Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8 Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia or Myelodysplastic Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01300572
First received: February 15, 2011
Last updated: August 29, 2014
Last verified: August 2014
  Purpose

This phase I trial studies the side effects and maximum tolerated dose of yttrium Y 90 anti-CD45 monoclonal antibody BC8 (90Y-BC8) followed by donor peripheral blood stem cell transplant (PBSC) in treating patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Giving chemotherapy drugs, such as fludarabine phosphate (FLU), and total-body irradiation (TBI) before a donor PBSC 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. Radiolabeled monoclonal antibodies, such as 90Y-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 FLU, 90Y-BC8, and TBI before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.


Condition Intervention Phase
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)
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Myeloid Leukemia
Refractory Anemia With Excess Blasts
Secondary Acute Myeloid Leukemia
Radiation: yttrium Y 90 anti-CD45 monoclonal antibody BC8
Biological: indium In 111 anti-CD45 monoclonal antibody BC8
Drug: fludarabine phosphate
Drug: cyclosporine
Drug: mycophenolate mofetil
Radiation: total-body irradiation
Procedure: peripheral blood stem cell transplantation
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: bone marrow transplantation
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Study Evaluating Escalating Doses of 90Y-DOTA-BC8 (Anti-CD45) Antibody Followed by Allogeneic Stem Cell Transplantation for High-Risk Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Proportion of patients who develop grades III/IV Bearman toxicity [ Time Frame: Within the first 100 days following transplant ] [ Designated as safety issue: Yes ]
    Assessed according to Bearman scale for Regimen-Related Toxicities. Two-parameter logistic model will be fit to the data, thereby generating a dose-response curve based on the observed toxicity rate at the various dose levels visited.


Secondary Outcome Measures:
  • Rates of engraftment [ Time Frame: Up to 84 days post-transplant ] [ Designated as safety issue: No ]
  • Rates of donor chimerism [ Time Frame: Up to 84 days post-transplant ] [ Designated as safety issue: No ]
  • Rates of non-relapse mortality [ Time Frame: Within the first 100 days following transplant ] [ Designated as safety issue: No ]
  • Rates of acute GvHD [ Time Frame: Up to 84 days post-transplant ] [ Designated as safety issue: No ]
  • Achievement of remission [ Time Frame: Prior to day 100 post-transplant ] [ Designated as safety issue: No ]
  • Duration of remission [ Time Frame: Prior to day 100 post-transplant ] [ Designated as safety issue: No ]
  • Duration of remission [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Disease-free survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Estimation of absorbed radiation doses to normal organs, marrow and tumor [ Time Frame: Approximately day -20 to day -12 prior to transplant ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: January 2012
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (radiolabeled monoclonal antibody, allogeneic HSCT)

PREPARATIVE REGIMEN: Patients receive 90Y-BC8 via central line on day -12, fludarabine phosphate IV over 30 minutes on days -4 to -2, and 2 Gy TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSC or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients receive mycophenolate mofetil IV every 12 hours on days 0-27 (for patients with related donors) or every 8 hours on days 0-40 with taper to day 96 (for patients with unrelated donors). Patients also receive cyclosporine PO every 12 hours on days -3 to 56 (for patients with related donors) or 100 (for patients with unrelated donors) with taper to day 180.

Radiation: yttrium Y 90 anti-CD45 monoclonal antibody BC8
Given via central line (therapeutic dose)
Other Names:
  • 90Y anti-CD45 MAb BC8
  • 90Y anti-CD45 MoAb BC8
Biological: indium In 111 anti-CD45 monoclonal antibody BC8
Given IV (dosimetric dose)
Other Names:
  • In 111 MOAB BC8
  • In 111 monoclonal antibody BC8
  • In111 MOAB BC8
  • indium In 111 MOAB BC8
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclosporine
Given PO or IV
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given PO or IV
Other Names:
  • Cellcept
  • MMF
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic PBSC transplant and allogeneic hematopoietic stem cell transplant
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Procedure: bone marrow transplantation
Undergo BMT
Other Names:
  • BMT
  • transplantation, bone marrow

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of radiation delivered via 90Y-DOTA-BC8 (90Y-BC8) antibody (Ab) when combined with FLU and 2 Gy TBI as a preparative regimen for patients aged >= 50 with advanced AML and high-risk MDS.

SECONDARY OBJECTIVES:

I. To determine disease response and duration of remission.

II. To determine the rates of engraftment and 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.

OUTLINE:

PREPARATIVE REGIMEN: Patients receive 90Y-BC8 via central line on day -12 and FLU intravenously (IV) over 30 minutes on days -4 to -2.

TRANSPLANTATION: Patients undergo TBI followed by allogeneic PBSC or bone marrow transplant on day 0.

GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive mycophenolate mofetil IV every 12 hours on days 0-27 (for patients with related donors) or every 8 hours on days 0-40 with taper to day 96 (for patients with unrelated donors). Patients also receive cyclosporine orally (PO) every 12 hours on days -3 to 56 (for patients with related donors) or 100 (for patients with unrelated donors) with taper to day 180.

After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24 months, and then annually thereafter.

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have advanced AML or high-risk MDS meeting one of the following descriptions:

    • AML beyond first remission (i.e., having relapsed at least one time after achieving remission in response to a treatment regimen)
    • AML representing primary refractory disease (i.e., having failed to achieve remission at any time following one or more prior treatment regimens)
    • AML evolved from MDS or myeloproliferative syndromes; or
    • MDS expressed as refractory anemia with excess blasts (RAEB)
  • 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 must be >= 50 years of age
  • 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
  • Bilirubin < 2 times the upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine transaminase (ALT) < 2 times the upper limit of normal
  • 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 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) or other donor center criteria for PBSC or bone marrow donation, as follows:

    • Sibling donor; a patient and sibling donor should be matched for HLA-A, B, C, DRB1 and DQB1 by an intermediate resolution deoxyribonucleic acid (DNA)-based method
    • Unrelated donor; an unrelated donor and recipient should be typed by a high resolution DNA-based method, and ideally matched for HLA-A, B, C, DRB1 and DQB1 alleles, or if there is only a single locus disparity mismatched for an HLA-DQB1 antigen or allele; an unrelated donor may also be mismatched for any single 1) one HLA-A, B or C antigen or allele, or 2) a single DR antigen or 3) a single DQ antigen or allele or 4) HLA-DRB1 allele (with or without matching for HLA-DQB1)
  • DONOR: Donors must meet HLA matching criteria and standard SCCA and/or National Marrow Donor Program (NMDP) or other donor center criteria for PBSC or bone marrow donation

Exclusion Criteria:

  • Circulating human anti-mouse antibody (HAMA)
  • Prior radiation to maximally tolerated levels to any critical normal organ, or > 20 Gy prior radiation to large areas of the bone marrow (e.g., external radiation therapy to whole pelvis)
  • 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 lung capacity of carbon monoxide (DLCO) < 35% 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 to be seropositive for human immunodeficiency virus (HIV)
  • Perceived inability to tolerate diagnostic or therapeutic procedures
  • Active central nervous system (CNS) leukemia at time of treatment
  • Women of childbearing potential who are pregnant (beta-human chorionic gonadotrophin [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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01300572

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: John M. Pagel    206-667-1868      
Principal Investigator: John M. Pagel         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: John Pagel Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01300572     History of Changes
Other Study ID Numbers: 2468.00, NCI-2011-00150, P30CA015704, P01CA044991, 2468.00, P01CA044991, P30CA015704
Study First Received: February 15, 2011
Last Updated: August 29, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on October 16, 2014