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

November 25, 2019 updated by: Alliance for Clinical Trials in Oncology

A Trial of Reduced Intensity Conditioning and Transplantation of Haplotype Mismatched and KIR Class I Epitope-Mismatched Highly Purified CD34 Cells

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • La Jolla, California, United States, 92093-0658
        • Moores UCSD Cancer Center
      • Los Angeles, California, United States, 90048
        • Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
      • San Francisco, California, United States, 94115
        • UCSF Comprehensive Cancer Center
    • Delaware
      • Newark, Delaware, United States, 19713
        • CCOP - Christiana Care Health Services
    • District of Columbia
      • Washington, District of Columbia, United States, 20007
        • Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
    • Illinois
      • Chicago, Illinois, United States, 60637-1470
        • University of Chicago Cancer Research Center
    • Iowa
      • Iowa City, Iowa, United States, 52242-1009
        • Holden Comprehensive Cancer Center at University of Iowa
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital Cancer Center
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota Cancer Center
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Siteman Cancer Center at Barnes-Jewish Hospital
    • Nebraska
      • Omaha, Nebraska, United States, 68198-7680
        • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
    • New Jersey
      • Paterson, New Jersey, United States, 07503
        • St. Joseph's Hospital and Medical Center
    • New York
      • Buffalo, New York, United States, 14263-0001
        • Roswell Park Cancer Institute
      • Manhasset, New York, United States, 11030
        • Don Monti Comprehensive Cancer Center at North Shore University Hospital
      • New York, New York, United States, 10021
        • Memorial Sloan-Kettering Cancer Center
      • New York, New York, United States, 10029
        • Mount Sinai Medical Center
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599-7295
        • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
      • Durham, North Carolina, United States, 27710
        • Duke Comprehensive Cancer Center
      • Winston-Salem, North Carolina, United States, 27157-1082
        • Wake Forest University Comprehensive Cancer Center
    • Ohio
      • Columbus, Ohio, United States, 43210-1240
        • Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15224
        • Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Hollings Cancer Center at Medical University of South Carolina
    • Virginia
      • Richmond, Virginia, United States, 23298-0037
        • Virginia Commonwealth University Massey Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Radiation: radiation therapy
Drug: fludarabine phosphate
Procedure: peripheral blood stem cell transplantation
Drug: melphalan
Biological: alemtuzumab
Drug: cyclosporine
Drug: mycophenolate mofetil

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Engraftment rate
Time Frame: Up to 6 years
Up to 6 years
Risk of graft-vs-host disease
Time Frame: Up to 6 years
Up to 6 years
Progression-free survival (PFS)
Time Frame: Up to 6 years
Up to 6 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Alliance for Clinical Trials in Oncology

Collaborators

National Cancer Institute (NCI)

Investigators

  • Study Chair: Sherif S. Farag, MD, PhD, Indiana University Melvin and Bren Simon Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2006

Primary Completion (Actual)

January 1, 2007

Study Completion (Actual)

January 1, 2007

Study Registration Dates

First Submitted

June 10, 2004

First Submitted That Met QC Criteria

June 10, 2004

First Posted (Estimate)

June 11, 2004

Study Record Updates

Last Update Posted (Actual)

November 27, 2019

Last Update Submitted That Met QC Criteria

November 25, 2019

Last Verified

November 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CALGB-100102
  • CDR0000370797 (Registry Identifier: NCI Physician Data Query)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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