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A Multi-Center Phase III Study Comparing Nonmyeloablative Conditioning With TBI Versus Fludarabine/TBI for HLA-matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies


Phase 3
N/A
75 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 Chronic Myelogenous Leukemia, Childhood Myelodysplastic Syndromes, Chronic Phase Chronic Myelogenous Leukemia, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Childhood Large Cell Lymphoma, Recurrent Childhood Lymphoblastic Lymphoma, Recurrent Childhood Small Noncleaved Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Recurrent/Refractory Childhood Hodgkin Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Multiple Myeloma, Relapsing Chronic Myelogenous Leukemia, Splenic Marginal Zone Lymphoma

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Trial Information

A Multi-Center Phase III Study Comparing Nonmyeloablative Conditioning With TBI Versus Fludarabine/TBI for HLA-matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies


PRIMARY OBJECTIVES:

I. To compare overall survival at 3 years after conditioning with 200 cGy TBI alone vs.
fludarabine/200 cGy TBI in heavily pretreated patients with hematologic malignancies at
low/moderate risk for graft rejection.

SECONDARY OBJECTIVES:

I. To compare the non-relapse mortality 1-year after conditioning in patients who received
TBI alone vs. fludarabine/TBI.

II. To compare the incidences of graft rejection in patients who received TBI alone vs.
fludarabine/TBI.

III. To compare the incidences of grades II-IV acute graft-versus-host disease (GVHD) and
chronic extensive GVHD.

IV. To compare rates of disease progression and/or relapse-related mortality. V. To compare
the immune reconstitution and the risks of infections.

OUTLINE:

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2. Patients
then undergo low-dose TBI on day 0.

ARM II: Patients undergo low-dose TBI on day 0.

ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTATION (PBSCT): After TBI, patients undergo
PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to
56 in the absence of GVHD. Patients with no evidence of GVHD at day 56 begin a cyclosporine
taper and continue the taper until day 180. Patients with evidence of disease progression
and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks.
Patients also receive mycophenolate mofetil (MMF) PO BID on days 0-28 in the absence of
GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid
taper begins.

Patients are followed up periodically for 1.5 years and then annually for 5 years
post-transplantation.


Inclusion Criteria:



- Patients must be not eligible for conventional allogeneic hematopoietic cell
transplantation (HCT) and must have disease expected to be stable for at least 100
days without chemotherapy

- An autograft immediately prior (less than 6 months) to nonmyeloablative HCT (tandem
approach) is not permitted

- Patients with hematologic malignancies treatable with HCT or with a B cell malignancy
except those curable with autologous transplant will be included

- Aggressive Non-Hodgkin lymphomas (NHLs) and Other Histologies such as Diffuse large B
cell NHL: patients are eligible IF they are not eligible for autologous hematopoietic
stem cell transplantation (HSCT), not eligible for conventional myeloablative HSCT,
or have failed an autologous HSCT

- Low grade NHL with < 6 month duration of complete remission (CR) between courses of
conventional therapy

- Mantle Cell NHL; may be treated in first CR

- Chronic lymphocytic leukemia (CLL) must have either:

- Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or
partial response after therapy with a regimen containing FLU (or another nucleoside
analog, e.g. 2-CDA, pentostatin) or experience disease relapse within 12 months after
completing therapy with a regimen containing FLU (or another nucleoside analog) -
Failed FLU-CY-Rituximab (FCR) combination chemotherapy at any time point

- Have "17p deletion" cytogenetic abnormality; patients should have received induction
chemotherapy but could be transplanted in 1st CR

- Or patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of
CLL that progresses to prolymphocytic leukemia (PLL), or T-Cell CLL or PLL

- Hodgkin lymphoma (HL): must have received and failed frontline therapy; patients must
have failed or were not eligible for autologous transplant

- Multiple myeloma (MM): must have chemosensitive disease after failed autografting (an
autografting immediately prior [within 6 months] to nonmyeloablative HCT [tandem
approach] is not permitted)

- Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant
and be beyond first CR

- Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of
transplant and be beyond first CR

- Chronic myelogenous leukemia (CML): patients will be accepted in CP beyond CP1 if
they have received previous myelosuppressive chemotherapy or HCT, < 5% marrow blasts
at time of transplant

- Myelodysplastic syndromes (MDS)/myeloproliferative disorders (MPD): must have
received previous myelosuppressive chemotherapy or HCT, < 5% marrow blasts at time of
transplant

- Waldenstroms Macroglobulinemia: must have failed 2 courses of therapy

- Patients will not be allowed to receive myelosuppressive chemotherapy for three weeks
prior to conditioning

- Patients < 12 years old must be approved by both the participating institutions'
patient review committee such as the Patient Care Conference (PCC) at the Fred
Hutchinson Cancer Research Center (FHCRC) and the FHCRC principal investigator

- Patients who refused to be treated on a conventional HCT protocol; for this inclusion
criterion, transplants must be approved by both the participating institution's
patient review committee such as the Patient Care Conference (PCC) at the FHCRC and
the FHCRC principal investigator

- Patients with human leukocyte antigen (HLA)-matched related donors

- DONOR: Related donor who is HLA genotypically identical at least at one haplotype and
may be phenotypically or genotypically identical at the allele level at HLA-A, -B,
-C, -DRB1, and -DQB1

- DONOR: Donor must consent to G-CSF administration and leukapheresis

- DONOR: Donor must have adequate veins for leukapheresis or agree to placement of
central venous catheter (femoral, subclavian)

- DONOR: For females of child bearing age, serum pregnancy qualitative (PGSTAT) within
72 hours prior to initial dose of filgrastim (G-CSF); results must be available prior
to filgrastim

Exclusion Criteria:

- Eligible for a high priority curative autologous transplant

- Patients with rapidly progressive, aggressive NHL unless in minimal disease state

- Patients with chronic myelomonocytic leukemia

- Presence of circulating leukemic blasts (in the peripheral blood) detected by
standard pathology for patients with AML, ALL or CML

- Life expectancy severely limited by diseases other than malignancy

- Any current central nervous system (CNS) involvement with disease refractory to
intrathecal chemotherapy

- Fertile men or women unwilling to use contraceptives during and for up to 12 months
post treatment

- Female patients who are pregnant or breastfeeding

- Human immunodeficiency virus (HIV) positive patients

- Patients with active non-hematological malignancies (except localized non-melanoma
skin malignancies)

- Patients with a history of non-hematologic malignancies (except non-melanoma skin
cancers) currently in a complete remission, who are less than 5 years from the time
of complete remission, and have a > 20% risk of disease recurrence

- Fungal infections with radiological progression after receipt of amphotericin
formulation or mold-active azoles for greater than 1 month

- Patients with active bacterial or fungal infections unresponsive to medical therapy

- Karnofsky score < 50 for adult patients

- Lansky-Play Performance Score < 50 for pediatric patients

- The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine
kinase inhibitors (imatinib mesylate), cytokine therapy, hydroxyurea, low dose
cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the
initiation of conditioning

- Patients with the following organ dysfunction:

- Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac
failure requiring therapy (required for patients with history of cardiac disease or
anthracycline use); ejection fraction is required if age > 50 years or there is a
history of anthracycline exposure or history of cardiac disease

- Poorly controlled hypertension on multiple antihypertensives

- Pulmonary: diffusion capacity of carbon monoxide (DLCO) < 30%, total lung capacity
(TLC) < 30%, forced expiratory volume in one second (FEV1) < 30% and/or receiving
supplementary continuous oxygen; the FHCRC study principal investigator (PI) must
approve enrollment of all patients with pulmonary nodules

- Liver function abnormalities: patients with clinical or laboratory evidence of liver
disease would be evaluated for the cause of liver disease, its clinical severity in
terms of liver function, bridging fibrosis, and the degree of portal hypertension;
patients will be excluded if they are found to have fulminant liver failure,
cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis,
esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy,
uncorrectable hepatic synthetic dysfunction evinced by prolongation of the
prothrombin time, ascites related to portal hypertension, bacterial or fungal liver
abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3
mg/dL, and symptomatic biliary disease

- DONOR: Age less than 12 years

- DONOR: Identical twin

- DONOR: Pregnancy

- DONOR: Infection with HIV

- DONOR: Known allergy to filgrastim

- DONOR: Current serious systemic illness that would result in increased risk for
filgrastim mobilization and harvest of PBSC

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall survival

Outcome Time Frame:

At 3 years after transplant

Safety Issue:

No

Principal Investigator

Brenda Sandmaier

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Institutional Review Board

Study ID:

1813.00

NCT ID:

NCT00075478

Start Date:

October 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 Chronic Myelogenous Leukemia
  • Childhood Myelodysplastic Syndromes
  • Chronic Phase Chronic Myelogenous Leukemia
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Nodal Marginal Zone B-cell Lymphoma
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Recurrent Childhood Large Cell Lymphoma
  • Recurrent Childhood Lymphoblastic Lymphoma
  • Recurrent Childhood Small Noncleaved Cell Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Recurrent/Refractory Childhood Hodgkin Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Multiple Myeloma
  • Relapsing Chronic Myelogenous Leukemia
  • Splenic Marginal Zone Lymphoma
  • Congenital Abnormalities
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myeloid, Chronic-Phase
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Myelodysplastic Syndromes
  • Preleukemia
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell

Name

Location

LDS HospitalSalt Lake City, Utah  84143
Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109
VA Puget Sound Health Care SystemSeattle, Washington  98101
University of UtahSalt Lake City, Utah  
OHSU Cancer Institute-Southern RegionMedford, Oregon  97504
Froedtert and the Medical College of WisconsinMilwaukee, Wisconsin  53226