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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


Phase 1
50 Years
N/A
Open (Enrolling)
Both
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

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Trial Information

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


OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of radiation delivered via 131I-BC8
antibody when combined with the non-myeloablative regimen of fludarabine, 2 Gy total-body
irradiation (TBI) + cyclosporine (CSP)/mycophenolate (MMF) in elderly patients with advanced
acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (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 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 or IV twice daily 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 orally or IV three times a day 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.


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 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 CD45 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 (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 undergo a 24-hour urine collection with documented creatinine clearance
> 50 ml/min

- Patients must have normal hepatic function (bilirubin, AST and ALT < 2 times the
upper limit of normal)

- Karnofsky score >= 70 or 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 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 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 HSC source

- DONOR: Donors must meet HLA matching criteria as outlined above as well as standard
SCCA and/or NMDP criteria for PBSC donation

Exclusion Criteria:

- Circulating antibody against mouse immunoglobulin (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 HIV

- Perceived inability to tolerate diagnostic or therapeutic procedures, particularly
treatment in radiation isolation

- Patients who have previously undergone marrow or PBSC transplantation

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 radiation delivered via 131I-BC8 antibody when combined with the nonmyeloablative regimen of fludarabine, TBI, and CSP/MMF

Outcome Time Frame:

Through day 100 following 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:

1432.00

NCT ID:

NCT00008177

Start Date:

July 1999

Completion Date:

Related Keywords:

  • 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
  • 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