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

Sponsor

Fred Hutchinson Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02251821

Collaborator

Incyte Corporation (Industry), National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

134.3

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Myelofibrosis Secondary Myelofibrosis	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Busulfan Drug: Cyclophosphamide Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Melphalan Drug: Methotrexate Drug: Mycophenolate Mofetil Drug: Ruxolitinib Drug: Tacrolimus Radiation: Total-Body Irradiation Procedure: Umbilical Cord Blood Transplantation	Phase 2

Detailed Description

OUTLINE:

PART 1: Patients receive ruxolitinib orally (PO) twice daily (BID) from at least 8 weeks prior to the start of conditioning 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

99 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

JAK Inhibitor Prior to Allogeneic Stem Cell Transplant for Patients With Primary and Secondary Myelofibrosis: A Prospective Study

Actual Study Start Date :

Oct 20, 2014

Anticipated Primary Completion Date :

Dec 28, 2022

Anticipated Study Completion Date :

Dec 28, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (ruxolitinib, transplant) Patients receive a ruxolitinib and undergo myeloablative or reduced-intensity conditioning followed by transplant and GVHD prophylaxis; see detailed description.	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Undergo allogeneic hematopoietic stem cell transplant Other Names: Allogeneic Hematopoietic Cell Transplantation allogeneic stem cell transplantation HSC HSCT Drug: Busulfan Given IV Other Names: 1, 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-19508 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 Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 Drug: Fludarabine Phosphate Given IV Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 Other: Laboratory Biomarker Analysis Correlative studies 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: Methotrexate Given IV Other Names: Abitrexate 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-19039 Drug: Mycophenolate Mofetil Given IV or PO Other Names: Cellcept MMF Drug: Ruxolitinib Given PO Other Names: INCB-18424 INCB18424 Oral JAK Inhibitor INCB18424 Jakafi Drug: Tacrolimus Given IV or PO Other Names: FK 506 Fujimycin Hecoria Prograf Protopic Radiation: Total-Body Irradiation Undergo TBI Other Names: TOTAL BODY IRRADIATION Whole-Body Irradiation SCT_TBI Procedure: Umbilical Cord Blood Transplantation Undergo umbilical cord blood transplant Other Names: Cord Blood Transplantation UCB transplantation

Arm

Intervention/Treatment

Experimental: Treatment (ruxolitinib, transplant)

Patients receive a ruxolitinib and undergo myeloablative or reduced-intensity conditioning followed by transplant and GVHD prophylaxis; see detailed description.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Undergo allogeneic hematopoietic stem cell transplant

Other Names:

Allogeneic Hematopoietic Cell Transplantation

allogeneic stem cell transplantation

HSC

HSCT

Drug: Busulfan

Given IV

Other Names:

1, 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-19508

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

Cyclophosphamidum

Cyclophosphan

Cyclophosphane

Cyclophosphanum

Cyclostin

Cyclostine

Cytophosphan

Cytophosphane

Cytoxan

Fosfaseron

Genoxal

Genuxal

Ledoxina

Mitoxan

Neosar

Revimmune

Syklofosfamid

WR- 138719

Drug: Fludarabine Phosphate

Given IV

Other Names:

2-F-ara-AMP

9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-

Beneflur

Fludara

SH T 586

Other: Laboratory Biomarker Analysis

Correlative studies

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: Methotrexate

Given IV

Other Names:

Abitrexate

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-19039

Drug: Mycophenolate Mofetil

Given IV or PO

Other Names:

Cellcept

MMF

Drug: Ruxolitinib

Given PO

Other Names:

INCB-18424

INCB18424

Oral JAK Inhibitor INCB18424

Jakafi

Drug: Tacrolimus

Given IV or PO

Other Names:

FK 506

Fujimycin

Hecoria

Prograf

Protopic

Radiation: Total-Body Irradiation

Undergo TBI

Other Names:

TOTAL BODY IRRADIATION

Whole-Body Irradiation

SCT_TBI

Procedure: Umbilical Cord Blood Transplantation

Undergo umbilical cord blood transplant

Other Names:

Cord Blood Transplantation

UCB transplantation

Outcome Measures

Primary Outcome Measures

Probability of 2-year survival in patients with myelofibrosis (MF) who receive treatment with a JAK inhibitor followed by an allogeneic transplant [At 2 years]
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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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