Alemtuzumab, Fludarabine Phosphate, and Low-Dose Total Body Irradiation Before Donor Stem Cell Transplantation in Treating Patients With Hematological Malignancies

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

Sponsors

Lead Sponsor: Fred Hutchinson Cancer Research Center

Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)

Source Fred Hutchinson Cancer Research Center
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.

Overall Status Completed
Start Date 2001-11-01
Completion Date 2009-12-01
Primary Completion Date 2009-12-01
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Evaluate the Risk of Transplant Related Mortality. 100 days after transplant
Evaluate the Risk of Occurrence of Acute and Chronic GVHD 1 year after transplant
Determine Whether Engraftment Can be Maintained With a Single Dose Fludarabine, DLI and Continued MMF/CSP, Defined as Rejection Rate < 20%. 100 days after transplant
Secondary Outcome
Measure Time Frame
Evaluate the Risk/Incidence of Infections 100 days after transplant
Evaluate the Risk for Disease Progression and Relapse 1 year after transplant
Enrollment 60
Condition
Intervention

Intervention Type: Biological

Intervention Name: alemtuzumab

Description: Given IV

Arm Group Label: Treatment (dose-escalation of alemtuzumab, HSCT)

Intervention Type: Drug

Intervention Name: fludarabine phosphate

Description: Given IV

Arm Group Label: Treatment (dose-escalation of alemtuzumab, HSCT)

Intervention Type: Radiation

Intervention Name: total-body irradiation

Description: Undergo TBI

Arm Group Label: Treatment (dose-escalation of alemtuzumab, HSCT)

Other Name: TBI

Intervention Type: Procedure

Intervention Name: allogeneic hematopoietic stem cell transplantation

Description: Undergo allogeneic HSCT

Arm Group Label: Treatment (dose-escalation of alemtuzumab, HSCT)

Intervention Type: Procedure

Intervention Name: peripheral blood stem cell transplantation

Description: Undergo allogeneic peripheral blood stem cell transplantation

Arm Group Label: Treatment (dose-escalation of alemtuzumab, HSCT)

Intervention Type: Drug

Intervention Name: mycophenolate mofetil

Description: Given PO

Arm Group Label: Treatment (dose-escalation of alemtuzumab, HSCT)

Intervention Type: Drug

Intervention Name: cyclosporine

Description: Given IV or PO

Arm Group Label: Treatment (dose-escalation of alemtuzumab, HSCT)

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

Minimum Age:

N/A

Maximum Age:

74 Years

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Brenda Sandmaier Principal Investigator Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Location
Facility:
Presbyterian - Saint Lukes Medical Center - Health One | Denver, Colorado, 80218, United States
Huntsman Cancer Institute/University of Utah | Salt Lake City, Utah, 84112, United States
LDS Hospital | Salt Lake City, Utah, 84143, United States
VA Puget Sound Health Care System | Seattle, Washington, 98101, United States
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Seattle, Washington, 98109, United States
Froedtert Memorial Lutheran Hospital, Medical College of Wisconsin | Milwaukee, Wisconsin, 53226, United States
University of Torino | Torino, 10126, Italy
Location Countries

Italy

United States

Verification Date

2020-01-01

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Fred Hutchinson Cancer Research Center

Investigator Full Name: Brenda Sandmaier

Investigator Title: Principal Investigator

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Treatment (dose-escalation of alemtuzumab, HSCT)

Type: Experimental

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.

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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