Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate 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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Treatment Completed 18 to 60 NCI CALGB-100102 NCT00085449

Objectives

1. 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.
2. Determine the risk of graft-versus-host-disease in patients treated with these regimens.
3. Determine, preliminarily, the efficacy of these regimens, in terms of progression-free survival, in these patients.
4. 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.
5. Determine immune reconstitution in patients treated with these regimens.

Entry 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

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

Radiotherapy

• Not specified

Surgery

• Not specified

Patient Characteristics:

Age

• 18 to 60

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Not specified

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

Expected Enrollment

A total of 14-56 patients (14-28 per regimen) will be accrued for this study.

Outcomes

Engraftment rate
Risk of graft-vs-host disease
Progression-free survival (PFS)
Correlation of outcomes, engraftment, and PFS with number of detectable alloreactive natural killer cell clones
Performance assessment

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.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Sherif Farag, MD, PhD, Protocol chair		Ph: 317-274-0843; 888-600-4822 Email: ssfarag@iupui.edu
Koen Van Besien, MD, Protocol co-chair		Ph: 773-702-6696; 888-824-0200

Registry Information
Official Title		A Trial of Reduced Intensity Conditioning and Transplantation of Haplotype Mismatched and KIR Class I Epitope-Mismatched Highly Purified CD34 Cells
Trial Start Date		2006-05-15
Registered in ClinicalTrials.gov		NCT00085449
Date Submitted to PDQ		2004-05-05
Information Last Verified		2007-04-05
NCI Grant/Contract Number		CA31946

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