Clinical trial NCT00085449: 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
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: 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)
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-06-11
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Engraftment rate
timeFrame: Up to 6 years
measure: Risk of graft-vs-host disease
timeFrame: Up to 6 years
measure: Progression-free survival (PFS)
timeFrame: Up to 6 years
Secondary outcomes:
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Moores UCSD Cancer Center
state: California
city: Los Angeles
country: United States
facility: Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Washington
country: United States
facility: Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at University of Iowa
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: UNMC Eppley Cancer Center at the University of Nebraska Medical Center
state: Nebraska
city: Paterson
country: United States
facility: St. Joseph's Hospital and Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Manhasset
country: United States
facility: Don Monti Comprehensive Cancer Center at North Shore University Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University
state: Ohio
city: Pittsburgh
country: United States
facility: Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center at Medical University of South Carolina
state: South Carolina
city: Richmond
country: United States
facility: Virginia Commonwealth University Massey Cancer Center
state: Virginia
Study officials:
affiliation: Indiana University Melvin and Bren Simon Cancer Center
name: Sherif S. Farag, MD, PhD
role: STUDY_CHAIR
References: