AzTrials
AzTrials

Chronic Lymphocytic LeukemiaPhase 2NCT00104858

Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

A Phase 2 study testing Allogeneic Hematopoietic Stem Cell Transplantation, Cyclosporine and Fludarabine Phosphate in people with Chronic Lymphocytic Leukemia and Prolymphocytic Leukemia, run by Fred Hutchinson Cancer Center at 5 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This phase II trial studies how well fludarabine phosphate with radiation therapy and rituximab followed by donor stem cell infusions work in treating patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with low side effects. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Allogeneic Hematopoietic Stem Cell Transplantation, Cyclosporine and Fludarabine Phosphate
Could I receive a placebo?
No, everyone receives an active treatment
How many people
66 participants
Where
5 sitesin 3 countries
Study dates
Dec 2004to 30 Mar 2018
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with a diagnosis of CLL (or SLL) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL)
  • Patients with B-Cell CLL or PLL who:
  • Failed to meet National Cancer Institute (NCI) Working Group criteria 2 for complete or partial response after 2 cycles of therapy with regimen containing fludarabine (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin) or with disease relapse within 12 months after completing therapy with a fludarabine (or another nucleoside analog) containing regimen
  • Failed FCR or pentostatin/cyclophosphamide/rituximab (PCR) combination chemotherapy at any time point
  • Patients with novo or acquired "17p deletion" cytogenetic abnormality; patients should have received induction treatment but could be transplanted in 1st CR
  • Patients who have suitable human leukocyte antigen (HLA)-matched related or unrelated donors willing to receive filgrastim (G-CSF), undergo leukapheresis to collect peripheral blood mononuclear cell (PBMC), and to donate stem cells
Show all 18Show fewer
  • RELATED DONORS: When more than one potential donor exists, priority should be given to donors based on HLA identity > cytomegalovirus (CMV) seronegativity > ABO compatibility > sex matching
  • Donor who is HLA phenotypically or genotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1
  • Must consent to G-CSF administration and leukapheresis;
  • Must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian);
  • Only G-CSF mobilized PBMC only will be permitted as a hematopoietic stem cell (HSC) source on this protocol
  • UNRELATED DONORS:
  • Fred Hutchinson Cancer Research Center (FHCRC) matching allowed will be Grades 1.0 to 2.1; Unrelated donors who are prospectively:
  • Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing
  • Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
  • UNRELATED DONORS: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody screens to class I and II antigens for all patients before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results; a positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
  • UNRELATED DONORS: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed
  • UNRELATED DONORS: Only G-CSF mobilized PBMC will be permitted as a HSC source on this protocol

Who cannot join

  • Infection with human immunodeficiency virus (HIV)
  • Active diagnosis of central nervous system (CNS) involvement with CLL
  • Patients unwilling to use contraceptive techniques before and for 12 months after HCT
  • Pregnant women or females who are breastfeeding
  • The addition of cytotoxic agents for 'cytoreduction' with the exception of tyrosine kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning
  • Active bacterial or fungal infections unresponsive to medical therapy
Show all 19Show fewer
  • Performance status: Karnofsky score < 60 for adult patients
  • Cardiac ejection fraction < 40%; ejection fraction is required if age > 50 years or there is a history of prior transplant, anthracycline exposure or history of cardiac disease; and poorly controlled hypertension despite multiple antihypertensives
  • Diffusing capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in 1 second (FEV1) < 40% and/or requiring continuous supplementary oxygen, or severe deficits in pulmonary function testing as defined by pulmonary consultant service; and the FHCRC principal investigator (PI) of the study must approve of enrollment of all patients with pulmonary nodules
  • Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, hepatic damage with bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices or hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced 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 > 3 mg/dl, or symptomatic biliary disease
  • Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • 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; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • DONOR: Age < 12 years
  • DONOR: Identical twin
  • DONOR: Pregnancy
  • DONOR: Infection with HIV
  • DONOR: Inability to achieve adequate venous access
  • DONOR: Known allergy to filgrastim (G-CSF)
  • DONOR: Current serious systemic illness

Trial locations and contacts

5 sites in 3 countries.

5 sites in 3 countries

United States3 sites

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • VA Puget Sound Health Care System

    Seattle, Washington, 98101

  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

Denmark1 site

  • Rigshospitalet University Hospital

    Copenhagen, 2100

Other trials in Denmark

Italy1 site

  • University of Torino

    Torino, 10126

Other trials in Italy

About this study

Official title: Nonmyeloablative Conditioning With Pre- and Post-Transplant Rituximab Followed by Related or Unrelated Donor Hematopoietic Cell Transplantation for Patients With Advanced Chronic Lymphocytic Leukemia: A Multi-Center Trial

This phase II trial studies how well fludarabine phosphate with radiation therapy and rituximab followed by donor stem cell infusions work in treating patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with low side effects. Nonmyeloablative stem cell transplants use low doses of chemotherapy (fludarabine phosphate) and radiation to suppress the patient's immune system enough to prevent rejection of the donor's stem cells. Following infusion of donor stem cells, a mixture of the patient's and the donor's stem cells will exist and is called "mixed chimerism". Donor cells will attack the patient's leukemia. This is called the "graft-versus-leukemia" effect. Rituximab will be given 3 days before and three times after infusing stem cells to help in controlling CLL early after transplant till the "graft-versus-leukemia" takes control. Further, rituximab could augment the "graft-versus-leukemia" effect by activating donor immune cells and hence improve disease control. Sometimes the transplanted cells from a donor can also attack the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Read the detailed description

PRIMARY OBJECTIVES:

  1. Determine whether nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation (HCT) improves survival at 18 months for patients with fludarabine (fludarabine phosphate)-refractory, fludarabine/cyclophosphamide/rituximab (FCR)-failed, or del 17p CLL over that of historical controls (45% at 18 months) given CAMPATH-1H (alemtuzumab).

SECONDARY OBJECTIVES:

  1. Estimate the overall response rate (complete remission [CR] + partial remission [PR]) by standard morphologic, flow cytometric, and molecular techniques.

II. Assess the rate of relapse/progression.

III. Define incidences of regimen-related toxicities (RRT) and infections within the first 100 days and the incidence of transplant-related mortality (TRM) within the first year.

IV. Estimate incidences of grade II-III and III-IV acute graft-versus-host disease (GVHD) and chronic GVHD.

  1. Determine whether the addition of rituximab to the nonmyeloablative conditioning and allogeneic HCT improves survival at 18 months over our historical data (57% at 18 months).

VI. Determine the incidence of serious adverse events with the addition of rituximab in comparison to historical data of unrelated nonmyeloablative HCT.

VII. Evaluate the pharmacokinetics of rituximab.

VIII. Evaluate B-cell and T-cell immune reconstitution in comparison to historical data of unrelated nonmyeloablative HCT.

IX. Describe donor and host polymorphisms of the FCgammaRIIIa receptor and cluster of differentiation (CD)32 and evaluate their impact on disease response and relapse.

  1. Investigate the mechanism of disease resistance in relapsed/nonresponding patients.

XI. Isolate donor cytotoxic T lymphocytes specific for host minor histocompatibility antigens.

OUTLINE:

Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV) on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38.

Patients undergo single fraction low-dose total-body irradiation (TBI) on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) on day 0. Patients then receive rituximab IV on days 10, 24, and 38.

Patients receive an immunosuppressive regimen comprising cyclosporine orally (PO) twice daily (BID) on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or three times daily (TID) on days 0-40 followed by a taper to day 96 (unrelated recipients).

After completion of study treatment, patients are followed up at 6 months, 1 year, 18 months, 2 years, and then annually thereafter.

Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Prolymphocytic, Leukemia, Large Granular Lymphocytic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT00104858
Study groupRoleWhat they receive
TreatmentExperimentalPatients receive a conditioning regimen comprising fludarabine IV on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38. Patients undergo single fraction low-dose TBI on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive rituximab IV on days 10, 24, and 38. Patients receive an immunosuppressive regimen comprising cyclosporine PO BID on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or TID on days 0-40 followed by a taper to day 96 (unrelated recipients).
Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Biological: Rituximab; Radiation: Total-Body Irradiation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Survival

    Number of participants surviving post-transplant

    Measured: At 18 months

Secondary outcomes (9)

  1. Comparison of Survival, Serious Adverse Events, and B-cell and T-cell Immune Reconstitution With Historical Data

    Measured: At 18 months

  2. Number of Participants With Relapse/Progression

    Relapse/Progression criteria for CLL

    Progressive disease:

    ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation.

    Relapsed disease:

    Criteria of progression occurring 6 months after achievement of complete or partial remission.

    Measured: Day 84

  3. Graft-versus-leukemia Analysis by Mechanism of Disease Resistance in Relapsed or Non-responding Patients and Isolation of Donor Cytotoxic T Lymphocytes Specific for Host Minor Histocompatibility Antigens

    Measured: Day 84

  4. Number of Participants With Grade II-III and III-IV Acute GVHD and Chronic GVHD

    Number of patients who developed acute GVHD post-transplant. Grade I +1 to +2 skin rash, No gut or liver involvement Grade II +1 to +3 skin rash, +1 gastrointestinal involvement and/or +1 liver involvement Grade III +2 to +4 gastrointestinal involvement and/or +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

    The diagnosis of chronic GVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD.

    Measured: Up to 1 year

  5. Number of Participants With Regimen-related Toxicity and Infections

    Reported using the adapted National Cancer Institute Common Toxicity Criteria.

    Measured: Within the first 100 days

  6. Number of Participants With Treatment-related Mortality

    Number of subjects expired without disease progression/relapse.

    Measured: Up to 1 year

  7. Rituxan Concentration

    Median rituxan level at days 60, 84, 180, and 1 year.

    Measured: Days 60, 84, 180, and 1 year

  8. Number of Patients Achieving Complete Response and Partial Response (Overall Response Rate)

    Complete Remission (CR):

    Imaging studies (Xray, CT, MRI) (nodes, liver, and spleen): Normal Peripheral blood by flow cytometry: No clonal lymphocytes Bone marrow by morphology: No nodules; or if present, nodules are free from CLL cells by immunohistochemistry Duration: ≥2 months

    CR with minimal residual disease Peripheral blood or bone marrow by flow cytometry: >0 - <1 CLL cells/1000 leukocytes (0.1%)

    Partial Remission (PR):

    Both criteria:

    Absolute lymphocyte count in peripheral blood: ≥50% decrease Physical exam/Imaging studies (nodes, liver, and/or spleen): ≥50% decrease Duration: ≥2 months

    Measured: Up to 1 year

  9. Donor and Host Polymorphisms of the FCgammaRIIIa Receptor and CD32 and Their Impact on Disease Response and Relapse

    Number of participants without progressive disease and surviving at one year. Participants with FCgammaRIIIa receptor vs participants without FCgammaRIIIa receptor.

    Measured: 1 Year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Mar 2005 (estimated)
  2. Study startDec 2004
  3. Primary completion30 Mar 2018
  4. Study completion30 Mar 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
66 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00104858
Sponsor's protocol ID
1840.00
Other IDs
NCI-2009-01594, 1840.00, P01CA018029, P30CA015704
Status last verified
Jun 2019
First submitted
3 Mar 2005
Last updated
11 Jul 2019
Data monitoring committee
Yes

Publications

  • Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.

    PubMed 32499241

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Allogeneic Hematopoietic Stem Cell Transplantation, Cyclosporine and Fludarabine Phosphate in people with Chronic Lymphocytic Leukemia and Prolymphocytic Leukemia, run by Fred Hutchinson Cancer Center at 5 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States, Denmark, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Jul 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival (time frame: At 18 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00104858, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jul 2019.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in