Peritransplant Ruxolitinib for Patients With Primary and Secondary Myelofibrosis

Primary Myelofibrosis Clinical Trial

Official title:

Peritransplant Ruxolitinib for Patients With Primary and Secondary Myelofibrosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04384692
• Other study ID #: RG1006507
• Secondary ID: NCI-2020-0162610
• Status: Recruiting
• Phase: Phase 2
• Start date: December 18, 2020
• Est. completion date: December 31, 2029

Study information

• Verified date: April 2024
• Source: Fred Hutchinson Cancer Center
• Contact: Rachel B. Salit
• Phone: 206.667.1317
• Email: rsalit[@]fredhutch.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well administering ruxolitinib before, during, and after allogeneic hematopoietic stem cell transplantation works in preventing graft versus host disease and improving transplant outcomes in patients with primary and secondary myelofibrosis. Donor hematopoietic stem cell transplantation (HSCT) is currently the only treatment with proven curative potential for myelofibrosis, however, myelofibrosis patients have a high risk for developing graft versus host disease post-transplant. Graft versus host disease is a condition where the transplanted cells from a donor can attack the body's normal cells. Ruxolitinib, a janus-associated kinase (JAK) inhibitor, is known to decrease inflammatory signals, which may reduce spleen size and decrease symptoms such as night sweats and weight loss. Administering ruxolitinib before, during, and after transplant may decrease the incidence and severity of graft versus host disease, increase survival, and improve quality of life in patients with primary and secondary myelofibrosis.

Description:

OUTLINE:

PART 1: Patients receive ruxolitinib orally (PO) starting 8 weeks prior to hematopoietic stem cell transplantation (HSCT) and continuing until approximately 14 days prior to conditioning regimen, then tapered per the treating clinician until day -4 in the absence of disease progression or unacceptable toxicity. Patients who join a different research study for Part 2 have their collected data and samples from Part 1 carried over to the new protocol.

PART 2: Patients are assigned to either a high (myeloablative) or reduced intensity conditioning regimens per the clinical provider together with the Clinical Coordinators Office (CCO):

MYELOABLATIVE CONDITIONING: Patients receive cyclophosphamide intravenously (IV) on days -7 and -6 and busulfan IV over 3 hours on days -5 to -2. Patients with umbilical cord blood (UCB) as their transplant source also receive fludarabine IV over 30 minutes on days -8 to -6. Treatment continues in the absence of disease progression or unacceptable toxicity.

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and melphalan IV over 15-30 minutes on days -3 and -2. Patients with UCB as their transplant source also undergo total body irradiation (TBI) on day -1. Treatment continues in the absence of disease progression or unacceptable toxicity.

TRANSPLANT: After completion of conditioning regimen, patients undergo HSCT on day 0.

GVHD PROPHYLAXIS: Patients receive ruxolitinib until approximately 7 months post-transplant and then tapered over 2 months until 9-12 months post HSCT. Patients also receive tacrolimus IV continuously (inpatients) or every 12 hours (outpatients) beginning day -1 (day -3 for patients with UCB as their donor source), then PO twice daily (BID) once therapeutic levels are reached, with a taper beginning on day 56 for patients with related donors, and day 100 for patients with unrelated donors over 4 months in the absence of GVHD. The duration of tacrolimus for patients with GVHD is determined by the attending physician. Patients with related and unrelated donors also receive methotrexate IV on days 1, 3, 6, and 11. Patients with UCB as their transplant source also receive mycophenolate mofetil IV or PO every 8 hours beginning on days 0-30, then tapered until day 40 in the absence of GVHD. All treatment continues in the absence of disease progression or unacceptable toxicity.

Patients undergo computed tomography (CT) scan and may undergo echocardiography on study and bone marrow aspiration and biopsy and blood sample collection and may undergo magneti resonance imaging (MRI) and ultrasound throughout the study.

Patients are followed up at 6 months, 1 year, and 2-5 years after completion of HSCT.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 45
• Est. completion date: December 31, 2029
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age >= 18 years

• JAK INHIBITOR ADMINISTRATION INCLUSION: (PART I)

• Disease criteria:

• Diagnosis of primary myelofibrosis (PMF) as defined by the 2016 World Health Organization classification system or diagnosis of secondary myelofibrosis (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 Dynamic International Prognostic Scoring System (DIPSS) or DIPSS plus

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

• Patient must be a potential hematopoietic stem cell transplant candidate as assessed by the consenting physician

• Patient must be willing to start ruxolitinib within a 6-month time period

• ALLOGENEIC STEM CELL TRANSPLANT INCLUSION: (PART II)

• Meeting criteria for part 1, as above, at time of initiation of ruxolitinib, including the 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 are met. These patients will have part 1 endpoints transcribed from medical records

• Received ruxolitinib for at least 8 weeks immediately prior to conditioning and be willing to continue until 9-12 months post-transplant as tolerated

• Performance status score: Karnofsky >= 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 > 3mg/dL, and symptomatic biliary disease will be excluded

• Diffusion capacity of lung for carbon monoxide (DLCO) corrected > 60% normal. May be not be on supplemental oxygen

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

• Comorbidity index < 5 at the time of pre-transplant evaluation

Exclusion Criteria:

• JAK INHIBITOR ADMINISTRATION EXCLUSION: (PART I)

• Contraindication to receiving ruxolitinib 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)

• ALLOGENEIC STEM CELL TRANSPLANT EXCLUSION: (PART II)

• Uncontrolled viral or bacterial infection at the time of transplant data review and consent conference

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

• History of HIV infection

• Pregnant or breastfeeding

• Patients without a human leukocyte antigen (HLA)-identical sibling donor, 10 of 10 HLA-matched or 9 of 10 allele mismatched unrelated donor, or umbilical cord blood units that meet transplant criteria

Related Conditions & MeSH terms

• Neoplasm Metastasis
• Primary Myelofibrosis
• Secondary Myelofibrosis

Intervention

Procedure:
• Allogeneic Hematopoietic Stem Cell Transplantation
Undergo HSCT

Drug:
• Busulfan
Given IV
• Cyclophosphamide
Given IV
• Fludarabine
Given IV
• Melphalan
Given IV
• Methotrexate
Given IV
• Mycophenolate Mofetil
Given IV or PO
• Ruxolitinib
Given PO
• Tacrolimus
Given IV and PO

Radiation:
• Total-Body Irradiation
Undergo TBI

Procedure:
• Computed Tomography
Undergo CT scan
• Echocardiography
Undergo echocardiography
• Bone Marrow Aspiration and Biopsy
Undergo bone marrow aspiration and biopsy
• Magnetic Resonance Imaging
Undergo MRI
• Ultrasound Imaging
Undergo ultrasound imaging

Locations

Country	Name	City	State
United States	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of grade II-IV graft versus host disease (GVHD) in myelofibrosis patients	The probability of grade II-IV acute GVHD observed in this study will be compared to a fixed benchmark, this fixed benchmark derived from the results of a previous study (FH Protocol 9033).	Up to day 100
Secondary	Incidence of grade III-IV GVHD	Estimated as simple proportions and informally compared to the results from FH Protocol 9033.	Up to day 100
Secondary	Incidence of chronic GVHD		At 1 and 2 years
Secondary	Overall survival rate (OS)		At 1 and 2 years
Secondary	Incidence of primary and secondary graft failure	Estimated as simple proportions and informally compared to the results from FH Protocol 9033.	6 months
Secondary	Time to neutrophil (ANC > 500) engraftment		Day 100
Secondary	Time to platelet (> 20,000) engraftment		Day 100
Secondary	Incidence of relapse		At 1 year
Secondary	Non-relapse mortality (NRM)	Estimated as simple proportions and informally compared to the results from FH Protocol 9033.	Day 100 and 1 year