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Donor Stem Cell Transplant or Donor White Blood Cell Infusions in Treating Patients With Hematologic Cancer

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ClinicalTrials.gov Identifier: NCT00281879
Recruitment Status : Terminated
First Posted : January 25, 2006
Results First Posted : June 19, 2012
Last Update Posted : September 27, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Richard Maziarz, OHSU Knight Cancer Institute

Tracking Information
First Submitted Date  ICMJE January 24, 2006
First Posted Date  ICMJE January 25, 2006
Results First Submitted Date  ICMJE May 17, 2012
Results First Posted Date  ICMJE June 19, 2012
Last Update Posted Date September 27, 2017
Study Start Date  ICMJE February 2006
Actual Primary Completion Date February 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 2, 2012)
Number of Participants With Disease Free Survival (DFS). [ Time Frame: Duration of the study; Up to 2 years ]
Determine the effectiveness of unrelated donor allogeneic hematopoietic stem cells for transplantation after conditioning for the treatment of high-risk hematopoietic malignancies. Disease-free survival: The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00281879 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Donor Stem Cell Transplant or Donor White Blood Cell Infusions in Treating Patients With Hematologic Cancer
Official Title  ICMJE Transplantation of Unrelated Donor Hematopoietic Stem Cells for the Treatment of Hematological Malignancies
Brief Summary

RATIONALE: A peripheral stem cell transplant or an umbilical cord blood transplant from a donor may be able to replace blood-forming cells that were destroyed by chemotherapy or radiation therapy. Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) after the transplant may help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells can make an immune response against the body's normal cells. Methotrexate, cyclosporine, tacrolimus, or methylprednisolone may stop this from happening.

PURPOSE: This clinical trial is studying how well a donor stem cell transplant or donor white blood cell infusions work in treating patients with hematologic cancer.

Detailed Description

OBJECTIVES:

Primary

  • Determine the effectiveness of unrelated donor allogeneic hematopoietic stem cells for transplantation after conditioning for the treatment of patients with high-risk hematologic malignancies.
  • Compare survival, disease-free survival (DFS), response rate, and toxicity rates in these patients with historical controls.
  • Compare the rate and severity of acute and chronic GVHD after allogeneic hematopoietic stem cell transplantation in patients with hematopoietic malignancies with historical controls transplanted with stem cells from related sibling donors
  • Assess engraftment, long-term hematopoietic recovery, relapse rate, and disease-free survival when allogeneic hematopoietic stem cells are used as a source of stem cells for transplantation in patients with high-risk hematological malignancies.
  • Assess engraftment, long-term hematopoietic recovery, and overall survival when allogeneic hematopoietic stem cells are used as a source of stem cells for transplantation in patients who have graft failure or graft rejection.
  • Compare engraftment, long-term hematopoietic recovery, rate of GVHD, rate of relapse, toxicity rates, overall disease-free survival and overall survival when donor leukocyte infusions (DLI) are given for patients who have disease recurrence, progression, or low donor chimerisms after unrelated stem cell transplantation or before DLI with historical controls of other donor leukocyte infusions.

Secondary

  • Determine the quality of life of patients undergoing hematopoietic stem cell transplantation or donor leukocyte infusions from unrelated HLA genotypically-identical donors.

OUTLINE: Patients are assigned to 1 of 8 treatment groups.

  • Group 1*: Patients undergo total body irradiation (TBI) twice a day on days -7 to -4. Patients then receive cyclophosphamide IV over 1 hour on days -3 and -2. On day 0 patients undergo stem cell transplantation (SCT). Beginning on day 7, patients receive filgrastim (G-CSF) IV once daily until blood counts recover.
  • Group 2 (patients who have previously experienced dose-limiting radiotherapy): Patients receive oral busulfan 4 times daily on days -7 to -4 and cyclophosphamide IV over 1 hour on days -3 and -2. On day 0 patients undergo SCT. Beginning on day 7, patients receive G-CSF IV once daily until blood counts recover.
  • Group 3 (pediatric patients only): Patients receive busulfan IV 4 times daily on days -9 to -6 and cyclophosphamide IV over 1 hour and fludarabine IV over 30 minutes on days -5 to -2. On day 0 patients undergo SCT. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
  • Group 4 (second SCT for patients who have experienced graft rejection or failure)*: Patients receive low-dose fludarabine IV over 30 minutes on days -4 to -2. Patients then undergo low-dose TBI once followed by SCT on day 0. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
  • Group 5 (patients who developed grade 3 cystitis after prior cyclophosphamide-containing therapy): Patients receive carmustine IV over 2 hours on day -6, etoposide IV over 2 hours and cytarabine IV over 30 minutes on days -5 to -2, and melphalan IV over 30 minutes on day -1 (BEAM). On day 0, patients undergo SCT. Beginning on day 7, patients receive G-CSF IV once daily until blood counts recover.
  • Group 6 (cord blood transplantation): Patients receive anti-thymocyte globulin IV once daily and methylprednisolone IV twice daily on days -3 to -1. On day 0, patients undergo an umbilical cord blood SCT.
  • Group 7 (patients with relapsing or progressive disease after prior transplants or low donor chimerisms)*: Patients must not have existing graft-versus-host disease (GVHD). Patients receive donor lymphocyte infusions with conditioning chemotherapy and/or radiotherapy at the discretion of the investigator.
  • Group 8 (pediatric patients only)*: Patients undergo TBI twice a day on days -7 to -5. Patients also receive etoposide IV over 24 hours on day -4 and cyclophosphamide IV over 1 hour on days -3 and -2. On day 0, patients undergo SCT. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.

NOTE: *Patients who have received > 3000 cGy to the central nervous system or > 2000 cGy to the lung or liver may not receive any regimen containing total body irradiation (TBI)

All patients receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11; cyclosporine and/or tacrolimus on days -2 to 100; and/or methylprednisolone IV on days 7 to 100.

Patients with an unrelated donor who experience a relapse prior to transplantation, may proceed directly to transplantation. However, if immediate transplantation from the unrelated donor is not possible, the patient must be re-induced into a complete hematological remission. Patients who experience graft failure or graft rejection after allogeneic transplantation are eligible for a second stem cell infusion from the original donor.

Quality of life is assessed at baseline and at 7 days, 3 months, and 1 year after transplantation.

After completion of study treatment, patients are followed periodically for survival.

PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Myeloproliferative Disorders
  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasms
  • Unusual Cancers of Childhood
Intervention  ICMJE
  • Biological: anti-thymocyte globulin
    Intravenous, 1.5 mg/kg of body weight daily for 7 to 14 days The first dose should be administered over a minimum of 6 hours and over at least 4 hours on subsequent doses through a high-flow vein.
    Other Name: ATG
  • Biological: filgrastim

    Will be given IV at 5 µg/kg/day. The first injection will be administered on day +7, i.e. 7 days after the hematopoietic stem cells are infused.

    Will be administered until the ANC is 1500 / µl for 2 days. Dose and schedule of G-CSF administration is left to each center's discretion.

    Other Name: G-CSF
  • Drug: busulfan
    Patients who take the drug PO, busulfan will be administered at 1 mg/kg/ dose given by mouth every 6 hours for 16 consecutive doses. Pediatric patients who receive busulfan IV continuous infusion will receive a dose of 3.0 mg/kg/IBW if under the age of 2.Pediatric patients over the age of 2 will receive busulfan at a dose of 0.8 mg/kg/dose.
  • Drug: carmustine
    300mg/m2 IV dissolved in 500 cc NS infused over 2 hours into right atrial catheter on day -6.
  • Drug: cyclophosphamide
    For transplantation, the drug is diluted in 250 to 500 cc of NS or D5W and administered IV over 2 hours.
  • Drug: cyclosporine
    Initial doses will be administered IV at a starting dose of 1.5 mg/kg BID. The infusion will vary from 2-24hr depending on the incidence of side-effects.
  • Drug: cytarabine
    400 mg/m2 dissolved in 200cc D5W and infused over 30 minutes into right atrial catheter on days -5, -4, -3, -2.
  • Drug: etoposide

    Etoposide administration 200 mg /m2 dissolved in 1 liter NS and infused over 2 hours into right atrial catheter. Infusion to begin after cytarabine administration on days -5, -4, -3, -2.

    Etoposide administration 50 mg/kg IV over 24 hours, divided into 3 doses. Dilute in normal saline at a concentration of 0.4 mg/ml (Observe for precipitation). Administered IV with continuous infusion over 24 hours. Diuretics may be given for fluid overload.

  • Drug: fludarabine phosphate

    Fludarabine administered at 30 mg/m2 IVPB infused over 30 minutes into right atrial catheter on days -4, -3, -2.

    Fludarabine administered at 40 mg/m2 IVPB infused over 30 into the right atrial catheter on days -5, -4, -3, and -2.

  • Drug: melphalan
    140 mg /m2 in concentration of 0.45 mg/ml of NS infused over 30 minutes into right atrial catheter on day -1.
  • Drug: methotrexate
    Administered on days +1, +3, and +7.
  • Drug: methylprednisolone
    Methyl-prednisolone is administered IV as a rapid infusion.
  • Drug: mycophenolate mofetil
    Mycophenolate may be used as a substitute for Methotrexate
  • Drug: tacrolimus
    A drug used to decrease the risk of graft versus host disease (GvHD).
    Other Name: FK-506
  • Procedure: peripheral blood stem cell transplantation
    The stem cells will be given to you by intravenous injection (through your vein) using a catheter that was placed prior to beginning chemotherapy. The stem cell infusion takes 1-6 hours.
  • Procedure: umbilical cord blood transplantation
    The patient will receive ATG to improve the changes of engraftment and decrease their risk of graft versus host disease. The patient may receive ATG 3 times during their transplant regimen on days -3 through days -1
  • Radiation: radiation therapy
    Radiation will be given to you 2 times a day for 3 or 4 days.
Study Arms  ICMJE
  • Active Comparator: Cyclophosphamide (Cytoxan) and Total Body Irradiation (TBI)
    Interventions:
    • Biological: filgrastim
    • Drug: cyclophosphamide
    • Drug: cyclosporine
    • Drug: methotrexate
    • Drug: mycophenolate mofetil
    • Drug: tacrolimus
    • Procedure: peripheral blood stem cell transplantation
    • Radiation: radiation therapy
  • Active Comparator: Busulfan and Cyclophosphamide (Cytoxan)
    Interventions:
    • Biological: filgrastim
    • Drug: busulfan
    • Drug: cyclophosphamide
    • Drug: cyclosporine
    • Drug: methotrexate
    • Drug: mycophenolate mofetil
    • Drug: tacrolimus
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: BEAM Regimen
    On the day of your admission, you will start to take a drug called allopurinol which helps to protect your kidneys as your body works to discharge cells killed off by your chemotherapy and TBI. Chemotherapy will begin on Day -6 with carmustine (BCNU), followed by etoposide (VP-16), cytosine arabinoside (ARA-C), and melphalan. This conditioning regimen is known as the BEAM regimen. The dose of this therapy is high enough to kill cancer cells but will also kill all of your normal blood forming cells. Subjects undergoing the BEAM regimen will not have total body irradiation (TBI).
    Interventions:
    • Biological: filgrastim
    • Drug: carmustine
    • Drug: cyclosporine
    • Drug: cytarabine
    • Drug: etoposide
    • Drug: melphalan
    • Drug: methotrexate
    • Drug: mycophenolate mofetil
    • Drug: tacrolimus
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: Low-Dose Fludarabine and TBI(for second stem cell donation)
    A conditioning regimen of low-dose fludarabine and TBI is used in the event that a second donation of hematopoietic stem cells is necessary. Chemotherapy with Fludarabine will begin 4 days prior to your transplant. This drug will be given through the catheter in your chest daily for 3 days. TBI (radiation) will be given to you on the day of your transplant. After your TBI, your donor's stem cells / bone marrow will be given to you through your catheter. The drugs cyclosporine and mycophenolate mofetil (MMF) will be given orally to help you accept your donor's cells.
    Interventions:
    • Biological: filgrastim
    • Drug: cyclosporine
    • Drug: fludarabine phosphate
    • Drug: methotrexate
    • Drug: mycophenolate mofetil
    • Drug: tacrolimus
    • Procedure: peripheral blood stem cell transplantation
    • Radiation: radiation therapy
  • Active Comparator: Busulfan, Cyclophosphamide, and Fludarabine (Pediatric only)
    On the day of your admission you will start to take a drug called Dilantin which is used to help prevent seizures while you receive your chemotherapy drugs. You will also start to take a drug called allopurinol which helps to protect your kidneys as your body works to discharge cells killed off by your chemotherapy and TBI. On the next day, you will then begin your conditioning therapy with a drug called busulfan. This medicine will be given to you by an infusion into your bloodstream through a small tube in the vein of your arm four times per day for four days. After the busulfan treatment, you will receive 4 doses each of two drugs, cyclophosphamide (also known as Cytoxan) and fludarabine, over 2 hours into your vein.
    Interventions:
    • Biological: filgrastim
    • Drug: busulfan
    • Drug: cyclophosphamide
    • Drug: cyclosporine
    • Drug: fludarabine phosphate
    • Drug: methotrexate
    • Drug: mycophenolate mofetil
    • Drug: tacrolimus
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: ATG For Cord Blood Transplants
    If you are undergoing a pre-transplant conditioning regimen prior to undergoing a cord blood transplant, you will receive a drug called ATG to improve your chances of engraftment and decrease your risk of graft versus host disease. You may receive ATG 3 times during your transplant regimen on days -3 through days -1 in addition to your pre-transplant conditioning therapy. Methylprednisolone will also be given during each dose of ATG to help reduce any reactions during infusion.
    Interventions:
    • Biological: anti-thymocyte globulin
    • Biological: filgrastim
    • Drug: cyclosporine
    • Drug: methotrexate
    • Drug: methylprednisolone
    • Drug: mycophenolate mofetil
    • Drug: tacrolimus
    • Procedure: peripheral blood stem cell transplantation
    • Procedure: umbilical cord blood transplantation
  • Active Comparator: DLI (Donor Leukocyte Infusion)
    Donor Leukocyte Infusions: You will receive DLI from your original transplant donor. This will be given through a vein , usually in your arm. It will be similar to getting a platelet or blood transfusion. You may require more than one DLI. The decision to give you another infusion will be determined by your condition, relapse status, GVHD and how much DLI you were given before. You may need chemotherapy and/or radiation to improve your disease status prior to additional DLI's.
    Interventions:
    • Biological: filgrastim
    • Drug: cyclosporine
    • Drug: methotrexate
    • Drug: mycophenolate mofetil
    • Drug: tacrolimus
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: Cyclophosphamide, Etoposide (VP16) and TBI (Pediatric only)
    On the day after your admission, you will start receiving radiation therapy (TBI). Radiation will be given to you 2 times a day for 3 days. On the next day, you will then begin your chemotherapy with a drug called etoposide. This medicine will be given to you by an infusion into your bloodstream through a small tube in the vein of your arm for one day. After the etoposide treatment, on the next day you will receive cyclophosphamide (also known as Cytoxan) for 2 days. When you are given cyclophosphamide, you will also be given a medication called MESNA to help protect your bladder from damage. After you have completed the cyclophosphamide you will rest one day without any anti-cancer therapy. This allows your body time to remove and inactivate the chemotherapy. After a day of rest, you will be given your donor's cells.
    Interventions:
    • Biological: filgrastim
    • Drug: cyclophosphamide
    • Drug: cyclosporine
    • Drug: etoposide
    • Drug: methotrexate
    • Drug: mycophenolate mofetil
    • Drug: tacrolimus
    • Procedure: peripheral blood stem cell transplantation
    • Radiation: radiation therapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 17, 2012)
200
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE March 2008
Actual Primary Completion Date February 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following*:

    • Acute lymphoblastic leukemia in any disease phase

      • Patients with any of the following high-risk features are encouraged to enroll:

        • Philadelphia chromosome positive disease
        • L3 morphology, especially in the presence of t(8;14), t(8;22), or t(2;8)
        • Patients not in remission at day 28 of first induction
        • High LDH (i.e., ≥ 300 IU/mL at presentation)
        • Pre-B-cell, mixed lineage, or Burkitt's markers
        • Relapsed in the marrow while receiving continuous chemotherapy
        • Within 6 months after stopping chemotherapy
        • Relapse in one organ or extramedullary relapses in more than one organ while still receiving chemotherapy
    • Hodgkin's or non-Hodgkin's lymphoma beyond first complete remission (CR) or in first CR with features of high-risk disease, including, but not limited to:

      • Lymphoma not in CR after 3 courses of primary therapy
      • Patients with bulky disease at presentation, especially bulky mediastinal disease
      • Patients with LDH ≥ 300 IU/mL at presentation
      • Patients with extranodal disease
      • Patients with first remission within less than 1 year
      • Stage IV disease at presentation, especially with marrow involvement
      • Patients with high-intermediate or high International Index Scores
    • Acute myeloid leukemia (AML) meeting the following criteria:

      • Beyond first remission or high-risk disease in first CR
      • Required multiple courses of induction therapy to achieve a remission
      • Had residual leukemia on day 14-28 bone marrow examination after initial induction
      • Patients with any cytogenetic abnormality except inv 16 or t(8;21)
    • Chronic myelogenous leukemia in the chronic or early accelerated phase of the disease

      • Patients with blast crisis that can be induced back into chronic phase may be transplanted in second chronic phase
    • Myelodysplastic syndromes (MDS) meeting the following requirements:

      • Transfusion-dependent refractory anemia (RA), RA with excess blasts (RAEB), RAEB in transformation, or chronic myelomonocytic leukemia (CMML)
      • Patients with MDS that present with or evolve to AML must be re-induced back to remission prior to initiating a search for an unrelated donor NOTE: *Patients with other hematologic malignancies not listed above, including diseases such as chronic lymphocytic leukemia (CLL), multiple myeloma, or rare pediatric malignancies, or patients who are felt to be at high-risk for relapse but who do not have features listed, may be allowed at the discretion of the investigator.
  • Must have failed prior stem cell transplantation
  • Must have a suitable unrelated allogeneic hematopoietic stem cell donor

    • A 5/6 match degree is acceptable for unrelated bone marrow donors
    • A 4/6 match degree is acceptable for unrelated cord blood units

PATIENT CHARACTERISTICS:

  • SWOG performance status (PS) 0-2 OR
  • Karnofsky PS 50-100% OR
  • Lansky PS 50-100%
  • Creatinine clearance ≥ 45 mL/min
  • Creatinine ≤ 2.5 mg/dL
  • Bilirubin ≤ 2 mg/dL (abnormally high liver function tests allowed if the only source for the elevation is due to lymphoma of the liver)
  • AST or ALT ≤ 2 times normal (abnormally high liver function tests allowed if the only source for the elevation is due to lymphoma of the liver)
  • No patients at high risk of veno-occlusive disease
  • Not pregnant or nursing
  • Negative serum pregnancy test
  • Fertile patients must use an effective contraceptive method
  • DLCO ≥ 50% of predicted
  • FEV_1/FVC ≥ 65% of predicted
  • No current congestive heart failure (CHF) and/or LVEF ≥ 45%
  • No myocardial infarction within the past 6 months
  • No unstable angina within the past 6 months
  • HIV negative
  • Life expectancy must not be limited by disease other than malignancy
  • No allergy to any chemotherapeutic agent included in the regimen

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 60 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00281879
Other Study ID Numbers  ICMJE CDR0000452794
P30CA016058 ( U.S. NIH Grant/Contract )
OHSU-TPI-9695-L
OHSU-540
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Richard Maziarz, OHSU Knight Cancer Institute
Study Sponsor  ICMJE OHSU Knight Cancer Institute
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: Richard Maziarz, MD OHSU Knight Cancer Institute
PRS Account OHSU Knight Cancer Institute
Verification Date September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP