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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04370301
Recruitment Status : Recruiting
First Posted : April 30, 2020
Last Update Posted : January 12, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE April 28, 2020
First Posted Date  ICMJE April 30, 2020
Last Update Posted Date January 12, 2021
Estimated Study Start Date  ICMJE February 11, 2021
Estimated Primary Completion Date August 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2020)
Probability of primary and secondary graft failure [ Time Frame: Up to 3 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2020)
  • Incidence of severe (grade 3 or 4) cytokine release syndrome [ Time Frame: Up to 3 years ]
  • Non-relapse mortality (NRM) [ Time Frame: Day 100 ]
  • NRM [ Time Frame: 1 year ]
  • Overall survival [ Time Frame: 1 year ]
  • Overall survival [ Time Frame: 3 years ]
  • Incidence and severity of acute and chronic graft versus host disease (GVHD) [ Time Frame: Up to 3 years ]
  • Incidence of relapse [ Time Frame: At 1 year ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis
Official Title  ICMJE Pilot Study of JAK Inhibitor Therapy Followed by Reduced Intensity Haploidentical Transplantation for Patients With Myelofibrosis
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Myelofibrosis
  • Secondary Myelofibrosis
Intervention  ICMJE
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-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- 138719
  • Drug: JAK Inhibitor
    Given PO
    Other Names:
    • Ruxolitinib
    • Fedratinib
  • Drug: Fludarabine
    Given IV
    Other Name: Fluradosa
  • Biological: Recombinant Granulocyte Colony-Stimulating Factor
    Given SC
    Other Names:
    • Recombinant Colony-Stimulating Factor 3
    • rhG-CSF
    • 143011-72-7
  • Drug: Melphalan
    Given IV
    Other Names:
    • Alanine 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-19813
  • Drug: Mycophenolate Mofetil
    Given PO
    Other Names:
    • Cellcept
    • MMF
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Given IV
    Other Names:
    • PBPC transplantation
    • PBSCT
    • Peripheral Blood Progenitor Cell Transplantation
    • peripheral stem cell support
    • Peripheral Stem Cell Transplant
    • peripheral stem cell transplantation
  • Drug: Tacrolimus
    Given IV and PO
    Other Names:
    • FK 506
    • Fujimycin
    • Hecoria
    • Prograf
    • Protopic
  • Radiation: Total-Body Irradiation
    Undergo TBI
    Other Names:
    • TBI
    • Total Body Irradiation
    • Whole Body Irradiation
    • Whole-Body Irradiation
    • Total-Body Irradiation Prior to Stem Cell Transplant
Study Arms  ICMJE Experimental: Treatment (JAK inhibitor, conditioning, GVHD prophylaxis)

JAK 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.

Interventions:
  • Drug: Cyclophosphamide
  • Drug: JAK Inhibitor
  • Drug: Fludarabine
  • Biological: Recombinant Granulocyte Colony-Stimulating Factor
  • Drug: Melphalan
  • Drug: Mycophenolate Mofetil
  • Procedure: Peripheral Blood Stem Cell Transplantation
  • Drug: Tacrolimus
  • Radiation: Total-Body Irradiation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 28, 2020)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 31, 2028
Estimated Primary Completion Date August 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rachel Salit 206-667-1317 rsalit@fredhutch.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04370301
Other Study ID Numbers  ICMJE RG1006957
NCI-2020-02422 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10441 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Rachel B Salit Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP