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

Primary Purpose

Primary Myelofibrosis, Secondary Myelofibrosis

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
JAK Inhibitor
Fludarabine
Recombinant Granulocyte Colony-Stimulating Factor
Melphalan
Mycophenolate Mofetil
Peripheral Blood Stem Cell Transplantation
Tacrolimus
Total-Body Irradiation
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 (or legally authorized representative)
  • 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

Sites / Locations

  • Fred Hutch/University of Washington Cancer ConsortiumRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (JAK inhibitor, conditioning, GVHD prophylaxis)

Arm Description

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.

Outcomes

Primary Outcome Measures

Probability of primary and secondary graft failure

Secondary Outcome Measures

Incidence of severe (grade 3 or 4) cytokine release syndrome
Non-relapse mortality (NRM)
NRM
Overall survival
Overall survival
Incidence and severity of acute and chronic graft versus host disease (GVHD)
Incidence of relapse

Full Information

First Posted
April 28, 2020
Last Updated
June 6, 2023
Sponsor
Fred Hutchinson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04370301
Brief Title
Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis
Official Title
Pilot Study of JAK Inhibitor Therapy Followed by Reduced Intensity Haploidentical Transplantation for Patients With Myelofibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 9, 2021 (Actual)
Primary Completion Date
August 31, 2024 (Anticipated)
Study Completion Date
August 31, 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis, Secondary Myelofibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (JAK inhibitor, conditioning, GVHD prophylaxis)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
JAK Inhibitor
Other Intervention Name(s)
JAK inhibitors, Janus Kinase Inhibitor, Ruxolitinib, Fedratinib
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fluradosa
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Recombinant Granulocyte Colony-Stimulating Factor
Other Intervention Name(s)
Recombinant Colony-Stimulating Factor 3, rhG-CSF, 143011-72-7
Intervention Description
Given SC
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, peripheral stem cell support, Peripheral Stem Cell Transplant, peripheral stem cell transplantation
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK 506, Fujimycin, Hecoria, Prograf, Protopic
Intervention Description
Given IV and PO
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Other Intervention Name(s)
TBI, Total Body Irradiation, Whole Body Irradiation, Whole-Body Irradiation, Total-Body Irradiation Prior to Stem Cell Transplant, SCT_TBI
Intervention Description
Undergo TBI
Primary Outcome Measure Information:
Title
Probability of primary and secondary graft failure
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Incidence of severe (grade 3 or 4) cytokine release syndrome
Time Frame
Up to 3 years
Title
Non-relapse mortality (NRM)
Time Frame
Day 100
Title
NRM
Time Frame
1 year
Title
Overall survival
Time Frame
1 year
Title
Overall survival
Time Frame
3 years
Title
Incidence and severity of acute and chronic graft versus host disease (GVHD)
Time Frame
Up to 3 years
Title
Incidence of relapse
Time Frame
At 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: PART 1: JAK INHIBITOR ADMINISTRATION INCLUSION CRITERIA Age > 18 years 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 (or legally authorized representative) 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Rachel B. Salit
Phone
206-667-1317
Email
rsalit@fredhutch.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rachel B. Salit
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rachel B. Salit
Phone
206-667-1317
Email
rsalit@fredhutch.org
First Name & Middle Initial & Last Name & Degree
Rachel B. Salit

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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