Clinical Trial 23456

• Overview

  Study Title:

  A Randomized, Multicenter, Phase III Trial of Tacrolimus/Methotrexate/Ruxolitinib versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation (CTN 2203)

  Summary:

  The purpose of this study is to assess Tacrolimus/Methotrexate/Ruxolitinib versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation

  Objective:

  Primary: The primary objective of the randomized, dose finding portion of the trial is to compare the safety, feasibility, and efficacy of two ruxolitinib doses in the setting of GVHD prophylaxis. In this portion of the study, these three evaluations will be assessed by: Safety: graft failure by Day 28 and overall mortality by Day 100 Feasibility: proportion of participants requiring dose reduction or interruption by Day 100 Efficacy: Grade II-IV acute GVHD-free survival by Day 100 The primary objective of the randomized Phase III portion of the trial is to compare GFS up to 24 months after HCT between Tac/MTX/Rux versus PTCy/Tac/MMF. There are co-primary objectives of demonstrating non-inferiority and superiority on the primary endpoint of GFS. An event for this time to event outcome is defined as Grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, or death by any cause. Secondary: Secondary objectives are the following comparisons between the two treatments in the Phase III portion based on: GVHD-free and relapse/progression-free survival Rates of NIH mild, moderate, and severe chronic GVHD (defined by the NIH Consensus Conference Criteria) Grade II-IV and III-IV acute GVHD per the NIH Consensus Conference Criteria on Acute GVHD Grading by Day +180 Hematologic recovery including neutrophil engraftment, platelet engraftment, lymphocyte recovery Proportion of participants with full (at least 95% or more) or mixed (5.0-94.9%) total donor chimerism or graft rejection (less than 5% total donor chimerism) Graft failure Disease relapse or progression Non-relapse mortality (NRM) Toxicity and Infections Disease-free survival OS PRO

• Treatments

  Therapies:

  Bone Marrow Transplant; Chemotherapy (NOS); Immunosuppressant; Janus kinase (JAK) inhibitor; Radiotherapy

  Medications:

  Alkeran (Melphalan); Cellcept (Mycophenolate Mofetil); FK506 (Tacrolimus); Jakafi (Ruxolitinib); Melphalan (); Mycophenolate Mofetil (); Radiotherapy (); Ruxolitinib (); Tacrolimus (); busulfan (); cyclophosphamide (); cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate); methotrexate ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Age 18.0 years or older at the time of enrollment.
  • Participants undergoing allogeneic HCT for one of the indications defined in the protocol.
  • Planned NMA/reduced intensity conditioning regimen.
  • Participants must have a related or unrelated PBSC donor.
  • Cardiac function: Left ventricular ejection fraction at least 45%.
  • Estimated creatinine clearance greater than 60 ml/min using the 2021 CKD-EPI formula or 24-hour urine creatinine clearance.
  • Pulmonary function: DLCO corrected for hemoglobin at least 40% and FEV1 predicted at least 50%.
  • Liver function: AST/ALT > Karnofsky Performance Score of at least 60%.
  • Female participants (unless postmenopausal for at least one year before the screening visit, or surgically sterilized), agree to practice two effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 15 months post-transplant. Fertility preservation methods will be left to institutional standards.
  • Male participants (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 15 months post-transplant.
  • Plans for the use of targeted small molecule inhibitor post-transplant maintenance therapy must be disclosed upon enrollment and must be used irrespective of the outcome of the randomization. Planned use of investigational maintenance agents is not permitted. Planned hypomethylating agents as maintenance therapy is not permitted.
  • Voluntary written consent obtained prior to the performance of any study-related procedure that is not a part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Prior allogeneic transplant.
  • Active CNS involvement by malignant cells.
  • Participants with secondary AML arising from myeloproliferative neoplasms or overlap syndromes, including CMML and MDS/MPN syndromes; participants with secondary AML arising from myelodysplastic neoplasm are eligible.
  • Participants with primary myelofibrosis.
  • Participants with uncontrolled bacterial, viral, or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
  • Active or inadequately treated latent infection with Mycobacterium tuberculosis (i.e., TB).
  • Presence of clinically significant fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated.
  • Participants seropositive for human immunodeficiency virus (HIV) with detectable viral load. HIV+ participants with an undetectable viral load on antiviral therapy are eligible.
  • Evidence of uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV).
  • Arterial or venous thrombosis including DVT, PE, stroke, and myocardial infarction within six (6) months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia. Catheter-associated DVT is not exclusionary.
  • Female participants who are pregnant (as per institutional practice) or lactating.
  • Participants with a serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • Participants with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent > Planned use of ATG or alemtuzumab in conditioning regimen.
  • Planned use of prophylactic donor leukocyte infusions.
  • Prior use of ruxolitinib.
  • Prior use of immune checkpoint inhibitors (i.e., PD1, PDL1, CTLA4 modulators) within six (6) months prior to conditioning.
  • Treatment with any other Investigational Medicinal Product (IMP) is not allowed while on study treatment. An IMP is defined as medications without any known FDA or EMA approved indications.

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