Clinical Trials /

Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis

NCT04370301

Description:

This phase II trial studies the outcomes of using a JAK inhibitor prior to reduced intensity haploidentical (Haplo) transplantation for the treatment of primary or secondary myelofibrosis (MF). Haplo transplant has been shown to be safe and effective in patients with leukemia and lymphoma who don't have an available sibling donor. The primary risk of using Haplo HCT in patients with MF is graft failure as the graft failure rate has been historically higher with Haplo HCT than with other donor sources and higher with MF patients due to bone marrow fibrosis than in patients with other hematologic malignancies. JAK inhibitors when used in patients with MF may decrease the size of the spleen and decrease inflammation in the bone marrow. Therefore using a JAK inhibitor prior to Haplo transplant has the potential to decrease graft failure in patients with MF. Haplo transplants for patients with MF have been done successfully at multiple institutions in patients not on a study and are currently being covered by Medicare.

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis
  • Official Title: Pilot Study of Reduced Intensity Haploidentical Transplantation for Patients With Myelofibrosis

Clinical Trial IDs

  • ORG STUDY ID: RG1006957
  • SECONDARY ID: NCI-2020-02422
  • SECONDARY ID: RG1006957
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT04370301

Conditions

  • Primary Myelofibrosis
  • Secondary Myelofibrosis

Interventions

DrugSynonymsArms
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, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (JAK inhibitor, conditioning, GVHD prophylaxis)
JAK InhibitorRuxolitinib, FedratinibTreatment (JAK inhibitor, conditioning, GVHD prophylaxis)
FludarabineFluradosaTreatment (JAK inhibitor, conditioning, GVHD prophylaxis)
Granulocyte Colony-Stimulating FactorColony Stimulating Factor 3, Colony-Stimulating Factor (Granulocyte), Colony-Stimulating Factor 3, CSF3, G CSF, G-CSF, Granulocyte Colony Stimulating Factor, PluripoietinTreatment (JAK inhibitor, conditioning, GVHD prophylaxis)
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 (JAK inhibitor, conditioning, GVHD prophylaxis)
Mycophenolate MofetilCellcept, MMFTreatment (JAK inhibitor, conditioning, GVHD prophylaxis)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (JAK inhibitor, conditioning, GVHD prophylaxis)

Purpose

This phase II trial studies the outcomes of using a JAK inhibitor prior to reduced intensity haploidentical (Haplo) transplantation for the treatment of primary or secondary myelofibrosis (MF). Haplo transplant has been shown to be safe and effective in patients with leukemia and lymphoma who don't have an available sibling donor. The primary risk of using Haplo HCT in patients with MF is graft failure as the graft failure rate has been historically higher with Haplo HCT than with other donor sources and higher with MF patients due to bone marrow fibrosis than in patients with other hematologic malignancies. JAK inhibitors when used in patients with MF may decrease the size of the spleen and decrease inflammation in the bone marrow. Therefore using a JAK inhibitor prior to Haplo transplant has the potential to decrease graft failure in patients with MF. Haplo transplants for patients with MF have been done successfully at multiple institutions in patients not on a study and are currently being covered by Medicare.

Detailed Description

      OUTLINE:

      JAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start
      of hematopoietic cell transplantation (HCT) conditioning through day -4 before
      transplantation.

      CONDITIONING: Patients receive melphalan intravenously (IV) over 1 hour on day -5,
      fludarabine IV over 30-60 minutes on days -5 to -2, and undergo total-body irradiation (TBI)
      on day -1.

      TRANSPLANT: Patients receive peripheral blood stem cell infusion on day 0.

      GVHD PROPHYLAXIS: Patients then receive cyclophosphamide IV over 3 hours on days 3-4,
      tacrolimus IV beginning day 5 then orally (PO) for 6 months, mycophenolate mofetil PO twice
      daily (BID) or three times daily (TID) beginning day 5 for 6 weeks, and granulocyte
      colony-stimulating factor (G-CSF) subcutaneously (SC) beginning day 7 until neutrophil
      recovery is > 1,500/mm^3.

      After completion of study treatment, patients are followed up between day 80-100, at 1 year,
      and then up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (JAK inhibitor, conditioning, GVHD prophylaxis)ExperimentalJAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start of HCT conditioning through day -4 before transplantation. CONDITIONING: Patients receive melphalan IV over 1 hour on day -5, fludarabine IV over 30-60 minutes on days -5 to -2, and undergo TBI on day -1. TRANSPLANT: Patients receive peripheral blood stem cell infusion on day 0. GVHD PROPHYLAXIS: Patients then receive cyclophosphamide IV over 3 hours on days 3-4, tacrolimus IV beginning day 5 then PO for 6 months, mycophenolate mofetil PO BID or TID beginning day 5 for 6 weeks, and G-CSF SC beginning day 7 until neutrophil recovery is > 1,500/mm^3.
  • Cyclophosphamide
  • JAK Inhibitor
  • Fludarabine
  • Granulocyte Colony-Stimulating Factor
  • Melphalan
  • Mycophenolate Mofetil
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

          -  PART 1: JAK INHIBITOR ADMINISTRATION INCLUSION CRITERIA

          -  Diagnosis of primary myelofibrosis (PMF) as defined by the 2016 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)-plus scoring system
             (DIPSS may be used if all data from DIPSS are not available)

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

          -  Patient must be a potential hematopoietic stem cell transplant candidate

          -  PART 2: ALLOGENEIC STEM CELL TRANSPLANT INCLUSION CRITERIA

          -  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

          -  Received JAK inhibitor for at least 8 weeks immediately prior to conditioning and be
             able to continue until day -4 pre-transplant

          -  Karnofsky performance status score >= 70

          -  Calculated creatinine clearance using the Cockcroft-Gault formula or 24 hour (hr)
             urine creatinine clearance must be > 60 ml/min

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

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

          -  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

          -  Diffusion capacity of the lung for carbon monoxide (DLCO) corrected > 60% normal; may
             not be on supplemental oxygen

          -  Left ventricular ejection fraction > 40% OR shortening fraction > 26%

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

          -  DONOR: Patients must be screened prior to transplant for donor-specific anti-HLA
             antibodies (DSA). Patients with DSA will be reviewed by the principal investigator and
             considered for desensitization treatment

          -  DONOR: Children are preferred over siblings and parents

          -  DONOR: Younger donors are preferred over older donors

          -  DONOR: ABO matched donors are preferred over minor ABO mismatched and over major ABO
             mismatch donors

        Exclusion Criteria:

          -  PART 1: JAK INHIBITOR ADMINISTRATION EXCLUSION CRITERIA

          -  Contraindication to receiving a JAK inhibitor including:

               -  Patients who have known hypersensitivity to JAK inhibitors

               -  Clinical or laboratory evidence of significant renal or hepatic impairment
                  including cirrhosis

               -  Active uncontrolled infection

               -  Known human immunodeficiency virus (HIV) positivity

               -  Women who are pregnant or trying to conceive

               -  Caution should be used in patients with platelets < 100 though adjustments in
                  dose can be made to accommodate anyone with platelets > 50

          -  History of prior allogeneic transplant

          -  Leukemic transformation (> 20% blasts)

          -  PART 2: ALLOGENEIC STEM CELL TRANSPLANT EXCLUSION CRITERIA

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

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

          -  Known HIV positivity

          -  Pregnant or breastfeeding

          -  Availability of an human leukocyte antigen (HLA)-identical or 1-allele-mismatched
             related donor or an HLA 10 of 10 matched unrelated donor
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Probability of primary and secondary graft failure
Time Frame:Up to 3 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of severe (grade 3 or 4) cytokine release syndrome
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Non-relapse mortality (NRM)
Time Frame:Day 100
Safety Issue:
Description:
Measure:NRM
Time Frame:1 year
Safety Issue:
Description:
Measure:Overall survival
Time Frame:1 year
Safety Issue:
Description:
Measure:Overall survival
Time Frame:3 years
Safety Issue:
Description:
Measure:Incidence and severity of acute and chronic graft versus host disease (GVHD)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Incidence of relapse
Time Frame:At 1 year
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated

May 8, 2020