Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

April 25, 2017 updated by: Brenda Sandmaier, Fred Hutchinson Cancer Center

Campath (Alemtuzumab) Dose Escalation, Low-Dose TBI and Fludarabine Followed by HLA Class II Mismatched Donor Stem Cell Transplantation for Patients With Hematologic Malignancies: A Multicenter Trial

This phase II trial is studying the side effects and best dose of alemtuzumab when given together with fludarabine phosphate and total-body irradiation followed by cyclosporine and mycophenolate mofetil in treating patients who are undergoing a donor stem cell transplant for hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, a monoclonal antibody, such as alemtuzumab, and radiation therapy before a donor stem cell transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune cells 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 after the transplant may stop this from happening.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To determine which dose of Campath (alemtuzumab) allows related and unrelated human leukocyte antigen (HLA) class-II mismatched hematopoietic cell transplantation (HCT) with an incidence of grade III-IV acute graft-versus-host disease (GVHD) less than 40%.

SECONDARY OBJECTIVES:

I. Incidence of graft rejection.

II. Number of days of steroids >= 1mg/kg required before day 100 in each patient.

III. Incidence of non-relapse mortality.

IV. Risk/incidence of infections.

V. Immune reconstitution.

VI. Risk for disease progression and relapse.

OUTLINE: This is a dose-escalation study of alemtuzumab.

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab intravenously (IV) over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose total-body irradiation (TBI) on day 0.

ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTATION (PBSCT): After completion of TBI, patients undergo allogeneic PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.

After completion of study treatment, patients are followed up periodically for 12 months, at 18 months, and then annually for 5 years.

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 2

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

  • Italy
      • Torino, Italy, 10126
        • University of Torino
  • United States
    • Washington
      • Seattle, Washington, United States, 98109
        • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

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

No older than 74 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • The patient must be not eligible for conventional transplants and must have disease expected to be stable for at least 100 days without chemotherapy

  • Patients with hematologic malignancies treatable with HCT will be included:

    • Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse large B-cell NHL: not eligible for autologous HCT, not eligible for conventional myeloablative HCT, or after failed autologous HCT;
    • Low grade NHL: with < 6 month duration of complete response (CR) between courses of conventional therapy;
    • Mantle cell NHL: may be treated in first CR;
    • Chronic lymphocytic leukemia (CLL): must have failed 2 lines of conventional therapy and must be refractory to fludarabine; this includes patients who fail to have a complete or partial response after therapy with a regimen containing fludarabine (or another nucleoside analog] or experience disease relapse within 12 months after completing therapy with a regimen containing fludarabine [or another nucleoside analog);
    • Hodgkin's disease (HD): must have received and failed frontline therapy and have failed or were not eligible for autologous transplant;
    • Multiple myeloma (MM): must have received prior chemotherapy or failed autografting; following a planned autologous transplant [tandem] is allowed;
    • Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant;
    • Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of transplant;
    • Chronic myelogenous leukemia (CML): patients will be accepted beyond first clinical progression (CP1) if they have received previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant;
    • Myelodysplastic syndrome/myeloproliferative disease (MDS/MPD): must have failed previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant;
    • Waldenstrom's macroglobulinemia: must have failed 2 courses of therapy
  • Patient refuses to be treated on a conventional transplant protocol; for this inclusion criteria, transplants must be approved by both the participating institution's patient review committee, such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC), and the FHCRC principal investigator

  • Patient with related or unrelated donors for whom:

    • There is a likelihood of disease progression while HLA typing and results of a preliminary search and the donor pool suggest that a 10/10 HLA-A, B, C, DRB1 and DQB1 matched unrelated donor will not be found;
    • Patient and donor must be matched for at least one DRB1 allele and one DQB1 allele;
    • Best available matches are HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch;
    • There is no indication for an autologous transplantation as a treatment option
  • DONOR: For HLA matching inclusion criteria, see patient inclusion criteria
  • DONOR: Only peripheral blood stem cells (PBSC) will be permitted as a HSC source on this protocol

Exclusion Criteria:

  • Positive crossmatch between donor and recipients
  • Patient's life expectancy is severely limited by diseases other than malignancy
  • Patient has central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
  • Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
  • Patient is a fertile man or woman unwilling to use contraceptives during and for up to 12 months post treatment
  • Patient is a female who is pregnant or breastfeeding
  • Patient is human immunodeficiency virus (HIV) positive
  • Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
  • Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
  • Patient has a fungal infection with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month

  • Patient has the following organ dysfunction:

    • Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac failure requiring therapy; ejection fraction is required if age > 50 years or if the patient has a history of anthracyclines or history of cardiac disease;
    • Diffusion capacity of the lung for carbon monoxide (DLCO) < 35% total lung capacity (TLC) < 35%, forced expiratory volume of the lung in one second (FEV1) < 35% and/or receiving supplementary continuous oxygen; the FHCRC study principal investigator (PI) must approve enrollment of all patients with pulmonary nodules;
    • Liver function abnormalities: patient with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; the patient will be excluded if he/she is found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3mg/dL, or symptomatic biliary disease
  • Patient has poorly controlled hypertension and on multiple antihypertensives
  • Karnofsky performance score < 70 for adult patients
  • Lansky play-performance score < 70 for pediatric patients
  • Patient received cytotoxic agents for "cytoreduction" within three weeks (or the interval in which a cycle of standard chemotherapy would be administered in a non-transplant setting) prior to initiating the nonmyeloablative transplant conditioning; (exceptions are hydroxyurea and imatinib mesylate)
  • DONOR: Marrow donors
  • DONOR: Positive crossmatch between donor and recipient
  • DONOR: Donor is HIV-positive and/or has a medical condition that would result in increased risk for filgrastim (G-CSF) mobilization and harvest of PBSC
  • DONOR: Donor age < 12 years

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: Treatment (chemotherapy, TBI, transplant)

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0.

ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Other: laboratory biomarker analysis
Correlative studies
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Procedure: peripheral blood stem cell transplantation
Undergo PBSCT
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Biological: alemtuzumab
Given IV
Other Names:
  • Campath-1H
  • anti-CD52 monoclonal antibody
  • MoAb CD52
  • Monoclonal Antibody Campath-1H
  • Monoclonal Antibody CD52
Radiation: total-body irradiation
Undergo low-dose TBI
Other Names:
  • TBI
Drug: cyclosporine
Given PO or IV
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic stem cell transplantation
Biological: graft versus host disease prophylaxis/therapy
Undergo GVHD prophylaxis/therapy
Other Names:
  • prophylaxis/therapy, graft versus host disease
  • prophylaxis/therapy, GVHD

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Grade III-IV Acute GVHD
Time Frame: 100 days after transplant

Severity of Individual Organ Involvement

Liver:

Stage 2 - bilirubin (3-5.9mg/100ml) Stage 3 - bilirubin (6-14.9mg/100ml) Stage 4 - bilirubin > 15mg/100ml

Gut:

Diarrhea is graded stage 1 to stage 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as stage 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall

Severity of GVHD

Grade III - Stage 2 to 4 gastrointestinal involvement and/or Stage 2 to 4 liver involvement with or without a rash Grade IV - Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death
100 days after transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Graft Rejection
Time Frame: 84 days after transplant
Percentage patients that experienced graft rejection.
84 days after transplant
Incidence of High-dose Corticosteroid Utilization.
Time Frame: 100 days after transplant
Percentage patients requiring steroids greater than 1 mg/kg.
100 days after transplant
Incidence of Non-relapse Mortality
Time Frame: 100 days after transplant
Percentage patient deaths due to non-relapse mortality
100 days after transplant
Incidence of Infection
Time Frame: Up to 5 years post-transplant
Percentage patients that experienced infection(s).
Up to 5 years post-transplant
Immune Reconstitution
Time Frame: Up to 1 year post-transplant
The outcome of immune reconstitution was not analyzed by the collaborating laboratory because only a small number of patients were only enrolled in Dose Level 1 (no alemtuzumab). The Dose Level 1 patients were going to be the baseline for which to compare the other patients on Dose Level 2 (and 3) who would have received alemtuzumab. The collaborating investigator determined that the study was not worthwhile performing based on this information.
Up to 1 year post-transplant
Disease Progression/Relapse
Time Frame: Up to 5 years

CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever greater than 38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes >20%.

AML, ALL >5% marrow blasts by morphologic or flow cytometric, or appearance of extramedullary disease.

CLL ≥1 of: Physical exam/Imaging studies (nodes, liver, and/or spleen) ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation.

NHL >25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions.

MM

≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions.
Up to 5 years

Collaborators and Investigators

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

Sponsor

Fred Hutchinson Cancer Center

Collaborators

National Cancer Institute (NCI)

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

March 1, 2005

Primary Completion (Actual)

July 1, 2010

Study Completion (Actual)

May 26, 2015

Study Registration Dates

First Submitted

July 8, 2005

First Submitted That Met QC Criteria

July 8, 2005

First Posted (Estimate)

July 11, 2005

Study Record Updates

Last Update Posted (Actual)

May 30, 2017

Last Update Submitted That Met QC Criteria

April 25, 2017

Last Verified

April 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1959.00 (Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium)
  • P30CA015704 (U.S. NIH Grant/Contract)
  • NCI-2009-01496 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • P01CA018029 (U.S. NIH Grant/Contract)

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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