual)
Primary Completion Date
March 21, 2009 (Actual)
Study Completion Date
December 15, 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial studies the side effects and best dose of iodine I 131 monoclonal antibody BC8 when given together with fludarabine phosphate and low-dose total-body irradiation followed by donor stem cell transplant and immunosuppression therapy in treating older patients with acute myeloid leukemia or high-risk myelodysplastic syndromes that cannot be controlled with treatment. Radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them. Giving chemotherapy, 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. It may also stop the patient's immune system from rejecting the donor's stem 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. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving radiolabeled monoclonal antibody therapy together with fludarabine phosphate and total-body irradiation before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of radiation delivered via 131I-BC8 antibody (iodine I 131 monoclonal antibody BC8) when combined with the non-myeloablative regimen of fludarabine (fludarabine phosphate), 2 Gy total-body irradiation (TBI) + cyclosporine (CSP)/mycophenolate (MMF) in elderly patients with advanced acute myeloid leukemia (AML) or high risk myelodysplastic syndromes (MDS). II. To determine the 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, within the limits of a phase I study, disease response and duration of remission. IV. To assess dose-limiting toxicity (DLT) at the estimated maximum tolerated dose (MTD) of 131I-BC8 (24 Gy) in order to gain more confidence that the DLT rate is acceptable at this level. OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8. CONDITIONING REGIMEN: Patients receive iodine I 131 monoclonal antibody BC8 intravenously (IV) on day -12 and fludarabine phosphate IV on days -4 to -2. Patients undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) or IV twice daily (BID) on days -3 to 56 with taper to day 80 (for patients with a related donor) OR days -3 to 100 with taper to day 177 (for patients with an unrelated donor) in the absence of graft-versus-host disease (GVHD). Patients also receive mycophenolate mofetil PO or IV thrice daily (TID) on days 0 to 27 (for patients with a related donor) OR on days 0 to 40 with taper to day 96 (for patients with an unrelated donor) in the absence of GVHD. After completion of study treatment, patients are followed up at 6, 9, and 12 months, every 6 months for 1 year, and then yearly thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Myeloid Leukemia in Remission, 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), Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult 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, Untreated Adult Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
79 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment ( I 131 BC8, chemotherapy, TBI, PBSCT, CSP, MMF)
Arm Type
Experimental
Arm Description
CONDITIONING REGIMEN: Patients receive iodine I 131 monoclonal antibody BC8 IV on day -12 and fludarabine phosphate IV on days -4 to -2. Patients undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV BID on days -3 to 56 with taper to day 80 (for patients with a related donor) OR days -3 to 100 with taper to day 177 (for patients with an unrelated donor) in the absence of GVHD. Patients also receive mycophenolate mofetil PO or IV TID on days 0 to 27 (for patients with a related donor) OR on days 0 to 40 with taper to day 96 (for patients with an unrelated donor) in the absence of GVHD.
Intervention Type
Radiation
Intervention Name(s)
iodine I 131 monoclonal antibody BC8
Other Intervention Name(s)
I 131 MOAB BC8, I 131 Monoclonal Antibody BC8, iodine I 131 MOAB BC8
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
total-body irradiation
Other Intervention Name(s)
TBI
Intervention Description
Undergo total-body irradiation
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo allogeneic peripheral blood stem cell transplantation
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Intervention Description
Undergo allogeneic peripheral blood stem cell transplantation
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Other Intervention Name(s)
ciclosporin, cyclosporin, cyclosporin A, CYSP, Sandimmune
Intervention Description
Given orally or IV
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given orally or IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum tolerated dose of radiation delivered via 131I-BC8 antibody when combined with the nonmyeloablative regimen of fludarabine phosphate, TBI, and CSP/MMF
Time Frame
Up to day 100 following transplant
Title
Rates of donor chimerism resulting from this combined preparative regimen
Description
Correlated with estimated radiation doses delivered to hematopoietic tissues via antibody.
Time Frame
Up to day 84 following transplant
Title
Disease response
Time Frame
Up to 11 years
Title
Duration of remission
Time Frame
Up to 11 years
Title
incidence of DLT at the estimated MTD of 131I-BC8
Time Frame
Up to day 100 following transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 [Note: classification removed under current World Health Organization [WHO] classification system]), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML) Patients in relapse must have documented cluster of differentiation (CD)45 expression by their myelodysplastic or leukemic cells to be studied and treated with 131I-labeled BC8 antibody; patients in remission do not require phenotyping and may have leukemia previously documented to be CD45 negative Patients should have a circulating blast count of less than 10,000/mm^3 (control with hydroxyurea or similar agent is allowed) Patients must undergo a 24-hour urine collection with documented creatinine clearance > 50 ml/min 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 human leukocyte antigen (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) 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 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; PBSC is the only permitted hematopoietic stem cell (HSC) source DONOR: Donors must meet HLA matching criteria as outlined above as well as standard Seattle Cancer Care Alliance (SCCA) and/or NMDP 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 marrow or PBSC transplantation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Johnnie Orozco
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
19786617
Citation
Pagel JM, Gooley TA, Rajendran J, Fisher DR, Wilson WA, Sandmaier BM, Matthews DC, Deeg HJ, Gopal AK, Martin PJ, Storb RF, Press OW, Appelbaum FR. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009 Dec 24;114(27):5444-53. doi: 10.1182/blood-2009-03-213298. Epub 2009 Sep 28.
Results Reference
derived

Learn more about this trial

Radiolabeled Monoclonal Antibody Therapy, Fludarabine Phosphate, and Low-Dose Total-Body Irradiation Followed by Donor Stem Cell Transplant and Immunosuppression Therapy in Treating Older Patients With Advanced Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

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