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

Study Overview
=================
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.

Official Title
-----------------
A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia

Conditions
-----------------
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 / Treatment
-----------------
* Drug: thiotepa
* Drug: cyclophosphamide
* Drug: tacrolimus
* Drug: methotrexate
* Drug: sirolimus
* Radiation: total body irradiation


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen<br>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<br>* Given IV<br>* Other names: TSPA;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: tacrolimus<br>* Given IV or orally<br>* Other names: Prograf;Drug: methotrexate<br>* Given IV<br>* Other names: MTX;Drug: sirolimus<br>* Given orally<br>* Other names: SLM;Radiation: total body irradiation<br>* Part of the transplant preparatory regimen<br>* Other names: TBI;|
| Active Comparator: Tacro-MTX GVHD Prophylaxis<br>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<br>* Given IV<br>* Other names: TSPA;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: tacrolimus<br>* Given IV or orally<br>* Other names: Prograf;Drug: methotrexate<br>* Given IV<br>* Other names: MTX;Radiation: total body irradiation<br>* Part of the transplant preparatory regimen<br>* Other names: TBI;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Percentage of Participants With Event Free Survival | An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol. | at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Relapses | An event is defined as relapse. | At 2 years | 
| Estimated Transplant Related Mortality Percentage | Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event. | 100 days | 
| Estimated Rate of Acute Graft VS Host Disease (GVHD) | Any grade acute graft vs host disease (defined in APPENDIX II study protocol). | At 200 days | 
| Estimated Rate of Overall Chronic Graft VS Host Disease | Chronic graft vs host disease is defined in APPENDIX III of study protocol. | At 2 years | 
| Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation | An event is defined as relapse or transplant-related mortality. | Up to 1 year | 
| Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) | An event is defined as relapse; estimated probability of relapse. | At 1 year | 
| Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD) | An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available. | At 2 months | 
| Chimerism | Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation. | Up to 12 months |