A Phase II Pediatric Study of a Graft-VS.-Host Disease (GVHD) Prophylaxis Regimen With no Calcineurin Inhibitors After Day +60 Post First Allogeneic Hematopoietic Cell Transplant for Hematological Malignancies

Study Overview
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Brief Summary
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The participants are being asked to take part in this clinical trial because the participant have a lymphoid or myeloid based cancer diagnosis that requires a bone marrow transplant. Primary Objectives To estimate the incidence of severe acute GVHD (saGVHD) using a prophylaxis regimen with no calcineurin inhibitors after day +60 post first allogeneic Human Leukocyte antigen (HLA)-matched sibling or unrelated donor HCT for hematological malignancies. Secondary objective Determine the cumulative incidence of relapse, NRM, chronic GVHD, and OS in study participants at one year post-transplant. Exploratory objectives To evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profiles of ruxolitinib, fludarabine, and rATG. To assess immune reconstitution in study participants within the first year post-HCT.

Detailed Description
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The investigator propose to employ two preparative regimens based on the underlying hematological malignancy. For hematological malignancies of the lymphoid lineage we will use a standard preparative regimen consisting of Total Body Irradiation and cyclophosphamide (TBI/Cy), unless TBI is contraindicated. For myeloid malignancies we will use thiotepa, busulfan, and fludarabine (TBF), a preparative regimen that has been associated with a reduced risk of relapse and trend for improved survival with comparable NRM in comparison to busulfan and cyclophosphamide (BuCy), our current regimen. All HCT recipients will receive cyclosporine in combination with methotrexate and ruxolitinib as GVHD prophylaxis. Recipients of MUD HCT will receive rATG for additional immunosuppression as is standard for unrelated donor transplants

Official Title
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A Phase II Pediatric Study of a Graft-VS.-Host Disease (GVHD) Prophylaxis Regimen With no Calcineurin Inhibitors After Day +60 Post First Allogeneic Hematopoietic Cell Transplant for Hematological Malignancies

Conditions
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Hematologic Malignancy, Myeloid Malignancy

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Mesna
* Drug: Anti-thymocyte globulin (ATG)
* Drug: Cyclosporine
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Methotrexate
* Radiation: Total Body Irradiation (radiation treatment)
* Drug: Bone marrow infusion
* Drug: Busulfan
* Drug: Thiotepa


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Diagnosis: Patients with high risk acute lymphoblastic leukemia in first remission. Examples include, but are not limited to, patients with certain leukemic cell cytogenetic findings (e.g. t(9;22) or t(4;11)); delayed response to induction chemotherapy; re-emergence of leukemic blasts by MRD (at any level) in patients previously MRD negative; persistently detectable MRD at lower levels; early T-cell precursor (ETP) ALL. Patients with acute lymphoblastic leukemia beyond first remission. Patients with Hodgkin's disease beyond first remission or with refractory disease. Patients with chronic myelogenous leukemia. Patients with primary or secondary myelodysplastic syndrome. Patients with Non-Hodgkin's lymphoma beyond first remission or with refractory disease. Patients with de novo acute myeloid leukemia in or beyond first remission or with relapsed or refractory disease, or myeloid sarcoma (extra-medullary AML). Patients with secondary acute myeloid leukemia. NK cell lymphoblastic leukemia in any CR. Biphenotypic, bilineage, or undifferentiated leukemia. Juvenile Myelomonocytic Leukemia (JMML) All patients with prior evidence of CNS leukemia must be treated and be in CNS CR. Patients must have a related or unrelated donor matched at 12 of 12 HLA alleles. Patient must have a Karnofsky/Lansky score of 70 or higher. Patients must be 12 years of age or older. Patients must have a shortening fraction >26% or left ventricular ejection fraction >40%. Patients must have bilirubin less than or equal to 2.5 mg/dL and alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal. Patients must have creatinine clearance, or a glomerular filtration rate (GFR), greater than 70 mL/min/1.73m2. Patients must be free of severe infection that upon determination of principal investigator precludes BMT. Patients must have FVC >50% predicted OR, if unable to perform pulmonary function testing, must maintain pulse oximetry oxygen saturation >92% on room air. Female patients of childbearing age must have a negative pregnancy test. Exclusion criteria Patients who have undergone prior HCT. Patients who have a peripheral blood stem cell graft source. Patients who have a non-permissive mismatch at the DPB1 allele. Patients who are HIV positive. Patients positive for Hepatitis B surface antigen (HBsAg). Patients positive for Hepatitis C. Patients with latent tuberculosis with positive TB IFN gamma release assay.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ArmA- Lymphoid<br>Total Body Irradiation and cyclophosphamide (TBI/Cy) | Drug: Ruxolitinib<br>* Day +40 Dosage and Route of Administration-Ruxolitinib tablets should be administered orally BID, approximately every 12 hours, continuously, Oral<br>* Other names: (Jakafi®);Drug: Mesna<br>* Days -3 and -2 Dosage and Route of Administration-Mesna is dosed based on the cyclophosphamide dose and generally administered in fractionated doses at approximately 20% of the total cyclophosphamide dose, Intravenous.<br>* Other names: (Mesnex);Drug: Anti-thymocyte globulin (ATG)<br>* Days -3, -2 and -1 Dosage and Route of Administration-(7 mg/kg total dose); intravenous.<br>* Other names: (Thymoglobulin®, rabbit ATG);Drug: Cyclosporine<br>* Day -1 Dosage and Route of Administration-3 mg/kg; dose will be adjusted to maintain a steady concentration between 250-350 ng/mL or trough concentration between 175-250 ng/mL when transitioned to intermittent dosing.<br>* Other names: (Gengraf);Drug: Cyclophosphamide<br>* Days -3 and -2 Dosage and Route of Administration-60 mg/kg for 2 consecutive days, (120 mg/kg total dose); intravenous.<br>* Other names: (Cytoxan);Drug: Methotrexate<br>* Days +1, +3, +6 and +11 Dosage and Route of Administration-10 mg/m2/dose, intravenous<br>Radiation: Total Body Irradiation (radiation treatment)<br>* Days -7, -6, -5 and -4 6.2.3 Target Dose 1200 cGy total dose delivered 150 cGy per treatment fraction delivered BID over 4 days with 6 MV photons. Dose rate should be < 10 cGy/min in patients treated at extended SSD (450-500 cm) in the TBI couch and will be less than 15 cGy/min in young children and infants treated at extended SSD (200-220 cm) on the floor. Intra-fraction interval should be 6 hours. Custom posteriorly placed (PA only) partial transmission lung shields (blocks) will be used to reduce the average dose to the lung to approximately 1000 cGy total dose. An additional 400 cGy supplemental testicular radiation delivered in 2 fractions of 200 cGy delivered for males with lymphoid lineage leukemia.<br>* Other names: TBI;Drug: Bone marrow infusion<br>* Day 0<br>|
| Active Comparator: ArmB-Myeloid<br>TBF with comparable NRM in comparison to busulfan and cyclophosphamide (BuCy) | Drug: Ruxolitinib<br>* Day +40 Dosage and Route of Administration-Ruxolitinib tablets should be administered orally BID, approximately every 12 hours, continuously, Oral<br>* Other names: (Jakafi®);Drug: Anti-thymocyte globulin (ATG)<br>* Days -3, -2 and -1 Dosage and Route of Administration-(7 mg/kg total dose); intravenous.<br>* Other names: (Thymoglobulin®, rabbit ATG);Drug: Cyclosporine<br>* Day -1 Dosage and Route of Administration-3 mg/kg; dose will be adjusted to maintain a steady concentration between 250-350 ng/mL or trough concentration between 175-250 ng/mL when transitioned to intermittent dosing.<br>* Other names: (Gengraf);Drug: Fludarabine<br>* Days -4, -3 and -2 Dosage and Route of Administration-50 mg/m2 daily for 3 consecutive days (150 mg/m2 total dose) intravenous<br>* Other names: (Fludara);Drug: Methotrexate<br>* Days +1, +3, +6 and +11 Dosage and Route of Administration-10 mg/m2/dose, intravenous<br>Drug: Bone marrow infusion<br>* Day 0<br>Drug: Busulfan<br>* Days -4, -3 and -2 Dosage and Route of Administration-3.2 mg/kg/day; intravenous.<br>* Other names: Busulfex);Drug: Thiotepa<br>* Days -6 and -5 Dosage and Route of Administration-(10 mg/kg total dose); intravenous<br>* Other names: TSPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of severe acute GVHD (saGVHD) using a prophylaxis regimen with no calcineurin inhibitors after day 100 post first allogeneic Human Leukocyte antigen (HLA)-matched sibling or unrelated donor HCT for hematological malignancies. | Development of saGVHD at or before Day 100 post transplant is considered as an event. | 100 days post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Leukemic Relapse | Bone marrow studies for disease status evaluation will be performed. | One-year post-transplantation. | 
| Non-relapse mortality | The one-year non-relapse mortality (NRM is defined by the patient who expire while in remission within one year. The probability of NRM is estimated by the cumulative incidence method. | One-year post-transplantation | 
| Overall Survival | The one-year survival is defined by the patient who has not died within one year after post transplantation. The probability is estimated by the Kaplan-Meier method. | one year post-transplantation | 
| Incidence of Chronic Graft Versus Host Disease (cGVHD) | Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The cumulative incidence of cGvHD will be estimated using Kalbfleisch-Prentice method. | 1 year post transplant |