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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


Phase 2
16 Years
50 Years
Open (Enrolling)
Both
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 Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes

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Trial Information

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


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-CD45
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 total
body irradiation (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 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 times daily on days 0 to 27. Patients with a matched
unrelated donor receive cyclosporine IV or PO twice daily 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 3 times daily 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.


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 cluster of differentiation (CD)45-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) criteria for 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 DQB; 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

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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Incidence of dose-limiting toxicities to determine MTD of radiation delivered to normal organ by iodine I 131 monoclonal antibody BC8

Outcome Description:

Escalation by 2 Gy increments will occur until a patient experiences a Grade III/IV regimen-related toxicity (Bearman) or dose-limiting toxicity (DLT), at which point the second stage will begin at the next lower dose level. Estimated to be the dose that is associated with a toxicity rate of 25%.

Outcome Time Frame:

Up to 100 days post transplant

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:

1809.00

NCT ID:

NCT00119366

Start Date:

May 2003

Completion Date:

Related Keywords:

  • 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 Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Congenital Abnormalities
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute
  • Anemia, Aplastic

Name

Location

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