Brief Title
Alemtuzumab, Fludarabine Phosphate, and Low-Dose Total Body Irradiation Before Donor Stem Cell Transplantation in Treating Patients With Hematological Malignancies
Official Title
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
Brief Summary
This phase II trial studies the side effects and the best dose of alemtuzumab when given
together with fludarabine phosphate and low-dose total body irradiation (TBI) and how well it
works before donor stem cell transplant in treating patients with hematological malignancies.
Giving chemotherapy and low-dose TBI before a donor peripheral blood stem cell transplant
helps stop the growth of cancer cells. It may also stop the patient's immune system from
rejecting the donor's stem cells. Also, monoclonal antibodies, such as alemtuzumab, can find
cancer cells and either kill them or deliver cancer-killing substances to them without
harming normal cells. When the healthy stem cells from a donor are infused into the patient
they may help the patient's bone marrow make stem cells, red blood cells, white blood cells,
and platelets. Sometimes the transplanted cells from a donor can also make an immune response
against the body's normal cells. Giving cyclosporine (CSP) and mycophenolate mofetil (MMF)
after transplant may stop this from happening.
Detailed Description
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Evaluate the Risk of Transplant Related Mortality.
Secondary Outcome
Evaluate the Risk/Incidence of Infections
Condition
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Intervention
alemtuzumab
Study Arms / Comparison Groups
Treatment (dose-escalation of alemtuzumab, HSCT)
Description: CONDITIONING REGIMEN: Patients receive alemtuzumab 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. HSCT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. IMMUNOSUPPRESSION: Patients receive CSP IV or PO BID on days -3 to 180 with taper to day 365 and MMF PO TID on days 0-100, with taper to day 156.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Biological
Estimated Enrollment
60
Start Date
November 2001
Completion Date
December 2009
Primary Completion Date
December 2009
Eligibility Criteria
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 principal investigator
- 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 for adult patients
- Lansky-Play Performance Score < 50 for pediatric patients
- 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
Gender
All
Ages
N/A - 74 Years
Accepts Healthy Volunteers
No
Contacts
Brenda Sandmaier, ,
Location Countries
Italy
Location Countries
Italy
Administrative Informations
NCT ID
NCT00040846
Organization ID
1591.00
Secondary IDs
NCI-2011-00471
Responsible Party
Principal Investigator
Study Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Study Sponsor
Brenda Sandmaier, Principal Investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Verification Date
January 2020