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
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ClinicalTrials.gov Identifier: NCT00382109 |
Recruitment Status :
Completed
First Posted : September 28, 2006
Results First Posted : February 9, 2017
Last Update Posted : August 7, 2019
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Condition or disease | Intervention/treatment | Phase |
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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 (Clinical Trial) |
Actual Enrollment : | 146 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (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 |
Study Start Date : | March 2007 |
Actual Primary Completion Date : | May 2011 |
Actual Study Completion Date : | June 30, 2017 |

Arm | Intervention/treatment |
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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.
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Drug: thiotepa
Given IV
Other Names:
Drug: cyclophosphamide Given IV
Other Names:
Drug: tacrolimus Given IV or orally
Other Names:
Drug: methotrexate Given IV
Other Names:
Drug: sirolimus Given orally
Other Names:
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).
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Drug: thiotepa
Given IV
Other Names:
Drug: cyclophosphamide Given IV
Other Names:
Drug: tacrolimus Given IV or orally
Other Names:
Drug: methotrexate Given IV
Other Names:
Radiation: total body irradiation Part of the transplant preparatory regimen
Other Name: TBI |
- 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.
- 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.

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Ages Eligible for Study: | 1 Year to 21 Years (Child, Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL) in second complete remission (CR2) (M1 bone marrow, < 5% blasts by morphology) meeting the following criteria:
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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)
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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)
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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).
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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
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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
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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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00382109

Principal Investigator: | Michael Pulsipher, MD | Children's Oncology Group |
Responsible Party: | Children's Oncology Group |
ClinicalTrials.gov Identifier: | NCT00382109 |
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 ) |
First Posted: | September 28, 2006 Key Record Dates |
Results First Posted: | February 9, 2017 |
Last Update Posted: | August 7, 2019 |
Last Verified: | June 2019 |
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 Sirolimus Cyclophosphamide Thiotepa Methotrexate Tacrolimus |
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 Dermatologic Agents |