Fludarabine Phosphate, Low-Dose Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer

September 6, 2019 updated by: Fred Hutchinson Cancer Center

Low-Dose TBI and Fludarabine Followed by Unrelated Donor Stem Cell Transplantation for Patients With Hematologic Malignancies and Renal Cell Carcinoma - A Multi-center Trial

This clinical trial studies fludarabine phosphate, low-dose total body irradiation, and donor stem cell transplant in treating patients with hematologic malignancies or kidney cancer. Giving chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine before the transplant and 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 whether stable allogeneic engraftment from unrelated hematopoietic stem cell donors can be safely established using a non-myeloablative conditioning regimen in patients with hematologic malignancies and renal cell carcinoma.

SECONDARY OBJECTIVES:

I. To evaluate whether donor lymphocyte infusion (DLI) can be safely used in patients with mixed or full donor chimerism to eliminate persistent or progressive disease.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2. Patients also undergo low-dose total-body irradiation (TBI) on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell (PBSC) or bone marrow transplantation on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO BID on days 0-40 with taper to day 96. Patients with mixed chimerism, persistent or progressive disease, and no evidence of graft-versus-host disease and who have been off immunosuppression for at least 2 weeks undergo DLI over 30 minutes. DLI may be repeated every 65 days for up to 3 doses.

After completion of study treatment, patients are follow-up periodically for 5 years.

Study Type

Interventional

Enrollment (Actual)

55

Phase

  • Not Applicable

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

  • Germany
      • Leipzig, Germany, D-04103
        • Universitaet Leipzig
  • United States
    • California
      • Duarte, California, United States, 91010
        • City of Hope Medical Center
      • Stanford, California, United States, 94305
        • Stanford University Hospitals and Clinics
    • Colorado
      • Denver, Colorado, United States, 80217-3364
        • University of Colorado
    • Texas
      • Dallas, Texas, United States, 75246
        • Baylor University Medical Center
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Huntsman Cancer Institute/University of Utah
    • 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

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age > 50 years with hematologic malignancies treatable by allogeneic hematopoietic stem cell transplant (HSCT) and all patients with B cell malignancies except those who may be cured by autologous stem cell transplantation (SCT)
  • Age =< 50 years of age with hematologic diseases treatable by allogeneic HSCT who through pre-existing medical conditions or prior therapy are considered to be of high risk for regimen related toxicity associated with a conventional transplant or those patients who refuse a conventional SCT; transplants must be approved for these inclusion criteria 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 by the principal investigator
  • Patients with metastatic renal cell carcinoma with the histologic subtypes of clear cell, papillary and medullary may be accepted regardless of age

  • The following diseases will be permitted although other diagnoses can be considered if approved by PCC or the participating institution's patient review committees and the principal investigator

    • Non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL) - must have received and failed frontline therapy
    • Multiple myeloma - must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HSCT is permitted
    • Acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) - must be in complete remission and have received cytotoxic chemotherapy at some stage before transplant; patients with molecular or early relapse will be accepted providing a donor is available; patients with persistent or refractory disease will be considered on a case by case basis and transplants must be approved by the institution's patient review committees
    • Chronic myelogenous leukemia (CML) - patients will be accepted in chronic phase or accelerated phase; patients who have received prior autografts after high dose therapy or have undergone intensive chemotherapy for either peripheral blood stem cell (PBSC) mobilization or treatment of advanced CML may be enrolled provided they are in complete remission (CR), chronic phase (CP) or accelerated phase (AP)
    • Myelodysplastic syndromes (MDS) - all patients with MDS will be eligible for this protocol; however, those patients with MDS and frank AML (> 30% blasts in bone marrow aspirate by morphology or flow cytometry) will require induction chemotherapy to obtain a complete remission (marrow blasts < 5%) and remain in complete remission at time of transplant
    • Renal cell carcinoma- must have evidence of disease not amenable to surgical cure or metastatic disease by radiological and histological criteria
  • DONOR: Human leukocyte antigen (HLA) matched unrelated donor; donors should be matched for HLA -A, -B, -C, -developmentally regulated ribonucleic acid (RNA) binding protein 1(DRB)1 and -class II, DQ beta 1 (DQB) 1; HLA -A and -B loci should be matched at least to the level of resolution; HLA -C, -DRB1, and -DQB1 should be typed at the highest level of resolution available at the time of donor selection; donor must consent to either a bone marrow harvest or PBSC mobilization with filgrastim (G-CSF) arranged through the National Marrow Donor Program (NMDP) or other donor centers

Exclusion Criteria:

  • Patients with rapidly progressive intermediate or high grade NHL

  • Renal cell carcinoma patients with expected survival of less than 6 months

    • Bulky disease resulting in severely limited performance status (< 70%)
    • Any vertebral instability
  • Any active central nervous system (CNS) involvement with disease
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Females who are pregnant
  • Patients with non-hematological tumors
  • Cardiac ejection fraction < 30%
  • Diffusion capacity of the lung for carbon monoxide (DLCO) < 30% and/or receiving supplementary continuous oxygen
  • Significant elevation of bilirubin and transaminases should be discussed at participating institutions' patient review committees in a case by case basis; evidence of synthetic dysfunction or severe cirrhosis will result in patient exclusion
  • Karnofsky score < 50 (except renal cell carcinoma [RCC])
  • Patients with poorly controlled hypertension on multiple antihypertensives
  • Human immunodeficiency virus (HIV) positive patients

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, HSCT)

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSC or bone marrow transplantation on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO BID on days 0-40 with taper to day 96. Patients with mixed chimerism, persistent or progressive disease, and no evidence of graft-versus-host disease and who have been off immunosuppression for at least 2 weeks undergo DLI over 30 minutes. DLI may be repeated every 65 days for up to 3 doses.
Other: laboratory biomarker analysis
Correlative studies
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Radiation: total-body irradiation
Undergo low-dose TBI
Other Names:
  • TBI
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo nonmyeloablative HSCT
Procedure: allogeneic bone marrow transplantation
Undergo nonmyeloablative allogeneic bone marrow transplantation
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Procedure: peripheral blood stem cell transplantation
Undergo nonmyeloablative allogeneic PBSC transplantation
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Biological: therapeutic allogeneic lymphocytes
Undergo DLI
Other Names:
  • ALLOLYMPH
Drug: cyclosporine
Given PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Establishment of an allograft as defined by stable mixed chimerism or full donor chimerism
Time Frame: At day 56
Engraftment will be assessed separately among patients who receive bone marrow and patients who receive PBSC. Patients with low-risk and high-risk disease will be assessed separately.
At day 56

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease-free survival
Time Frame: Up to 200 days
Will be summarized.
Up to 200 days
Relapse
Time Frame: Assessed up to 5 years
Will be summarized.
Assessed up to 5 years
Disease-related mortality
Time Frame: Before day 200
Will be summarized.
Before day 200
Response of malignancy to DLI
Time Frame: Assessed up to 5 years
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Assessed up to 5 years
Incidence of myelosuppression
Time Frame: Greater than 2 days after initial PBSC infusion
Absolute neutrophil count (ANC) less than 500/ul for more than 2 days, platelets less than 20,000/ul for more than 2 days. Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Greater than 2 days after initial PBSC infusion
Incidence of aplasia after DLI
Time Frame: Greater than 2 days after initial PBSC infusion
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Greater than 2 days after initial PBSC infusion
Incidence of grades 2-4 acute GVHD after DLI
Time Frame: Until day 90
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Until day 90
Incidence of grades 2-4 acute GVHD after PBSC infusion
Time Frame: Up to day 177
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Up to day 177
Incidence of grades 2-4 chronic extensive GVHD after DLI
Time Frame: Assessed up to 5 years
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Assessed up to 5 years
Dose of CD3+ required to convert mixed to full lymphoid chimeras
Time Frame: Day 28 post-transplant
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Day 28 post-transplant
Dose of CD3+ required to convert mixed to full lymphoid chimeras
Time Frame: Day 56 post-transplant
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Day 56 post-transplant
Dose of CD3+ required to convert mixed to full lymphoid chimeras
Time Frame: Day 84 post-transplant
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Day 84 post-transplant
Incidence of infections
Time Frame: Assessed up to 5 years
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Assessed 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)
National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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

November 1, 1999

Primary Completion (Actual)

July 1, 2002

Study Registration Dates

First Submitted

June 2, 2000

First Submitted That Met QC Criteria

April 1, 2004

First Posted (Estimate)

April 2, 2004

Study Record Updates

Last Update Posted (Actual)

September 10, 2019

Last Update Submitted That Met QC Criteria

September 6, 2019

Last Verified

September 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1463.00 (Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium)
  • P30CA015704 (U.S. NIH Grant/Contract)
  • P01CA018029 (U.S. NIH Grant/Contract)
  • NCI-2012-00667 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

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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