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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Procedure: Biospecimen Collection; Drug: Methotrexate; Procedure: Hematopoietic Cell Transplantation; Procedure: Echocardiography; Procedure: Multigated Acquisition Scan; Drug: Tacrolimus; Drug: Ruxolitinib Phosphate; Procedure: Chest Computed Tomography

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Medical Center
      • Contact: Haris Ali; Phone Number: 626-218-2405; Email: harisali@coh.org
      • Principal Investigator: Haris Ali

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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
• Weight ≥25kg
• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Prevention (Ruxolitinib, tacrolimus, methotrexate); 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; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Methotrexate; Given IV; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Procedure: Hematopoietic Cell Transplantation; Undergo HCT; Other Names: HSCT; HCT; Hematopoietic Stem Cell Transplantation; stem cell transplantation; Hematopoietic Stem Cell Infusion; Stem Cell Transplant; SCT; Stem Cell Transplantation, NOS; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; Drug: Tacrolimus; Given IV; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic; FK-506; Tacforius; Drug: Ruxolitinib Phosphate; Given PO; Other Names: Jakafi; Jakavi; INCB-18424 Phosphate; Procedure: Chest Computed Tomography; Undergo chest CT; Other Names: Chest CT; Computed Tomography of the Chest

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Haris Ali, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2024
• Primary Completion (Estimated): November 22, 2030
• Study Completion (Estimated): November 22, 2030

Study Registration Dates

• First Submitted: October 27, 2023
• First Submitted That Met QC Criteria: November 9, 2023
• First Posted (Actual): November 13, 2023

Study Record Updates

• Last Update Posted (Estimated): October 31, 2025
• Last Update Submitted That Met QC Criteria: October 30, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia, Lymphoid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Transplantation; Macrolides; Lactones; Pterins; Pteridines; Aminopterin; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Methotrexate; Tacrolimus; Specimen Handling; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; ruxolitinib; merphos
• Other Study ID Numbers: 23010 (Other Identifier: City of Hope Medical Center); P30CA033572 (U.S. NIH Grant/Contract); NCI-2023-07401 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No