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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

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00008177
First Posted: December 12, 2003
Last Update Posted: November 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
  Purpose
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.

Condition Intervention Phase
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 Radiation: iodine I 131 monoclonal antibody BC8 Radiation: total-body irradiation Procedure: allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Drug: fludarabine phosphate Drug: cyclosporine Drug: mycophenolate mofetil Other: laboratory biomarker analysis Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

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 [ Time Frame: Up to day 100 following transplant ]
  • Rates of donor chimerism resulting from this combined preparative regimen [ Time Frame: Up to day 84 following transplant ]
    Correlated with estimated radiation doses delivered to hematopoietic tissues via antibody.

  • Disease response [ Time Frame: Up to 11 years ]
  • Duration of remission [ Time Frame: Up to 11 years ]
  • incidence of DLT at the estimated MTD of 131I-BC8 [ Time Frame: Up to day 100 following transplant ]

Enrollment: 79
Actual Study Start Date: July 27, 1999
Primary Completion Date: March 21, 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment ( I 131 BC8, chemotherapy, TBI, PBSCT, CSP, MMF)

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.

Radiation: iodine I 131 monoclonal antibody BC8
Given IV
Other Names:
  • I 131 MOAB BC8
  • I 131 Monoclonal Antibody BC8
  • iodine I 131 MOAB BC8
Radiation: total-body irradiation
Undergo total-body irradiation
Other Name: TBI
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic peripheral blood stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic peripheral blood stem cell transplantation
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclosporine
Given orally or IV
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given orally or IV
Other Names:
  • Cellcept
  • MMF
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   50 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00008177


Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Johnnie Orozco Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00008177     History of Changes
Other Study ID Numbers: 1432.00
NCI-2010-02046 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
1432
1432.00 ( Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
P01CA044991 ( U.S. NIH Grant/Contract )
First Submitted: January 6, 2001
First Posted: December 12, 2003
Last Update Posted: November 8, 2017
Last Verified: November 2017

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Anemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Chronic
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Anemia, Aplastic
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Antibodies
Immunoglobulins
Fludarabine phosphate
Antibodies, Monoclonal
Cyclosporins
Cyclosporine
Fludarabine
Mycophenolic Acid
Vidarabine
Iodine
Immunologic Factors