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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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00382109
First received: September 26, 2006
Last updated: December 16, 2016
Last verified: September 2016
  Purpose
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.

Condition Intervention Phase
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 Drug: thiotepa Drug: cyclophosphamide Drug: tacrolimus Drug: methotrexate Drug: sirolimus Radiation: total body irradiation Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 146
Study Start Date: March 2007
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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).
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
Radiation: total body irradiation
Part of the transplant preparatory regimen
Other Name: TBI

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00382109

  Show 50 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Michael Pulsipher, MD Children's Oncology Group
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00382109     History of Changes
Other Study ID Numbers: 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 )
Study First Received: September 26, 2006
Results First Received: October 6, 2015
Last Updated: December 16, 2016

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Graft vs Host Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Methotrexate
Tacrolimus
Sirolimus
Everolimus
Thiotepa
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on July 21, 2017