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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Lymphoblastic Leukemia in Remission, 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 Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Ringed Sideroblasts, Refractory Cytopenia With Multilineage Dysplasia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes

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Trial Information

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


OBJECTIVES:

I. To determine the maximum tolerated dose of radiation delivered via 131 I-BC8 antibody
(iodine I 131monoclonal 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 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.

RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via
central line on day -14.

NONMYELOABLATIVE CONDITIONING: Patients receive FLU intravenously (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, MM IV
or orally (PO) three times daily on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on
days 4 to 180 with taper on day 84 .

Treatment continues in the absence of disease progression or unacceptable toxicity.

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


Inclusion Criteria:



- 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 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

Exclusion Criteria:

- 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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of iodine I 131 monoclonal antibody BC8

Outcome Description:

Occurrence of grade III/IV regimen related toxicities (Bearman scale)

Outcome Time Frame:

Through day 100

Safety Issue:

Yes

Principal Investigator

John Pagel

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

2186.00

NCT ID:

NCT00589316

Start Date:

October 2007

Completion Date:

Related Keywords:

  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • Adult Acute Lymphoblastic Leukemia in Remission
  • 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 Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Refractory Anemia With Excess Blasts
  • Refractory Anemia With Ringed Sideroblasts
  • Refractory Cytopenia With Multilineage Dysplasia
  • Secondary Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Congenital Abnormalities
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109