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Alemtuzumab Plus Fludarabine and Melphalan With or Without Cyclosporine, Mycophenolate Mofetil, and Low-Dose Total-Body Irradiation Therapy Followed by Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer

Primary Purpose

Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
alemtuzumab
cyclosporine
fludarabine phosphate
melphalan
mycophenolate mofetil
peripheral blood stem cell transplantation
radiation therapy
Sponsored by
Alliance for Clinical Trials in Oncology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia focused on measuring recurrent adult acute myeloid leukemia, adult acute myeloid leukemia in remission, recurrent adult acute lymphoblastic leukemia, adult acute lymphoblastic leukemia in remission, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, atypical chronic myeloid leukemia, BCR-ABL1 negative, chronic myelomonocytic leukemia, recurrent adult Burkitt lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent small lymphocytic lymphoma, recurrent marginal zone lymphoma, recurrent mantle cell lymphoma, recurrent adult lymphoblastic lymphoma, accelerated phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse large cell lymphoma, refractory chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, refractory multiple myeloma, secondary myelodysplastic syndromes, de novo myelodysplastic syndromes, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12)

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS: Histologically confirmed hematological malignancy of 1 of the following types: Acute myeloid leukemia meeting at least 1 of the following criteria: Poor-risk cytogenetics, including -5, 5q-, -7, 7q-, 11q23, and Philadelphia (Ph) chromosome-positive in first or subsequent complete remission (CR) Relapsed or primary refractory disease with ≤ 10% blasts in the peripheral blood and ≤ 20% blasts in the bone marrow Standard-risk cytogenetics in second CR AND autologous transplantation is not feasible Standard-risk cytogenetics in third or subsequent CR Acute lymphoblastic leukemia meeting 1 of the following criteria: Second or subsequent CR High-risk cytogenetics, including Ph chromosome-positive and t(4:11) in first CR Relapsed or primarily refractory disease with ≤ 10% blasts in the peripheral blood and ≤ 20% blasts in the bone marrow High-risk myelodysplasia International Prognostic Scoring System Score ≥ 2.5 Chronic myeloid leukemia (CML)* with an inadequate response to imatinib meeting 1 of the following criteria: Second or subsequent chronic phase Accelerated phase NOTE: *Patients with CML in blast crisis (> 30% promyelocytes and myeloblasts in the bone marrow) are not eligible Non-Hodgkin's lymphoma meeting 1 of the following criteria: Primarily refractory disease or in refractory relapse Relapsed disease after autologous stem cell transplantation Chemosensitive relapsed disease without CR to standard salvage therapy AND no option for autologous stem cell transplantation due to blood or marrow involvement or failure to harvest sufficient autologous stem cells Chronic lymphocytic leukemia meeting both of the following criteria: Stage III or IV disease Refractory to fludarabine Multiple myeloma meeting 1 of the following criteria: Primarily refractory disease or in refractory relapse Relapsed disease after autologous stem cell transplantation No relapsed disease < 6 months after autologous stem cell transplantation No available eligible HLA-matched (i.e., 5 of 6 or 6 of 6 antigen match for HLA-A, -B, and -DR loci) family donor by serological or molecular typing Available suitable family donor meeting the following criteria: Parent, sibling, or child of the recipient ≥ 16 years of age Identical for only one HLA haplotype (i.e., haploidentical) AND incompatible at the HLA-A, -B, -C, and -DR loci of the unshared haplotype by serological or molecular typing Mismatched with respect to KIR class I epitopes graft-vs-host directional activity Mismatching that predicts both graft-vs-host and host-vs-graft bi-directional activity eligible No mismatching that predicts only host-vs-graft directional activity PATIENT CHARACTERISTICS: Age 18 to 60 Performance status ECOG 0-1 Hepatic Bilirubin < 2 times upper limit of normal (ULN) AST and ALT < 2 times ULN Renal Creatinine ≤ 2 mg/dL Cardiovascular LVEF > 40% (corrected) Pulmonary DLCO > 50% of predicted Other No active infection requiring oral or IV antibiotics HIV negative Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy See Disease Characteristics Endocrine therapy Concurrent corticosteroids allowed for adrenal failure, treatment of graft-vs-host disease, or as premedication during study No concurrent corticosteroids for antiemesis

Sites / Locations

  • Moores UCSD Cancer Center
  • Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
  • UCSF Comprehensive Cancer Center
  • CCOP - Christiana Care Health Services
  • Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
  • University of Chicago Cancer Research Center
  • Holden Comprehensive Cancer Center at University of Iowa
  • Massachusetts General Hospital Cancer Center
  • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • University of Minnesota Cancer Center
  • Siteman Cancer Center at Barnes-Jewish Hospital
  • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • St. Joseph's Hospital and Medical Center
  • Roswell Park Cancer Institute
  • Don Monti Comprehensive Cancer Center at North Shore University Hospital
  • Memorial Sloan-Kettering Cancer Center
  • Mount Sinai Medical Center
  • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
  • Duke Comprehensive Cancer Center
  • Wake Forest University Comprehensive Cancer Center
  • Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University
  • Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
  • Hollings Cancer Center at Medical University of South Carolina
  • Virginia Commonwealth University Massey Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Regimen A + B

Arm Description

Conditioning regimen A: Patients receive alemtuzumab IV over 2 hours on days -14 to -12; fludarabine IV over 30 minutes on days -7 to -3; and melphalan IV over 20-30 minutes on day -2. Conditioning regimen B: Patients receive oral or IV cyclosporine twice daily and oral or IV mycophenolate mofetil twice daily on days -15 to 0. Patients also receive alemtuzumab, fludarabine, and melphalan as in conditioning regimen A. Patients undergo low-dose total body irradiation twice daily on days -2 and -1. All patients undergo allogeneic, T-cell-depleted, CD34-positive peripheral blood stem cell transplantation on day 0. Patients receive sargramostim (GM-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover. Patients are followed every 3 months for 1 year and then every 6 months for 5 years.

Outcomes

Primary Outcome Measures

Engraftment rate
Risk of graft-vs-host disease
Progression-free survival (PFS)

Secondary Outcome Measures

Full Information

First Posted
June 10, 2004
Last Updated
November 25, 2019
Sponsor
Alliance for Clinical Trials in Oncology
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00085449
Brief Title
Alemtuzumab Plus Fludarabine and Melphalan With or Without Cyclosporine, Mycophenolate Mofetil, and Low-Dose Total-Body Irradiation Therapy Followed by Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer
Official Title
A Trial of Reduced Intensity Conditioning and Transplantation of Haplotype Mismatched and KIR Class I Epitope-Mismatched Highly Purified CD34 Cells
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Withdrawn
Why Stopped
Funding cut, no patients enrolled
Study Start Date
May 2006 (undefined)
Primary Completion Date
January 2007 (Actual)
Study Completion Date
January 2007 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alliance for Clinical Trials in Oncology
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
RATIONALE: Giving low doses of chemotherapy, monoclonal antibodies, and radiation therapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells when they do not exactly match the patient's blood. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil before transplant may stop this from happening. PURPOSE: This phase I/II trial is studying the side effects of alemtuzumab, fludarabine, and melphalan with or without cyclosporine, mycophenolate mofetil, and total-body irradiation before donor peripheral blood stem cell transplant and to see how well they work in treating patients with relapsed or refractory hematologic cancer.
Detailed Description
OBJECTIVES: Determine the ability of a reduced-intensity conditioning regimen comprising alemtuzumab, fludarabine, and melphalan with or without cyclosporine, mycophenolate mofetil, and low-dose total body radiotherapy followed by haplotype-mismatched, KIR class I epitope-mismatched CD34-positive allogeneic peripheral blood stem cell transplantation to facilitate engraftment by day 35 post-transplantation in at least 85% of patients with relapsed, refractory, or poor-risk hematological malignancies. Determine the risk of graft-versus-host-disease in patients treated with these regimens. Determine, preliminarily, the efficacy of these regimens, in terms of progression-free survival, in these patients. Correlate outcomes, engraftment, and progression-free survival with the number of detectable alloreactive natural killer cell clones before transplantation and after engraftment in patients treated with these regimens. Determine immune reconstitution in patients treated with these regimens. OUTLINE: This is a multicenter, pilot study. Patients are initially treated with conditioning regimen A. If adequate donor engraftment is not achieved, subsequent patients are treated with conditioning regimen B. Conditioning regimen A: Patients receive alemtuzumab IV over 2 hours on days -14 to -12; fludarabine IV over 30 minutes on days -7 to -3; and melphalan IV over 20-30 minutes on day -2. Conditioning regimen B: Patients receive oral or IV cyclosporine twice daily and oral or IV mycophenolate mofetil twice daily on days -15 to 0. Patients also receive alemtuzumab, fludarabine, and melphalan as in conditioning regimen A. Patients undergo low-dose total body irradiation twice daily on days -2 and -1. All patients undergo allogeneic, T-cell-depleted, CD34-positive peripheral blood stem cell transplantation on day 0. Patients receive sargramostim (GM-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover. Patients are followed every 3 months for 1 year and then every 6 months for 5 years. PROJECTED ACCRUAL: A total of 14-56 patients (14-28 per regimen) will be accrued for this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms
Keywords
recurrent adult acute myeloid leukemia, adult acute myeloid leukemia in remission, recurrent adult acute lymphoblastic leukemia, adult acute lymphoblastic leukemia in remission, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, atypical chronic myeloid leukemia, BCR-ABL1 negative, chronic myelomonocytic leukemia, recurrent adult Burkitt lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent small lymphocytic lymphoma, recurrent marginal zone lymphoma, recurrent mantle cell lymphoma, recurrent adult lymphoblastic lymphoma, accelerated phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse large cell lymphoma, refractory chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, refractory multiple myeloma, secondary myelodysplastic syndromes, de novo myelodysplastic syndromes, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Regimen A + B
Arm Type
Experimental
Arm Description
Conditioning regimen A: Patients receive alemtuzumab IV over 2 hours on days -14 to -12; fludarabine IV over 30 minutes on days -7 to -3; and melphalan IV over 20-30 minutes on day -2. Conditioning regimen B: Patients receive oral or IV cyclosporine twice daily and oral or IV mycophenolate mofetil twice daily on days -15 to 0. Patients also receive alemtuzumab, fludarabine, and melphalan as in conditioning regimen A. Patients undergo low-dose total body irradiation twice daily on days -2 and -1. All patients undergo allogeneic, T-cell-depleted, CD34-positive peripheral blood stem cell transplantation on day 0. Patients receive sargramostim (GM-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover. Patients are followed every 3 months for 1 year and then every 6 months for 5 years.
Intervention Type
Biological
Intervention Name(s)
alemtuzumab
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Intervention Type
Drug
Intervention Name(s)
melphalan
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Intervention Type
Radiation
Intervention Name(s)
radiation therapy
Primary Outcome Measure Information:
Title
Engraftment rate
Time Frame
Up to 6 years
Title
Risk of graft-vs-host disease
Time Frame
Up to 6 years
Title
Progression-free survival (PFS)
Time Frame
Up to 6 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Histologically confirmed hematological malignancy of 1 of the following types: Acute myeloid leukemia meeting at least 1 of the following criteria: Poor-risk cytogenetics, including -5, 5q-, -7, 7q-, 11q23, and Philadelphia (Ph) chromosome-positive in first or subsequent complete remission (CR) Relapsed or primary refractory disease with ≤ 10% blasts in the peripheral blood and ≤ 20% blasts in the bone marrow Standard-risk cytogenetics in second CR AND autologous transplantation is not feasible Standard-risk cytogenetics in third or subsequent CR Acute lymphoblastic leukemia meeting 1 of the following criteria: Second or subsequent CR High-risk cytogenetics, including Ph chromosome-positive and t(4:11) in first CR Relapsed or primarily refractory disease with ≤ 10% blasts in the peripheral blood and ≤ 20% blasts in the bone marrow High-risk myelodysplasia International Prognostic Scoring System Score ≥ 2.5 Chronic myeloid leukemia (CML)* with an inadequate response to imatinib meeting 1 of the following criteria: Second or subsequent chronic phase Accelerated phase NOTE: *Patients with CML in blast crisis (> 30% promyelocytes and myeloblasts in the bone marrow) are not eligible Non-Hodgkin's lymphoma meeting 1 of the following criteria: Primarily refractory disease or in refractory relapse Relapsed disease after autologous stem cell transplantation Chemosensitive relapsed disease without CR to standard salvage therapy AND no option for autologous stem cell transplantation due to blood or marrow involvement or failure to harvest sufficient autologous stem cells Chronic lymphocytic leukemia meeting both of the following criteria: Stage III or IV disease Refractory to fludarabine Multiple myeloma meeting 1 of the following criteria: Primarily refractory disease or in refractory relapse Relapsed disease after autologous stem cell transplantation No relapsed disease < 6 months after autologous stem cell transplantation No available eligible HLA-matched (i.e., 5 of 6 or 6 of 6 antigen match for HLA-A, -B, and -DR loci) family donor by serological or molecular typing Available suitable family donor meeting the following criteria: Parent, sibling, or child of the recipient ≥ 16 years of age Identical for only one HLA haplotype (i.e., haploidentical) AND incompatible at the HLA-A, -B, -C, and -DR loci of the unshared haplotype by serological or molecular typing Mismatched with respect to KIR class I epitopes graft-vs-host directional activity Mismatching that predicts both graft-vs-host and host-vs-graft bi-directional activity eligible No mismatching that predicts only host-vs-graft directional activity PATIENT CHARACTERISTICS: Age 18 to 60 Performance status ECOG 0-1 Hepatic Bilirubin < 2 times upper limit of normal (ULN) AST and ALT < 2 times ULN Renal Creatinine ≤ 2 mg/dL Cardiovascular LVEF > 40% (corrected) Pulmonary DLCO > 50% of predicted Other No active infection requiring oral or IV antibiotics HIV negative Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy See Disease Characteristics Endocrine therapy Concurrent corticosteroids allowed for adrenal failure, treatment of graft-vs-host disease, or as premedication during study No concurrent corticosteroids for antiemesis
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sherif S. Farag, MD, PhD
Organizational Affiliation
Indiana University Melvin and Bren Simon Cancer Center
Official's Role
Study Chair
Facility Information:
Facility Name
Moores UCSD Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093-0658
Country
United States
Facility Name
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
UCSF Comprehensive Cancer Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
CCOP - Christiana Care Health Services
City
Newark
State/Province
Delaware
ZIP/Postal Code
19713
Country
United States
Facility Name
Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
University of Chicago Cancer Research Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637-1470
Country
United States
Facility Name
Holden Comprehensive Cancer Center at University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242-1009
Country
United States
Facility Name
Massachusetts General Hospital Cancer Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Minnesota Cancer Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Siteman Cancer Center at Barnes-Jewish Hospital
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
UNMC Eppley Cancer Center at the University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198-7680
Country
United States
Facility Name
St. Joseph's Hospital and Medical Center
City
Paterson
State/Province
New Jersey
ZIP/Postal Code
07503
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263-0001
Country
United States
Facility Name
Don Monti Comprehensive Cancer Center at North Shore University Hospital
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599-7295
Country
United States
Facility Name
Duke Comprehensive Cancer Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Wake Forest University Comprehensive Cancer Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157-1082
Country
United States
Facility Name
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210-1240
Country
United States
Facility Name
Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Hollings Cancer Center at Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Virginia Commonwealth University Massey Cancer Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298-0037
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Alemtuzumab Plus Fludarabine and Melphalan With or Without Cyclosporine, Mycophenolate Mofetil, and Low-Dose Total-Body Irradiation Therapy Followed by Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer

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