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Trial record 17 of 48 for:    cord blood | ( Map: Canada )

Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00382109
Recruitment Status : Completed
First Posted : September 28, 2006
Results First Posted : February 9, 2017
Last Update Posted : August 7, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE September 26, 2006
First Posted Date  ICMJE September 28, 2006
Results First Submitted Date  ICMJE October 6, 2015
Results First Posted Date  ICMJE February 9, 2017
Last Update Posted Date August 7, 2019
Study Start Date  ICMJE March 2007
Actual Primary Completion Date May 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 16, 2016)
Estimated Percentage of Participants With Event Free Survival [ Time Frame: at 2 years ]
An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00382109 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2016)
  • Rate of Relapses [ Time Frame: At 2 years ]
    An event is defined as relapse.
  • Estimated Transplant Related Mortality Percentage [ Time Frame: 100 days ]
    Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event.
  • Estimated Rate of Acute Graft VS Host Disease (GVHD) [ Time Frame: At 200 days ]
    Any grade acute graft vs host disease (defined in APPENDIX II study protocol).
  • Estimated Rate of Overall Chronic Graft VS Host Disease [ Time Frame: At 2 years ]
    Chronic graft vs host disease is defined in APPENDIX III of study protocol.
  • Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation [ Time Frame: Up to 1 year ]
    An event is defined as relapse or transplant-related mortality.
  • Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) [ Time Frame: At 1 year ]
    An event is defined as relapse; estimated probability of relapse.
  • Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD) [ Time Frame: At 2 months ]
    An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available.
  • Chimerism [ Time Frame: Up to 12 months ]
    Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation.
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 Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission
Official Title  ICMJE A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia
Brief Summary This randomized phase III trial is studying tacrolimus, methotrexate, and sirolimus to see how well they work compared to tacrolimus and methotrexate in preventing graft-versus-host disease in young patients who are undergoing donor stem cell transplant for intermediate-risk or high-risk acute lymphoblastic leukemia in second complete remission and high risk acute lymphoblastic leukemia in first remission. Giving chemotherapy, such as thiotepa and cyclophosphamide, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also helps 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). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, and sirolimus after the transplant may stop this from happening. It is not yet known whether tacrolimus and methotrexate are more effective with or without sirolimus in preventing graft-versus-host disease.
Detailed Description

PRIMARY OBJECTIVES:

I. Compare the post-transplant 2-year event-free survival of pediatric patients with intermediate-risk or high-risk acute lymphoblastic leukemia (ALL) in second complete remission or high risk ALL in first remission undergoing allogeneic hematopoietic stem cell transplantation treated with graft-versus-host disease (GVHD) prophylaxis comprising tacrolimus and methotrexate with or without sirolimus.

SECONDARY OBJECTIVES:

I. Compare rates of relapses, transplant-related mortality, and acute and chronic GVHD in these patients.

II. Evaluate the relative contribution of resistance by ALL blasts to cytolytic therapy (e.g., chemotherapy/irradiation) as a cause of relapse post-transplantation by correlating ALL in vivo blast resistance with in vivo sirolimus, inhibition levels of the mTOR pathway in patients treated with sirolimus, and altered resistance pathways in ALL blasts measured by microarray analysis.

III. Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post-transplantation by correlating the development of donor anti-ALL T-cell response, the development of acute and/or chronic GVHD, and the detection of altered ALL blast immunogenicity after transplant with increased minimal residual disease, persistent recipient chimerism, and relapse.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to specific combinations of risk (intermediate CR2 vs high CR2 vs high CR1), donor type (matched sibling vs unrelated or other related), and stem cell source (filgrastim [G-CSF]-primed bone marrow vs unprimed bone marrow vs bone marrow vs peripheral blood vs umbilical cord blood).

PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily on days -8 to -6 and receive thiotepa IV on days -5 and -4 and cyclophosphamide IV on days -3 and -2.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients are randomized to 1 of 2 treatment arms.

ARM I: (experimental) Patients receive tacrolimus IV continuously or orally (when able) daily beginning on day -2 followed by a taper beginning on day 42 and continuing until day 98 (for patients undergoing matched sibling donor transplantation) OR tacrolimus IV continuously or orally daily beginning on day -2 followed by a taper beginning on day 100 and continuing until day 180 (for patients undergoing related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, and 6 (for patients with matched sibling and umbilical cord blood donors) OR days 1, 3, 6, and 11 (for patients with unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus daily beginning on day 0 followed by a taper beginning on day 180 and continuing until day 207.

ARM II: (control) Patients receive tacrolimus and methotrexate as in arm I.

After completion of study treatment, patients are followed periodically for approximately 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • B-cell Childhood Acute Lymphoblastic Leukemia
  • Childhood Acute Lymphoblastic Leukemia in Remission
  • Graft Versus Host Disease
  • L1 Childhood Acute Lymphoblastic Leukemia
  • L2 Childhood Acute Lymphoblastic Leukemia
  • T-cell Childhood Acute Lymphoblastic Leukemia
Intervention  ICMJE
  • Drug: thiotepa
    Given IV
    Other Names:
    • Oncotiotepa
    • STEPA
    • TESPA
    • Tespamin
    • TSPA
  • Drug: cyclophosphamide
    Given IV
    Other Names:
    • CPM
    • CTX
    • Cytoxan
    • Endoxan
    • Endoxana
  • Drug: tacrolimus
    Given IV or orally
    Other Names:
    • FK 506
    • Prograf
  • Drug: methotrexate
    Given IV
    Other Names:
    • amethopterin
    • Folex
    • methylaminopterin
    • Mexate
    • MTX
  • Drug: sirolimus
    Given orally
    Other Names:
    • AY 22989
    • Rapamune
    • rapamycin
    • SLM
  • Radiation: total body irradiation
    Part of the transplant preparatory regimen
    Other Name: TBI
Study Arms  ICMJE
  • Experimental: Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
    Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, & -6, Thiotepa IV (dose 5 mg/kg/day on days -5 & -4) & cyclophosphamide IV (dose 60 mg/kg/day on days -3 & -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, & 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, & 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207.
    Interventions:
    • Drug: thiotepa
    • Drug: cyclophosphamide
    • Drug: tacrolimus
    • Drug: methotrexate
    • Drug: sirolimus
    • Radiation: total body irradiation
  • Active Comparator: Tacro-MTX GVHD Prophylaxis
    Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, & -6, Thiotepa IV (dose 5 mg/kg/day on days -5 & -4) & cyclophosphamide IV (dose 60 mg/kg/day on days -3 & -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, & 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, & 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors).
    Interventions:
    • Drug: thiotepa
    • Drug: cyclophosphamide
    • Drug: tacrolimus
    • Drug: methotrexate
    • Radiation: total body irradiation
Publications *

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: June 14, 2013)
146
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE June 30, 2017
Actual Primary Completion Date May 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL) in second complete remission (CR2) (M1 bone marrow, < 5% blasts by morphology) meeting the following criteria:

    • Intermediate risk relapsed ALL in CR2 (may receive matched sibling transplantation only) meeting 1 of the following criteria:

      • B-lineage ALL in CR2 after a late first bone marrow (BM) relapse (≥ 36 months after the initiation of primary chemotherapy) with or without associated extramedullary disease
      • B-lineage ALL in CR2 after a very early isolated extramedullary relapse (<18 months from the initiation of primary chemotherapy)
    • High risk relapsed ALL in CR2 (may receive other related donor, unrelated donor, or matched sibling transplantation) meeting 1 of the following criteria:

      • In CR2 after an early first BM relapse (< 36 months from initiation of primary chemotherapy)
      • T-lineage ALL in CR2 after a first BM relapse occurring at any time after initiation of primary chemotherapy
      • Philadelphia chromosome-positive ALL in CR2 after a first BM relapse occurring at any time after the initiation of primary chemotherapy
      • T-lineage ALL in CR2 after a very early isolated extramedullary relapse (<18 months from the initiation of primary chemotherapy)
    • High risk de novo ALL in CR1 (may receive matched sibling, other related/unrelated BM/PBSC or unrelated CB transplantation) meeting 1 of the following criteria:

      • Patients with the presence of t(9;22) translocation (Ph+) detected by cytogenetic or PCR analysis at initial diagnosis. For patients on AALL0622, the criteria for transplant are 1) any patient with Ph+ ALL with an available matched sibling donor or 2) any patient with Ph+ ALL that is defined as high risk (MRD > 1% Day 29 or MRD > 0.01% end-Consolidation Block 2) with any available donor, related or unrelated. Patients enrolled on AALL0622 are only eligible if they follow this algorithm.
      • Patients with the presence of extreme hypodiploidy (< 44 chromosomes or DNA index of < 0.81) detected by cytogenetic/ploidy analysis at initial diagnosis.
      • Patients with the presence of 11q23 (MLL) rearrangements detected by cytogenetic or PCR analysis at initial diagnosis who are slow early responders (M2/M3 at Day 14 or MRD > 0.1% at Day 29).
  • Enrolled on an appropriate COG relapsed ALL clinical trial after completing the required study therapy (i.e., minimum 1 re-induction course (4-6 weeks) and 1 round of intensive consolidation chemotherapy (3-6 weeks). Patients with high risk ALL in CR1 are eligible as soon as they have achieved a CR.

    • Patients not on a COG relapsed ALL clinical trial are eligible provided they have received ≥ 1 round of re-induction lasting 4-6 weeks and 1 round of intensive consolidation chemotherapy lasting 3-6 weeks
  • No B-cell ALL L3 morphology with evidence of myc translocation by molecular or cytogenetic technique
  • No Down syndrome
  • No evidence of active CNS or other extramedullary disease (i.e., no CNS2)
  • Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age)
  • Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
  • ALT or AST < 5 times upper limit of normal
  • Bilirubin < 2.5 mg/dL (unless an increase is attributable to Gilbert's syndrome)
  • Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min
  • FEV_1 ≥ 60% by pulmonary function tests (PFTs)
  • FVC ≥ 60% by PFTs
  • DLCO ≥ 60% by PFTs
  • For children who are unable to cooperate for PFTs all of the following criteria must be met:

    • No evidence of dyspnea at rest
    • No exercise intolerance
    • No requirement for supplemental oxygen therapy
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No HIV or uncontrolled fungal, bacterial, or viral infection

    • Fungal infection acquired during induction therapy allowed provided there is a significant response to antifungal therapy with minimal or no evidence of disease by CT scan
  • Other concurrent immunosuppressants allowed
  • No prior allogeneic or autologous stem cell transplantation
  • No prior or concurrent voriconazole unless prior voriconazole therapy is completed or a different agent is substituted for voriconazole prior to study entry
  • No concurrent grapefruit juice during sirolimus administration
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 21 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 Canada,   Australia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00382109
Other Study ID Numbers  ICMJE ASCT0431
NCI-2009-01068 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000500131 ( Other Identifier: Clinical Trials.gov )
COG-PBMTC-ONCO51 ( Other Identifier: Children's Oncology Group )
COG-ASCT0431 ( Other Identifier: Children's Oncology Group )
U10CA098543 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Oncology Group
Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Michael Pulsipher, MD Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date June 2019

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