Clinical Trials /

JAK Inhibitor Before Donor Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis

NCT02251821

Description:

This phase II trial studies how well giving a JAK inhibitor before a donor stem cell transplant works in treating patients with myelofibrosis that developed without another condition (primary) or evolved from other bone marrow disorders (secondary). JAK inhibitors are a class of drugs that may stop the growth of abnormal cells by blocking an enzyme needed for cell growth. Giving a JAK inhibitor such as ruxolitinib before a donor stem cell transplant may help reduce symptoms of myelofibrosis such as inflammation and enlargement of the spleen, improve the patient's general physical condition, and prevent complications from occurring after the transplant. Infusing healthy stem cells from a donor into the patient may help the patient's bone marrow work normally and make stem cells, red blood cells, white blood cells, and platelets. Giving a JAK inhibitor before a donor stem cell transplant may help improve transplant outcomes in patients with myelofibrosis.

Related Conditions:
  • Primary Myelofibrosis
  • Secondary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: JAK Inhibitor Before Donor Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis
  • Official Title: JAK Inhibitor Prior to Allogeneic Stem Cell Transplant for Patients With Primary and Secondary Myelofibrosis: A Prospective Study

Clinical Trial IDs

  • ORG STUDY ID: 9033
  • SECONDARY ID: NCI-2014-01882
  • SECONDARY ID: 9033
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG9214017
  • NCT ID: NCT02251821

Conditions

  • Primary Myelofibrosis
  • Secondary Myelofibrosis

Interventions

DrugSynonymsArms
Busulfan1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508Treatment (ruxolitinib, transplant)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (ruxolitinib, transplant)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (ruxolitinib, transplant)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment (ruxolitinib, transplant)
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Treatment (ruxolitinib, transplant)
Mycophenolate MofetilCellcept, MMFTreatment (ruxolitinib, transplant)
RuxolitinibINCB-18424, INCB18424, Oral JAK Inhibitor INCB18424Treatment (ruxolitinib, transplant)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (ruxolitinib, transplant)

Purpose

This phase II trial studies how well giving a JAK inhibitor before a donor stem cell transplant works in treating patients with myelofibrosis that developed without another condition (primary) or evolved from other bone marrow disorders (secondary). JAK inhibitors are a class of drugs that may stop the growth of abnormal cells by blocking an enzyme needed for cell growth. Giving a JAK inhibitor such as ruxolitinib before a donor stem cell transplant may help reduce symptoms of myelofibrosis such as inflammation and enlargement of the spleen, improve the patient's general physical condition, and prevent complications from occurring after the transplant. Infusing healthy stem cells from a donor into the patient may help the patient's bone marrow work normally and make stem cells, red blood cells, white blood cells, and platelets. Giving a JAK inhibitor before a donor stem cell transplant may help improve transplant outcomes in patients with myelofibrosis.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To optimize the role of allogeneic transplantation for primary and secondary myelofibrosis
      (MF) in the JAK inhibitor era.

      OUTLINE:

      PART 1: Patients receive a ruxolitinib orally (PO) twice daily (BID) from at least 8 weeks
      prior to the start of conditioning until best response through day -4 before transplantation,
      with a taper schedule reducing the dose every 2-3 days beginning after day -4.

      PART 2: Patients are assigned to 1 of 2 conditioning regimens at the discretion of the
      clinical provider and Clinical Coordinators Office (CCO).

      MYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 1
      hour on days -8 to -6 (umbilical cord blood transplant recipients only), cyclophosphamide IV
      on days -7 and -6, and busulfan IV over 3 hours on days -5 to -2.

      REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 1 hour on days
      -6 to -2 and melphalan IV over 15-30 minutes on days -3 and -2. Patients also undergo
      total-body irradiation (TBI) on day -1 (umbilical cord blood transplant recipients only).

      TRANSPLANT: Patients undergo allogeneic hematopoietic stem cell transplant or umbilical cord
      blood transplant on day 0.

      GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus IV continuously
      (inpatients) or over 1-2 hours twice daily (BID) (outpatients) or orally (PO) BID on days -1
      to +180 (patients receiving related or unrelated stem cells) or days -3 to +180 (patients
      receiving umbilical cord blood) with taper beginning on day +56 (related donor recipients) or
      +100 (unrelated donor or umbilical cord blood recipients) in the absence of GVHD. Patients
      also receive methotrexate IV on days +1, +3, +6, and +11 (related and unrelated donor
      recipients only) or mycophenolate mofetil IV or PO every 8 hours on days 0 to +40 with taper
      to day +96 (umbilical cord blood transplant recipients only).

      After completion of study treatment, patients are followed up at 6 months, 1 year, and then
      yearly for 4 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ruxolitinib, transplant)ExperimentalPatients receive a ruxolitinib and undergo myeloablative or reduced-intensity conditioning followed by transplant and GVHD prophylaxis; see detailed description.
  • Busulfan
  • Cyclophosphamide
  • Fludarabine Phosphate
  • Melphalan
  • Methotrexate
  • Mycophenolate Mofetil
  • Ruxolitinib
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

        PART 1:

          -  PART 1: Disease criteria

               -  Diagnosis of primary MF (PMF) as defined by the 2008 World Health Organization
                  classification system or diagnosis of secondary MF as defined by the
                  International Working Group (IWG) for Myeloproliferative Neoplasms Research and
                  Treatment criteria

               -  Patients meeting the criteria for intermediate-1, intermediate-2 or high-risk
                  disease by the Dynamic International Prognostic Scoring System (DIPSS) or
                  DIPSS-plus scoring system

          -  PART 1: Ability to understand and the willingness to sign a written informed consent
             document

          -  PART 1: Patient must be a potential hematopoietic stem cell transplant candidate

        PART 2:

          -  PART 2: Meeting criteria for 1st phase as above, at time of initiation of JAK
             inhibitor, including ability to understand and willingness to sign a written informed
             consent; patients arriving to our institution for transplant and not enrolled in Part
             1 may still be enrolled in Part 2 if Part 1 criteria met; these patients will have
             Part 1 endpoints transcribed from medical records

          -  PART 2: Received ruxolitinib for at least 8 weeks immediately prior to conditioning
             and be able to continue until Day -4 pre-transplant

          -  PART 2: Performance status score

               -  Karnofsky >= 70

          -  PART 2: Calculated creatinine clearance using the Cockcroft-Gault formula or 24 hr
             urine creatinine clearance must be > 60 ml/min

          -  PART 2: Total serum bilirubin must be < 3 mg/dL unless the elevation is thought to be
             due to Gilbert's disease or hemolysis

          -  PART 2: Transaminases must be < 3 x the upper limit of normal

          -  PART 2: Patients with clinical or laboratory evidence of liver disease will be
             evaluated for the cause of liver disease, its clinical severity in terms of liver
             function, and the degree of portal hypertension; patients with fulminant liver
             failure, cirrhosis with evidence of portal hypertension or bridging fibrosis,
             alcoholic hepatitis, hepatic encephalopathy, or correctable hepatic synthetic
             dysfunction evidenced by prolongation of the prothrombin time, ascites related to
             portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral
             hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will
             be excluded

          -  PART 2: Diffusing capacity of the lung for carbon monoxide (DLCO) corrected > 60%
             normal

               -  May not be on supplemental oxygen

          -  PART 2: Left ventricular ejection fraction > 40% OR

          -  PART 2: Shortening fraction > 26%

          -  PART 2: Comorbidity Index < 5 at the time of pre-transplant evaluation

        DONOR:

          -  DONOR: Human leukocyte antigen (HLA)-matched or 1 antigen mismatched sibling donor

          -  DONOR: 10 of 10 HLA-matched or 1 allele mismatched (9 of 10) unrelated donor

          -  DONOR: Peripheral blood is preferred over bone marrow for non-umbilical cord blood
             recipients

          -  DONOR: Umbilical cord blood units will be selected according to the following
             umbilical cord blood graft selection criteria; one or 2 cord blood (CB) units may be
             used to achieve the required cell dose

          -  DONOR: The CB graft(s) must be matched at 4-6 HLA-A, B, DR Beta 1 (DRB1) loci with the
             recipient and therefore may include 0-2 mismatches at the A or B or DRB1 loci; unit
             selection will be based on cryopreserved nucleated cell dose and intermediate
             resolution A, B antigen and DRB1 allele typing for determination of HLA-match; while
             HLA-C antigen/allele level typing is not considered in the matching criteria, if
             available, it may be used to optimize unit selection

          -  DONOR: Selection of two CB units is allowed to provide sufficient cell dose (see below
             for algorithm to determine single versus double unit transplant); when multiple units
             are selected, the following rules apply:

               -  The CB unit with the least HLA disparity (with the patient) will be selected
                  first (i.e., selection priority is 6/6 match > 5/6 match > 4/6 match); additional
                  CB units then may be selected to achieve the required cell dose, as outlined
                  below; if a second unit is required, this unit will be the unit that most closely
                  HLA matches the patient and meets minimum size criteria outlined below of at
                  least 1.5 x 10^7 total nucleated cells (TNC)/kg (i.e. a smaller, more closely
                  matched unit will be selected over a larger, less well matched unit as long as
                  minimum criteria are met)

               -  If two CB units are used:

                    -  The total cell dose of the combined units must be at least 3.0 x 10^7 TNC
                       per kilogram recipient weight

                    -  Each CB unit MUST contain at least 1.5 x 10^7 TNC per kilogram recipient
                       weight

               -  Algorithm for determining single versus double unit cord blood transplant:

                    -  Match grade 6/6: TNC dose >= 2.5 x 10^7/kg

                    -  Match grade 5/6, 4/6: TNC dose >= 4.0 (+/- 0.5) x 10^7/kg

          -  DONOR: General comments:

               -  Units will be selected first based on the TNC dose and HLA matching

               -  Cluster of differentiation (CD)34+ cell dose will not be used for unit selection
                  unless 2 units of equal HLA-match grade and similar TNC dose (+/- 0.5 x 10^7
                  TNC/kg) are available; in this case, the unit with the larger CD34+ cell dose (if
                  data available) should be selected

               -  A CB unit that is 5/6 mismatched but homozygous at the locus of mismatch should
                  be chosen over a 5/6 unit with bidirectional mismatch even if the latter unit is
                  larger (has more cells); this also applies to 4/6 units; this is only applicable
                  to choosing units within a given match grade

               -  Other factors to be considered:

                    -  Within the same HLA match grade, matching at DR takes preference

                    -  Cord blood banks located in the United States are preferred

               -  Up to 5% of the cord blood product(s), when ready for infusion, may be withheld
                  for research purposes as long as thresholds for infused TNC dose are met; these
                  products will be used to conduct studies involving the kinetics of engraftment
                  and immunobiology of double cord transplantation

        Exclusion Criteria:

        PART 1:

          -  PART 1: Evidence of human immunodeficiency virus (HIV) infection or known HIV positive
             serology

          -  PART 1: Uncontrolled viral, bacterial, or fungal infections at the time of study
             enrollment

          -  PART 1: History of prior allogeneic transplant

          -  PART 1: Pregnant or breastfeeding (only if patients have not been started on
             ruxolitinib [Rux] by their primary oncologist prior to enrollment)

        PART 2:

          -  PART 2: Uncontrolled viral or bacterial infection at the time of study enrollment

          -  PART 2: Active or recent (prior 6 month) invasive fungal infection without infectious
             disease (ID) consult and approval

          -  PART 2: History of HIV infection

          -  PART 2: Pregnant or breastfeeding

          -  PART 2: Patients without an HLA-identical or 1-allele-mismatched related donor or
             unrelated donor or umbilical cord blood units that meet transplant criteria
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Probability of 2-year survival in patients with myelofibrosis (MF) who receive treatment with a JAK inhibitor followed by an allogeneic transplant
Time Frame:At 2 years
Safety Issue:
Description:The exact benchmark that will be used for comparison will be determined from the mix of Dynamic International Prognostic Scoring System (DIPSS) categories among those enrolled and treated with JAK on the current trial. From this mix, an expected two-year survival will be created as a weighted average of the data cited above. This weighted average will be used as the benchmark to which the data from the current trial will be compared.

Secondary Outcome Measures

Measure:Incidence and severity of acute graft versus host disease (GVHD)
Time Frame:Up to 70 days post-transplant
Safety Issue:
Description:
Measure:Incidence and severity of chronic GVHD
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Incidence of relapse
Time Frame:1 year
Safety Issue:
Description:
Measure:Non-relapse mortality (NRM)
Time Frame:Day 100
Safety Issue:
Description:
Measure:Non-relapse mortality (NRM)
Time Frame:1 year
Safety Issue:
Description:
Measure:Overall incidence of primary graft failure/rejection
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Overall incidence of secondary graft failure/rejection
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated

March 27, 2019