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CAMPATH (ALEMTUZUMAB) DOSE ESCALATION, LOW-DOSE TBI AND FLUDARABINE FOLLOWED BY HLA CLASS II MISMATCHED DONOR STEM CELL TRANSPLANTATION FOR PATIENTS WITH HEMATOLOGIC MALIGNANCIES: A MULTICENTER TRIAL


Phase 2
N/A
74 Years
Open (Enrolling)
Both
Acute Undifferentiated Leukemia, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Childhood Burkitt Lymphoma, Childhood Chronic Myelogenous Leukemia, Childhood Diffuse Large Cell Lymphoma, Childhood Immunoblastic Large Cell Lymphoma, Childhood Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Chronic Phase Chronic Myelogenous Leukemia, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Intraocular Lymphoma, Juvenile Myelomonocytic Leukemia, Mast Cell Leukemia, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, 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, Secondary Myelodysplastic Syndromes, Splenic Marginal Zone Lymphoma, Testicular Lymphoma, Waldenström Macroglobulinemia

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Trial Information

CAMPATH (ALEMTUZUMAB) DOSE ESCALATION, LOW-DOSE TBI AND FLUDARABINE FOLLOWED BY HLA CLASS II MISMATCHED DONOR STEM CELL TRANSPLANTATION FOR PATIENTS WITH HEMATOLOGIC MALIGNANCIES: A MULTICENTER TRIAL


PRIMARY OBJECTIVES:

I. To determine which dose of Campath allows related and unrelated human leukocyte antigen
(HLA) class-II mismatched hematopoietic cell transplantation (HCT) with an incidence of
grade III-IV acute graft-versus-host disease (GVHD) less than 40%.

SECONDARY OBJECTIVES:

I. Incidence of graft rejection.

II. Number of days of steroids greater than or equal to 1mg/kg required before day 100 in
each patient.

III. Incidence of nonrelapse mortality.

IV. Risk/incidence of infections.

V. Immune reconstitution.

VI. Risk for disease progression and relapse.

OUTLINE: This is a dose-escalation study of alemtuzumab.

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab intravenously (IV) over
6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV
over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose total-body
irradiation (TBI) on day 0.

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

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) or IV every 12 hours on days -3
to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after
completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on
days 0 to 100 followed by a taper until day 156 in the absence of GVHD.

After completion of study treatment, patients are followed periodically for 12 months, at 18
months, and then annually for 5 years.


Inclusion Criteria:



- The patient must be not eligible for conventional transplants and must have disease
expected to be stable for at least 100 days without chemotherapy

- Patients with hematologic malignancies treatable with HCT will be included:

- Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as Diffuse
Large B-cell NHL: not eligible for autologous HCT, not eligible for conventional
myeloablative HCT, or after failed autologous HCT;

- Low Grade NHL: with < 6 month duration of complete response (CR) between courses
of conventional therapy;

- Mantle Cell NHL: may be treated in first CR;

- Chronic lymphocytic leukemia (CLL): must have failed 2 lines of conventional
therapy and must be refractory to fludarabine (this includes patients who fail
to have a complete or partial response after therapy with a regimen containing
fludarabine [or another nucleoside analog] or experience disease relapse within
12 months after completing therapy with a regimen containing fludarabine [or
another nucleoside analog]);

- Hodgkin's disease (HD): must have received and failed frontline therapy and have
failed or were not eligible for autologous transplant;

- Multiple myeloma (MM): must have received prior chemotherapy or failed
autografting; following a planned autologous transplant [tandem] is allowed;

- Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of
transplant;

- Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of
transplant;

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

- Myelodysplastic syndrome/myeloproliferative disease (MDS/MPD): must have failed
previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at
time of transplant;

- Waldenstrom's Macroglobulinemia: must have failed 2 courses of therapy

- Patient refuses to be treated on a conventional transplant protocol (for this
inclusion criteria, transplants must be approved by both the participating
institution's patient review committee, such as the Patient Care Conference [PCC] at
the Fred Hutchinson Cancer Research Center [FHCRC], and the FHCRC principal
investigator)

- Patient with related or unrelated donors for whom:

- There is a likelihood of disease progression while HLA typing and results of a
preliminary search and the donor pool suggest that a 10/10 HLA-A, B, C, DRB1 and
DQB1 matched unrelated donor will not be found;

- Patient and donor must be matched for at least one DRB1 allele and one DQB1
allele;

- Best available matches are HLA class I HLA-A, -B, -C allele matched donors
allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch;

- There is no indication for an autologous transplantation as a treatment option

- DONOR: For HLA matching inclusion criteria, see Patient Inclusion Criteria

- DONOR: Only peripheral blood stem cells (PBSC) will be permitted as a HSC source on
this protocol

Exclusion Criteria:

- Positive crossmatch between donor and recipients

- Patient's life expectancy is severely limited by diseases other than malignancy

- Patient has central nervous system (CNS) involvement with disease refractory to
intrathecal chemotherapy

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

- Patient is a fertile man or woman unwilling to use contraceptives during and for up
to 12 months post treatment

- Patient is a female who is pregnant or breastfeeding

- Patient is human immunodeficiency virus (HIV) positive

- Patients with active non-hematologic malignancies (except non-melanoma skin cancers)

- 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

- Patient has a fungal infection with radiological progression after receipt of
amphotericin B or active triazole for greater than 1 month

- Patient has the following organ dysfunction:

- Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac
failure requiring therapy (ejection fraction is required if age > 50 years or if
the patient has a history of anthracyclines or history of cardiac disease);

- Diffusion capacity of the lung for carbon monoxide (DLCO) < 35% total lung
capacity (TLC) < 35%, forced expiratory volume of the lung in one second (FEV1)
< 35% and/or receiving supplementary continuous oxygen; the FHCRC study
principal investigator (PI) must approve enrollment of all patients with
pulmonary nodules;

- Liver function abnormalities: Patient with clinical or laboratory evidence of
liver disease will be evaluated for the cause of liver disease, its clinical
severity in terms of liver function, bridging fibrosis, and the degree of portal
hypertension

- The patient will be excluded if he/she is 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 >
3mg/dL, or symptomatic biliary disease

- Patient has poorly controlled hypertension and on multiple antihypertensives

- Karnofsky Performance Score < 70 for adult patients

- Lansky Play-Performance Score < 70 for pediatric patients

- Patient received cytotoxic agents for "cytoreduction" within three weeks (or the
interval in which a cycle of standard chemotherapy would be administered in a
non-transplant setting) prior to initiating the nonmyeloablative transplant
conditioning (exceptions are hydroxyurea and imatinib mesylate)

- DONOR: Marrow donors

- DONOR: Positive crossmatch between donor and recipient

- DONOR: Donor is HIV-positive and/or has a medical condition that would result in
increased risk for G-CSF mobilization and harvest of PBSC

- DONOR: Donor age < 12 years

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Dose of alemtuzumab that allows an incidence of grade III-IV acute GVHD less than 40%

Outcome Time Frame:

Day +100

Safety Issue:

Yes

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:

1959.00

NCT ID:

NCT00118352

Start Date:

March 2005

Completion Date:

Related Keywords:

  • Acute Undifferentiated Leukemia
  • Adult Acute Lymphoblastic Leukemia in Remission
  • Adult Acute Myeloid Leukemia in Remission
  • Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
  • Childhood Acute Lymphoblastic Leukemia in Remission
  • Childhood Acute Myeloid Leukemia in Remission
  • Childhood Burkitt Lymphoma
  • Childhood Chronic Myelogenous Leukemia
  • Childhood Diffuse Large Cell Lymphoma
  • Childhood Immunoblastic Large Cell Lymphoma
  • Childhood Myelodysplastic Syndromes
  • Chronic Myelomonocytic Leukemia
  • Chronic Phase Chronic Myelogenous Leukemia
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Intraocular Lymphoma
  • Juvenile Myelomonocytic Leukemia
  • Mast Cell Leukemia
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • 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
  • Secondary Myelodysplastic Syndromes
  • Splenic Marginal Zone Lymphoma
  • Testicular Lymphoma
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Neoplasms
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Mast-Cell
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myeloid, Chronic-Phase
  • Leukemia, Myelomonocytic, Chronic
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Waldenstrom Macroglobulinemia
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute
  • Myeloproliferative Disorders
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell
  • Leukemia, Myelomonocytic, Juvenile
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
  • Myelodysplastic-Myeloproliferative Diseases

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
Presbyterian - Saint Lukes Medical Center - Health OneDenver, Colorado  80218