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Campath® [Alemtuzumab] Dose Escalation, Low-Dose TBI and Fludarabine Followed by HLA Class I Mismatched Donor Stem Cell Transplantation for Patients With Hematologic Malignancies - A Multi-Center Trial


Phase 2
N/A
74 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), Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Childhood Burkitt Lymphoma, Childhood Chronic Myelogenous Leukemia, Childhood Diffuse Large Cell Lymphoma, Childhood Immunoblastic Large Cell Lymphoma, Childhood Nasal Type Extranodal NK/T-cell Lymphoma, Chronic Phase Chronic Myelogenous Leukemia, Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma, Contiguous Stage II Grade 1 Follicular Lymphoma, Contiguous Stage II Grade 2 Follicular Lymphoma, Contiguous Stage II Marginal Zone Lymphoma, Contiguous Stage II Small Lymphocytic Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Nodal Marginal Zone B-cell Lymphoma, Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma, Noncontiguous Stage II Grade 1 Follicular Lymphoma, Noncontiguous Stage II Grade 2 Follicular Lymphoma, Noncontiguous Stage II Marginal Zone Lymphoma, Noncontiguous Stage II Small Lymphocytic Lymphoma, Peripheral T-cell Lymphoma, Previously Treated Myelodysplastic Syndromes, Progressive Hairy Cell Leukemia, Initial Treatment, 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 Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Childhood Large Cell Lymphoma, Recurrent Childhood Lymphoblastic Lymphoma, Recurrent Childhood Small Noncleaved Cell Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin 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 Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Recurrent/Refractory Childhood Hodgkin Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Hairy Cell Leukemia, Refractory Multiple Myeloma, Relapsing Chronic Myelogenous Leukemia, Splenic Marginal Zone Lymphoma, Stage I Adult Diffuse Small Cleaved Cell Lymphoma, Stage I Childhood Anaplastic Large Cell Lymphoma, Stage I Childhood Large Cell Lymphoma, Stage I Cutaneous T-cell Non-Hodgkin Lymphoma, Stage I Grade 1 Follicular Lymphoma, Stage I Grade 2 Follicular Lymphoma, Stage I Mantle Cell Lymphoma, Stage I Marginal Zone Lymphoma, Stage I Mycosis Fungoides/Sezary Syndrome, Stage I Small Lymphocytic Lymphoma, Stage II Childhood Anaplastic Large Cell Lymphoma, Stage II Childhood Large Cell Lymphoma, Stage II Cutaneous T-cell Non-Hodgkin Lymphoma, Stage II Mycosis Fungoides/Sezary Syndrome, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Adult Diffuse Small Cleaved Cell Lymphoma, Stage III Childhood Anaplastic Large Cell Lymphoma, Stage III Childhood Large Cell Lymphoma, Stage III Cutaneous T-cell Non-Hodgkin Lymphoma, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage III Marginal Zone Lymphoma, Stage III Mycosis Fungoides/Sezary Syndrome, Stage III Small Lymphocytic Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Childhood Anaplastic Large Cell Lymphoma, Stage IV Childhood Large Cell Lymphoma, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Mycosis Fungoides/Sezary Syndrome, Stage IV Small Lymphocytic Lymphoma, T-cell Large Granular Lymphocyte Leukemia, Waldenström Macroglobulinemia

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Trial Information

Campath® [Alemtuzumab] Dose Escalation, Low-Dose TBI and Fludarabine Followed by HLA Class I Mismatched Donor Stem Cell Transplantation for Patients With Hematologic Malignancies - A Multi-Center Trial


PRIMARY OBJECTIVES:

I. To determine whether stable allogeneic engraftment from related and unrelated human
leukocyte antigen (HLA)-mismatched stem cell donors can be safely established using a
non-myeloablative conditioning regimen plus escalating doses of the anti-CD52 monoclonal
antibody (mAb) Campath (alemtuzumab) in patients with hematologic malignancies.

SECONDARY OBJECTIVES:

I. Evaluate the risk of occurrence of acute and chronic graft-vs-host disease (GVHD).

II. Evaluate the risk/incidence of infections. III. Determine whether engraftment can be
maintained with a single dose fludarabine, donor lymphocyte infusion (DLI) and continued
MMF/CSP.

IV. Evaluate the risk for disease progression and relapse.

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

CONDITIONING REGIMEN: Patients receive alemtuzumab intravenously (IV) over 2 hours on days
-8 to -5 and fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI
on day 0.

HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT): Patients undergo allogeneic peripheral blood
stem cell transplantation on day 0.

IMMUNOSUPPRESSION: Patients receive CSP IV or orally (PO) twice daily (BID) on days -3 to
180 with taper to day 365 and MMF PO thrice daily (TID) on days 0-100 with taper to day 156.

After completion of study treatment, patients are followed up periodically.


Inclusion Criteria:



- Patients 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 hematopoietic stem cell transplant (HSCT) or
with a B cell malignancy except those treatable with autologous transplant will be
included

- Aggressive non-Hodgkin lymphomas (NHLs) and Other Histologies Such as Diffuse large B
cell NHL

- Patients with primary refractory or relapsed disease not eligible for an
autologous transplant

- Patients are eligible following an autologous transplant in remission or in
relapse

- Planned tandem transplant is allowed for patients at high risk of relapse

- Low grade NHL with < 6 months 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 failed 2 lines of conventional therapy
and be refractory to fludarabine

- Hodgkin disease (HD) - Must have received and failed frontline therapy; patients must
have had a prior autologous transplant or were not eligible for autologous
transplant; planned tandem transplants are allowed for patients at high risk of
relapse

- Multiple myeloma (MM) - Must have received prior chemotherapy and a prior autologous
transplant, unless autologous transplant was not possible; planned tandem transplants
are allowed for patients at high risk of relapse

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

- Acute lymphocytic leukemia (ALL) - Must have < 5% blasts at the time of transplant

- Chronic myeloid leukemia (CML) - Patients will be accepted beyond chronic phase 1
(CP1) if they have received previous myelosuppressive chemotherapy or HSCT, and have
< 5% marrow blasts at time of transplant

- Myelodysplastic (MDS)/Myeloproliferative disorders - Must have failed previous
myelosuppressive chemotherapy or HSCT, and have < 5% marrow blasts at time of
transplant

- Waldenstrom's Macroglobulinemia - Must have failed 2 courses of therapy

- Patients < 12 years old must be approved by the Fred Hutchinson Cancer Research
Center (FHCRC) principal investigator (PI)

- Patients who refuse 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 FHCRC and the FHCRC PI

- Patients with related or unrelated donors for whom

- The best available match is a HLA class II DRB1 and DQB1 matched donor
incompatible for any single serologically detectable class I HLA-A, -B, -C
mismatch; one additional allele level class I mismatch is allowed OR any
combination of 2 allele level mismatches (if typed at the molecular level)

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

- There is no HLA-A, -B or -C one locus allelic mismatched related donor available

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

- DONOR: Related or unrelated donors who are matched for HLA-DRB1 and DQB1 alleles
(must be defined by high resolution typing), and who are mismatched for:

- Any single serologically detectable HLA-A or B or C antigen +/- 1 allele or

- Any combination of two HLA-A, -B, or -C alleles (if prospectively typed at
molecular level)

Exclusion Criteria:

- Patients who are homozygous at the mismatched major histocompatibility complex (MHC)
class I locus

- A positive cross-match exists between the donor and recipient

- Patients with rapidly progressive intermediate or high grade NHL

- 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

- 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 breast-feeding

- Human immunodeficiency virus (HIV) positive patients

- 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

- Fungal infections with radiological progression after receipt of amphotericin B or
active triazole for greater than 1 month

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

- Patients with the following organ dysfunction symptomatic coronary artery disease or
ejection fraction < 35% or other cardiac failure requiring therapy; ejection fraction
is required if the patient is > 50 years of age, or history of cardiac disease or
anthracycline exposure

- Diffusion capacity of carbon monoxide (DLCO) < 35%; total lung capacity (TLC) <
35%; or forced expiratory volume in one second (FEV1) < 35% and/or receiving
supplementary continuous oxygen

- 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; or symptomatic biliary disease

- Patients with poorly controlled hypertension on multiple antihypertensives

- Karnofsky score < 70

- Lansky-Play Performance Score < 50

- DONOR: Bone marrow (BM) donors

- DONOR: Donors who are HIV-positive and/or, medical conditions that would result in
increased risk for granulocyte colony-stimulating factor (G-CSF) mobilization and
harvest of peripheral blood stem cell (PBSC)

- DONOR: Donors < 12 years of age

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Dose level of alemtuzumab with fludarabine phosphate and TBI that has an acceptable rate of graft rejection that is not associated with high rate GVHD or transplant related mortality.

Outcome Description:

In this setting using HLA mismatched related and unrelated donors, an acceptable dose level will have a rejection rate of less than 20%, a rate of acute grade 3 or 4 GVHD of 50% or less, and a rate of day 100 transplant related mortality of 35% or less.

Outcome Time Frame:

Assessed up to day 28

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: Food and Drug Administration

Study ID:

1591.00

NCT ID:

NCT00040846

Start Date:

November 2001

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)
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Childhood Burkitt Lymphoma
  • Childhood Chronic Myelogenous Leukemia
  • Childhood Diffuse Large Cell Lymphoma
  • Childhood Immunoblastic Large Cell Lymphoma
  • Childhood Nasal Type Extranodal NK/T-cell Lymphoma
  • Chronic Phase Chronic Myelogenous Leukemia
  • Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
  • Contiguous Stage II Grade 1 Follicular Lymphoma
  • Contiguous Stage II Grade 2 Follicular Lymphoma
  • Contiguous Stage II Marginal Zone Lymphoma
  • Contiguous Stage II Small Lymphocytic Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Hepatosplenic T-cell Lymphoma
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Nodal Marginal Zone B-cell Lymphoma
  • Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
  • Noncontiguous Stage II Grade 1 Follicular Lymphoma
  • Noncontiguous Stage II Grade 2 Follicular Lymphoma
  • Noncontiguous Stage II Marginal Zone Lymphoma
  • Noncontiguous Stage II Small Lymphocytic Lymphoma
  • Peripheral T-cell Lymphoma
  • Previously Treated Myelodysplastic Syndromes
  • Progressive Hairy Cell Leukemia, Initial Treatment
  • 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 Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Recurrent Childhood Anaplastic Large Cell Lymphoma
  • Recurrent Childhood Large Cell Lymphoma
  • Recurrent Childhood Lymphoblastic Lymphoma
  • Recurrent Childhood Small Noncleaved Cell Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin 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 Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Recurrent/Refractory Childhood Hodgkin Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Hairy Cell Leukemia
  • Refractory Multiple Myeloma
  • Relapsing Chronic Myelogenous Leukemia
  • Splenic Marginal Zone Lymphoma
  • Stage I Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage I Childhood Anaplastic Large Cell Lymphoma
  • Stage I Childhood Large Cell Lymphoma
  • Stage I Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage I Grade 1 Follicular Lymphoma
  • Stage I Grade 2 Follicular Lymphoma
  • Stage I Mantle Cell Lymphoma
  • Stage I Marginal Zone Lymphoma
  • Stage I Mycosis Fungoides/Sezary Syndrome
  • Stage I Small Lymphocytic Lymphoma
  • Stage II Childhood Anaplastic Large Cell Lymphoma
  • Stage II Childhood Large Cell Lymphoma
  • Stage II Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage II Mycosis Fungoides/Sezary Syndrome
  • Stage III Adult Diffuse Large Cell Lymphoma
  • Stage III Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage III Childhood Anaplastic Large Cell Lymphoma
  • Stage III Childhood Large Cell Lymphoma
  • Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage III Grade 1 Follicular Lymphoma
  • Stage III Grade 2 Follicular Lymphoma
  • Stage III Mantle Cell Lymphoma
  • Stage III Marginal Zone Lymphoma
  • Stage III Mycosis Fungoides/Sezary Syndrome
  • Stage III Small Lymphocytic Lymphoma
  • Stage IV Adult Diffuse Large Cell Lymphoma
  • Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage IV Childhood Anaplastic Large Cell Lymphoma
  • Stage IV Childhood Large Cell Lymphoma
  • Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Mantle Cell Lymphoma
  • Stage IV Marginal Zone Lymphoma
  • Stage IV Mycosis Fungoides/Sezary Syndrome
  • Stage IV Small Lymphocytic Lymphoma
  • T-cell Large Granular Lymphocyte Leukemia
  • Waldenström Macroglobulinemia
  • Congenital Abnormalities
  • Burkitt Lymphoma
  • Neoplasms
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myeloid, Chronic-Phase
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Mycoses
  • Mycosis Fungoides
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, T-Cell, Peripheral
  • Lymphoma, Large-Cell, Anaplastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell
  • Hematologic Neoplasms
  • Myelodysplastic-Myeloproliferative Diseases
  • Leukemia, Large Granular Lymphocytic

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
Froedtert Memorial Lutheran Hospital, Medical College of WisconsinMilwaukee, Wisconsin  53226
Presbyterian - Saint Lukes Medical Center - Health OneDenver, Colorado  80218
Huntsman Cancer Institute/University of UtahSalt Lake City, Utah  84112