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RecruitingInterventionalPhase 2

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

NCT ID: NCT06128070Sponsor: City of Hope Medical CenterLast updated: 2025-10-31

Summary

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

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.

Arms & interventions

  • ProcedureBiospecimen Collection

    Undergo blood sample collection

  • ProcedureChest Computed Tomography

    Undergo chest CT

  • ProcedureEchocardiography

    Undergo ECHO

  • ProcedureHematopoietic Cell Transplantation

    Undergo HCT

  • DrugMethotrexate

    Given IV

  • ProcedureMultigated Acquisition Scan

    Undergo MUGA

  • DrugRuxolitinib Phosphate

    Given PO

  • DrugTacrolimus

    Given IV

Outcome measures

Primary

  • 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.

    Time frame: 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.

    Time frame: 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

  • Patients receiving planned doses of ruxolitinib (feasibility)

    Time frame: At completion of therapy (up to day+100)

  • Incidence of acute GVHD

    Time frame: At 100 days post HCT transplant

  • Incidence of non-relapse mortality

    Time frame: At 100 days post HCT transplant

  • Incidence of chronic GVHD

    Time frame: At 1 and 2 years post HCT transplant

  • Overall survival

    Time frame: From the day of stem cell infusion until death, up to 2 years

  • Progression free survival

    Time frame: 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

    Time frame: From day of stem cell infusion (day 0) to first observation of disease relapse/progression, up to 2 years

  • Infection rate

    Time frame: From day -1 to day 130 post HCT transplant

  • Incidence of secondary malignancies

    Time frame: 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

    Time frame: Up to 2 years

  • Incidence of adverse events during phase II segment

    Time frame: Up to day +30 post HCT transplant

  • Acute GVHD biomarkers

    Time frame: Up to 2 years

  • JAK-regulated pro-inflammatory cytokines

    Time frame: Up to 2 years

  • STAT3 phosphorylation

    Time frame: Up to 2 years

Eligibility criteria

Sex: AllAge: 2 Years to 22 YearsHealthy volunteers: No
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 locations (1)

City of Hope Medical Center

Duarte, California, 91010

Recruiting
Haris Ali · Contact
626-218-2405harisali@coh.org
Haris Ali · Principal Investigator