Ruxolitinib With Tacrolimus and Methotrexate for the Prevention of Graft Versus Host Disease in Pediatric and Young Adult Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

Study Overview
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Brief Summary
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This phase II trial tests how well ruxolitinib with tacrolimus and methotrexate work to prevent the development of graft versus host disease in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. Ruxolitinib is a type of medication called a kinase inhibitor. It works by blocking the signals of cells that cause inflammation and cell proliferation, which may help prevent graft versus host disease (GVHD). Tacrolimus is a drug used to help reduce the risk of rejection by the body of organ and bone marrow transplants by suppressing the immune system. Methotrexate stops cells from making DNA, may kill cancer cells, and also suppress the immune system, which may reduce the risk of GVHD. Giving ruxolitinib with tacrolimus and methotrexate may prevent GVHD in pediatric and young adults undergoing allogeneic hematopoietic cell transplants.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine if the addition of ruxolitinib phosphate (ruxolitinib) to tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis, is safe in pediatric and young adult patients with hematologic malignancies who are eligible to undergo allogeneic hematopoietic cell transplantation (HCT) from a matched donor. (Safety lead-in segment) II. Following a patient safety lead-in, evaluate the efficacy of ruxolitinib, when given as part of reduced intensity HCT from a matched related/unrelated donor, as assessed by 1 year graft-versus-host disease-free and relapse-free (GRFS) rates in pediatric and young adult patients. (Phase II segment) SECONDARY OBJECTIVES: I. Estimate the cumulative incidence of acute GVHD (aGVHD) and non-relapse mortality (NRM) at 100-days after transplant. II. Estimate the cumulative incidence of chronic GVHD (cGVHD) at 1- and 2-years after transplant. III. Estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and 2-years after transplant. IV. Estimate the relapse/progression rate. V. Estimate rate of infection and development of second malignancies including lymphoproliferative disorders at 1- and 2-years post-transplant. VI. Further evaluate the safety of this regimen by assessing: VIa. Adverse event type, frequency, severity, attribution, time-course, and duration; VIb. Complications including: infection, and delayed engraftment. EXPLORATORY OBJECTIVES: I. Characterize and evaluate hematologic recovery, donor cell engraftment and immune reconstitution by cell count and flow cytometry of lymphocyte subsets. II. Characterize changes in aGVHD biomarkers (Reg-3alpha, sTNF RI, IL2Ralpha), JAK-regulated pro-inflammatory cytokines (i.e. IL-6, TNFalpha, C-reactive protein [CRP], beta2Microglubuolin) and STAT3 phosphorylation (downstream of JAK signaling) over time and by aGVHD status/grade. III. Evaluate the pharmacokinetics of ruxolitinib in pediatric and young adult patients. OUTLINE: Patients receive ruxolitinib orally (PO) twice daily (BID) from day -1 to day +100, tacrolimus intravenously (IV) on day -1, and methotrexate IV on days +1, +3, +6, and +11, and undergo HCT on day 0. Patients also undergo chest computed tomography (CT) and echocardiography (ECHO)/multigated acquisition scan (MUGA) at screening and undergo collection of blood samples throughout the trial. After completion of study treatment, patients are followed up at 30 days after the last dose of ruxolitinib and at 1 and 2 years post transplant.

Official Title
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Phase 2a Study of Adding Ruxolitinib With Tacrolimus/Methotrexate Regimen for Graft-versus-Host Disease Prophylaxis in Myeloablative Conditioning Hematopoietic Cell Transplantation in Pediatric and Young Adult Patients

Conditions
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Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Chest Computed Tomography
* Procedure: Echocardiography
* Procedure: Hematopoietic Cell Transplantation
* Drug: Methotrexate
* Procedure: Multigated Acquisition Scan
* Drug: Ruxolitinib Phosphate
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative Assent, when appropriate, will be obtained per institutional guidelines Agreement to allow the use of archival tissue from diagnostic tumor biopsies If unavailable, exceptions may be granted with study primary investigator (PI) approval Age: 2-22 Eastern Cooperative Oncology Group (ECOG) ≤ 2 Performance status: Karnofsky ≥ 60% for patients ≥ 16 years old OR Lansky status ≥ 60% for patients < 16 years old Candidate for allogeneic bone marrow transplant with and available matched related donor (MRD) or an 8/8 matched unrelated donor (MUD) who is willing to donate bone marrow (BM) or mobilized peripheral blood stem cells Note: Donor selection process will be in accordance with City of Hope (COH)-standard operating procedures (SOPs) (B.001.09 Allogeneic Cellular Therapy Product Donor Evaluation, Selection & Consent), which follows Food and Drug Administration (FDA) guidelines for donation of hematopoietic stem/progenitor cells (HPCs) obtained from peripheral blood or bone marrow Diagnosis of acute leukemia (acute myeloid leukemia [AML] or acute lymphoblastic leukemia [ALL]) in complete remission, or myelodysplastic syndrome (MDS) Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 from prior anti-cancer therapy Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (to be performed within 30 days prior to day 1 of protocol therapy) Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Exclusion Criteria: Autologous stem cell transplant within 1 year prior to day 1 of protocol therapy Prior allogeneic transplantation Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days prior to day 1 of protocol therapy Note: Conditioning regimen within 21 days prior to day 1 of protocol therapy is not considered as an exclusion criterion. Note: Patients on maintenance chemotherapy with agents listed are not excluded Herbal medications History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent History of active tuberculosis Patients with history of thrombosis including but not limited to myocardial infarction (MI)/stroke and pulmonary embolism (PE)/deep vein thrombosis (DVT) within 6 months of enrollment Active diarrhea due to inflammatory bowel disease or malabsorption syndrome Clinically significant uncontrolled illness Active, uncontrolled systemic infection (viral, bacterial, or fungal) requiring antibiotics Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection Other active malignancy Females only: Pregnant or breastfeeding Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 22 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: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (Ruxolitinib, tacrolimus, methotrexate)<br>Patients receive ruxolitinib PO BID from day -1 to day +100, tacrolimus IV on day -1, and methotrexate IV on days +1, +3, +6, and +11, and undergo HCT on day 0. Patients also undergo chest CT and ECHO/MUGA at screening and undergo collection of blood samples throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Chest Computed Tomography<br>* Undergo chest CT<br>* Other names: Computed Tomography of the Chest;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Hematopoietic Cell Transplantation<br>* Undergo HCT<br>* Other names: Stem Cell Transplantation, NOS;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Ruxolitinib Phosphate<br>* Given PO<br>* Other names: Jakavi;Drug: Tacrolimus<br>* Given IV<br>* Other names: Tacforius;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Defined using the modified Bearman Scale and the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 scale. | Up to day +30 post hematopoietic cell transplant (HCT) | 
| Graft-versus-host disease (GVHD)-free and relapse-free (GRFS) | Will be estimated using the product-limit method of Kaplan and Meier. | From the date of transplantation to the first time of observing the following events: grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death, assessed at 1 year post transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients receiving planned doses of ruxolitinib (feasibility) | Patients who have received at least 80% of planned doses of ruxolitinib are deemed to meet feasibility criteria. | At completion of therapy (up to day+100) | 
| Incidence of acute GVHD | Will be graded and staged according to Mount Sinai Acute GVHD International Consortium criteria. Will be estimated using the method described by Gooley et al (1999). | At 100 days post HCT transplant | 
| Incidence of non-relapse mortality | Defined as death occurring in a patient from causes other than relapse or progression. Will be estimated using the method described by Gooley et al (1999). | At 100 days post HCT transplant | 
| Incidence of chronic GVHD | Will be evaluated and scored according to National Institutes of Health Consensus Staging. Will be estimated using the method described by Gooley et al (1999). | At 1 and 2 years post HCT transplant | 
| Overall survival | Will be estimated using the product-limit method of Kaplan and Meier. | From the day of stem cell infusion until death, up to 2 years | 
| Progression free survival | Will be estimated using the product-limit method of Kaplan and Meier. | From the date of stem cell infusion to the date of death, disease relapse/progression, whichever occurs first, up to 2 years | 
| incidence of relapse/progression | Will be estimated using the method described by Gooley et al (1999). | From day of stem cell infusion (day 0) to first observation of disease relapse/progression, up to 2 years | 
| Infection rate | Will be reported by site of disease, date of onset, severity and resolution, if any. | From day -1 to day 130 post HCT transplant | 
| Incidence of secondary malignancies |  | From day of stem cell infusion (day 0) to first observation of event of interest, assessed at 1 and 2 years post HCT transplant | 
| Hematologic recovery, donor cell engraftment and immune reconstitution | Assessed using: absolute neutrophil count ≥ 0.5 x 10^3/uL achieved and sustained for 3 consecutive lab values on different days with no subsequent decline; platelets ≥ 20 K/uL independent of platelet transfusion support; immune reconstitution studies done by flow cytometry. | Up to 2 years | 
| Incidence of adverse events during phase II segment | Defined using the modified Bearman Scale and the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 scale. | Up to day +30 post HCT transplant | 
| Acute GVHD biomarkers |  | Up to 2 years | 
| JAK-regulated pro-inflammatory cytokines |  | Up to 2 years | 
| STAT3 phosphorylation |  | Up to 2 years |