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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:
NCT00085449
First received: June 10, 2004
Last updated: July 14, 2015
Last verified: July 2015
  Purpose

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.


Condition Intervention Phase
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Biological: alemtuzumab
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: melphalan
Drug: mycophenolate mofetil
Procedure: peripheral blood stem cell transplantation
Radiation: radiation therapy
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Trial of Reduced Intensity Conditioning and Transplantation of Haplotype Mismatched and KIR Class I Epitope-Mismatched Highly Purified CD34 Cells

Resource links provided by NLM:


Further study details as provided by Alliance for Clinical Trials in Oncology:

Primary Outcome Measures:
  • Engraftment rate [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  • Risk of graft-vs-host disease [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  • Progression-free survival (PFS) [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]

Enrollment: 56
Study Start Date: May 2006
Study Completion Date: January 2007
Primary Completion Date: January 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Regimen A + 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.

Biological: alemtuzumab Drug: cyclosporine Drug: fludarabine phosphate Drug: melphalan Drug: mycophenolate mofetil Procedure: peripheral blood stem cell transplantation Radiation: radiation therapy

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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00085449

  Show 24 Study Locations
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
Investigators
Study Chair: Sherif S. Farag, MD, PhD Indiana University Melvin and Bren Simon Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT00085449     History of Changes
Other Study ID Numbers: CALGB-100102, CALGB-100102, CDR0000370797
Study First Received: June 10, 2004
Last Updated: July 14, 2015
Health Authority: United States: Federal Government

Keywords provided by Alliance for Clinical Trials in Oncology:
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)

Additional relevant MeSH terms:
Multiple Myeloma
Myelodysplastic Syndromes
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms
Neoplasms, Plasma Cell
Plasmacytoma
Preleukemia
Blood Protein Disorders
Bone Marrow Diseases
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Paraproteinemias
Precancerous Conditions
Vascular Diseases
Alemtuzumab
Cyclosporine
Cyclosporins
Fludarabine
Fludarabine phosphate
Melphalan
Mycophenolate mofetil
Mycophenolic Acid
Alkylating Agents

ClinicalTrials.gov processed this record on July 28, 2015