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Ruxolitinib Pre-, During- and Post-HSCT for Patients With Primary or Secondary Myelofibrosis.

Primary Purpose

Myelofibrosis

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ruxolitinib
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelofibrosis focused on measuring Myelofibrosis

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participants must have pathologically confirmed primary myelofibrosis according to WHO criteria1 or secondary myelofibrosis as defined by the IWG-MRT criteria.19

    • Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria2 (Appendix 1) OR
    • Intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely
    • Red cell transfusion dependency2
    • Unfavorable Karyotype2
    • Platelet count ≤100 x 109/L
  • Age 18-75
  • Participants must be designated to undergo reduced intensity allogeneic peripheral blood (PB) or bone marrow (BM) hematopoietic stem cell transplantation. Consent will be obtained prior to admission for HCT.
  • Participants who will undergo HCT from the following donor types are eligible:
  • 5/6 or 6/6 (HLA-A, B, DR) matched related donor
  • 7/8 or 8/8 (HLA-A, B, DR, C) matched unrelated donor. Matching in the unrelated setting must be at the allele level
  • ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
  • Life expectancy of greater than 3 months
  • Able to give informed consent
  • Off all MF-directed therapy at the time of enrollment, with the exception of ruxolitinib
  • Additional Criteria for Cohort 1 Only:
  • Patients are candidates for enrollment in cohort 1 if they have an indication for ruxolitinib based on splenomegaly or symptoms and are either on ruxolitinib already or going to start therapy with ruxolitinib.
  • Patients that are on ruxolitinib may enroll in study as long as they are willing to remain on ruxolitinib during the study and have not lost response to ruxolitinib defined as an increase in >5 cm in spleen size from nadir. There is no minimum or maximum time requirement for time on ruxolitinib.
  • Participants must have splenomegaly (defined by ultrasound or CT scan of the abdomen) or symptoms (demonstrated by the presence of 1 symptom score >5 or 2 symptom scores >3) related to myelofibrosis as measured by the myeloproliferative neoplasm symptom assessment form MPN-SAF (see Appendix F) and platelets >25/μL and hemoglobin >7/dL
  • Additional Criteria Cohort 2 Only:
  • Participants are ineligible for ruxolitinib - do not have splenomegaly or symptoms of myelofibrosis as defined by the MPN-SAF.

Or

  • Participants failed ruxolitinib as defined by loss of response to therapy and
  • No allergy to ruxolitinib in the past

Exclusion Criteria:

  • Hypersensitivity to any JAK inhibitor
  • Prior allogeneic transplant for any hematopoietic disorder
  • Had accelerated phase or leukemic transformation (≥10% blasts in PB or BM any time prior to HCT)
  • Active uncontrolled infection
  • History of another malignancy within 5-years of date of except h/o basal cell or squamous cell carcinoma of skin or Polycythemia Vera or Essential Thrombocythemia
  • Patients without normal organ function defined as follows:

    • AST (SGOT), ALT (SGPT) and Alkaline Phosphatase ≥ 3 × institutional Upper Limit of Normal (ULN)
    • Direct bilirubin >2.0 mg/dL
    • Adequate renal function as defined by calculated creatinine clearance≤60 mL/min (Cockcroft-Gault formula)
  • Have a chronic or active infection that requires systemic antibiotics, antifungal or antiviral treatment
  • Have current or a history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 40%, as measured by MUGA scan or echocardiogram)
  • Pregnancy at the time of enrollment
  • Unable to give informed consent
  • Have an uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Subjects who require therapy with a strong CYP3A4 inhibitor prior to enrollment to this study
  • Not able to take oral medication

Sites / Locations

  • Massachusetts General HospitalRecruiting
  • Washington UniversityRecruiting
  • Memorial Sloan Kettering Cancer CenterRecruiting
  • The Ohio State University Wexner Medical CenterRecruiting
  • Vanderbilt UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Ruxolitinib Eligible pre-HSCT

Ruxolitinib Not Eligible pre-HSCT

Arm Description

Ruxolitinib will be taken orally at a fixed dose twice every day Dosing will be continuous, with a new cycle scheduled to start every 28 days. There will be no break in dosing between cycles Ruxolitinib can be administered with or without food.

Ruxolitinib will be taken orally at a fixed dose twice every day after transplant Dosing will be continuous, with a new cycle scheduled to start every 28 days. There will be no break in dosing between cycles Ruxolitinib can be administered with or without food.

Outcomes

Primary Outcome Measures

GVHD free and relapse free survival at 1 year
The number of participants surviving after one year that have not experienced graft-versus host disease (GVHD) or relapse (GRFS rate)

Secondary Outcome Measures

Progression Free Survival
Kaplan-Meier estimates of progression free survival (PFS) will be calculated, with patients without an event being censored at 1 and 2 years
Overall Survival
Overall survival is measured as the time from the hematopoietic stem cell transplantation (HSCT) until death. Participants without an event will be censored at the date of last contact.
Cumulative incidence of aGVHD
Cumulative incidence of grades II-IV and II-IV acute GVHD at 6 months after HSCT
Cumulative incidence of cGVHD
Cumulative incidence of moderate to severe chronic GVHD at 1 year and 2 years after HSCT
Rate of Engraftment
Engraftment defined as ANC >500/ugx3 consecutive measurements and platelets of >20x10e9/L for three consecutive days.
Median time on ruxolitinib after HSCT as a measure of feasibility
The amount of time patients remain on ruxolitinib from transplant until discontinuation.
Toxicity rate
Cumulative incidence of treatment related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE 4). Early deaths from all other causes are considered a competing risk.

Full Information

First Posted
February 2, 2018
Last Updated
October 21, 2022
Sponsor
Massachusetts General Hospital
Collaborators
Incyte Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT03427866
Brief Title
Ruxolitinib Pre-, During- and Post-HSCT for Patients With Primary or Secondary Myelofibrosis.
Official Title
A Phase II Study of Ruxolitinib Pre-, During- and Post-Hematopoietic Stem Cell Transplantation for Patients With Primary or Secondary Myelofibrosis.
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 28, 2018 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
Incyte Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This research study is studying a drug called Ruxolitinib as a possible treatment for Myelofibrosis.
Detailed Description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied. The FDA (the U.S. Food and Drug Administration) has approved Ruxolitinib as a treatment option for this disease. This study examines two different cohorts of participants: Cohort 1: Participants who are eligible for Ruxolitinib therapy before transplant, based on their platelet counts. These participants will receive their first dose of the study drug between 2 and 6 months before HCT. Cohort 2: Participants who are not eligible for Ruxolitinib therapy pre-treatment based on their platelet counts. These participants will receive their first dose of Ruxolitinib 1 week before the conditioning period. Ruxolitinib is a medication that blocks certain proteins called tyrosine kinases. Specifically, it blocks tyrosine kinases called JAK2. Many cancers have over active "cell signaling." What this means is that certain functions in the cancer cells never turn off and this makes them grow in an uncontrolled way. Ruxolitinib, shuts down the pathway that depends on the JAK2 tyrosine kinases. The JAK2 pathway is over active in the participant's disease, acute myeloid leukemia. The exact way ruxolitinib does this is not yet clear but it may have to do with its ability to block the JAK2 pathway since this pathway can also lead to inflammation in the body. Ruxolitinib has also been shown to lower the rates of Graft-Versus-Host-Disease (GVHD), a complication of transplant. GVHD is a disease that occurs when the immune cells in transplanted donor tissue from your HCT attack the participant's own tissues and organs. There are two types of GVHD: acute and chronic. Acute GVHD generally occurs within 1 week to 3 months after your HCT and may affect your skin, intestines, and liver. Chronic GVHD begins later on and may affect the organs prone to acute GVHD complications, as well as the lungs, mucous membranes, or other organs. There is also evidence that ruxolitinib is associated with reduced instances of enlarged spleen size after HCT. Enlarged spleens play a role in the engraftment rate after HCT, which is the rate at which donated tissue and your own tissue begin reproducing and growing together. In this research study, the investigators are: assessing the efficacy (how well the study drug works) and tolerability of Ruxolitinib before, during, and after HCT. examining the rates of GVHD after HCT when ruxolitinib is administered. determining whether engraftment rates improve when ruxolitinib is given

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
54 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ruxolitinib Eligible pre-HSCT
Arm Type
Experimental
Arm Description
Ruxolitinib will be taken orally at a fixed dose twice every day Dosing will be continuous, with a new cycle scheduled to start every 28 days. There will be no break in dosing between cycles Ruxolitinib can be administered with or without food.
Arm Title
Ruxolitinib Not Eligible pre-HSCT
Arm Type
Experimental
Arm Description
Ruxolitinib will be taken orally at a fixed dose twice every day after transplant Dosing will be continuous, with a new cycle scheduled to start every 28 days. There will be no break in dosing between cycles Ruxolitinib can be administered with or without food.
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
Jakafi
Intervention Description
Ruxolitinib is a medication that blocks certain proteins called tyrosine kinases. Specifically, it blocks tyrosine kinases called JAK2. The JAK2 pathway is over active in the disease, acute myeloid leukemia.
Primary Outcome Measure Information:
Title
GVHD free and relapse free survival at 1 year
Description
The number of participants surviving after one year that have not experienced graft-versus host disease (GVHD) or relapse (GRFS rate)
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Progression Free Survival
Description
Kaplan-Meier estimates of progression free survival (PFS) will be calculated, with patients without an event being censored at 1 and 2 years
Time Frame
1 and 2 years
Title
Overall Survival
Description
Overall survival is measured as the time from the hematopoietic stem cell transplantation (HSCT) until death. Participants without an event will be censored at the date of last contact.
Time Frame
1 and 2 years
Title
Cumulative incidence of aGVHD
Description
Cumulative incidence of grades II-IV and II-IV acute GVHD at 6 months after HSCT
Time Frame
6 months
Title
Cumulative incidence of cGVHD
Description
Cumulative incidence of moderate to severe chronic GVHD at 1 year and 2 years after HSCT
Time Frame
1 and 2 years
Title
Rate of Engraftment
Description
Engraftment defined as ANC >500/ugx3 consecutive measurements and platelets of >20x10e9/L for three consecutive days.
Time Frame
2 years
Title
Median time on ruxolitinib after HSCT as a measure of feasibility
Description
The amount of time patients remain on ruxolitinib from transplant until discontinuation.
Time Frame
2 years
Title
Toxicity rate
Description
Cumulative incidence of treatment related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE 4). Early deaths from all other causes are considered a competing risk.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants must have pathologically confirmed primary myelofibrosis according to WHO criteria1 or secondary myelofibrosis as defined by the IWG-MRT criteria.19 Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria2 (Appendix 1) OR Intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely Red cell transfusion dependency2 Unfavorable Karyotype2 Platelet count ≤100 x 109/L Age 18-75 Participants must be designated to undergo reduced intensity allogeneic peripheral blood (PB) or bone marrow (BM) hematopoietic stem cell transplantation. Consent will be obtained prior to admission for HCT. Participants who will undergo HCT from the following donor types are eligible: 5/6 or 6/6 (HLA-A, B, DR) matched related donor 7/8 or 8/8 (HLA-A, B, DR, C) matched unrelated donor. Matching in the unrelated setting must be at the allele level ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) Life expectancy of greater than 3 months Able to give informed consent Off all MF-directed therapy at the time of enrollment, with the exception of ruxolitinib Additional Criteria for Cohort 1 Only: Patients are candidates for enrollment in cohort 1 if they have an indication for ruxolitinib based on splenomegaly or symptoms and are either on ruxolitinib already or going to start therapy with ruxolitinib. Patients that are on ruxolitinib may enroll in study as long as they are willing to remain on ruxolitinib during the study and have not lost response to ruxolitinib defined as an increase in >5 cm in spleen size from nadir. There is no minimum or maximum time requirement for time on ruxolitinib. Participants must have splenomegaly (defined by ultrasound or CT scan of the abdomen) or symptoms (demonstrated by the presence of 1 symptom score >5 or 2 symptom scores >3) related to myelofibrosis as measured by the myeloproliferative neoplasm symptom assessment form MPN-SAF (see Appendix F) and platelets >25/μL and hemoglobin >7/dL Additional Criteria Cohort 2 Only: Participants are ineligible for ruxolitinib - do not have splenomegaly or symptoms of myelofibrosis as defined by the MPN-SAF. Or Participants failed ruxolitinib as defined by loss of response to therapy and No allergy to ruxolitinib in the past Exclusion Criteria: Hypersensitivity to any JAK inhibitor Prior allogeneic transplant for any hematopoietic disorder Had accelerated phase or leukemic transformation (≥10% blasts in PB or BM any time prior to HCT) Active uncontrolled infection History of another malignancy within 5-years of date of except h/o basal cell or squamous cell carcinoma of skin or Polycythemia Vera or Essential Thrombocythemia Patients without normal organ function defined as follows: AST (SGOT), ALT (SGPT) and Alkaline Phosphatase ≥ 3 × institutional Upper Limit of Normal (ULN) Direct bilirubin >2.0 mg/dL Adequate renal function as defined by calculated creatinine clearance≤60 mL/min (Cockcroft-Gault formula) Have a chronic or active infection that requires systemic antibiotics, antifungal or antiviral treatment Have current or a history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 40%, as measured by MUGA scan or echocardiogram) Pregnancy at the time of enrollment Unable to give informed consent Have an uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Subjects who require therapy with a strong CYP3A4 inhibitor prior to enrollment to this study Not able to take oral medication
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gabriela Hobbs, MD
Phone
617-724-3456
Email
ghobbs@partners.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gabriela Hobbs, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02214
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Meridith E. Bailey, MD
Phone
617-643-4970
Email
mebailey@partners.org
First Name & Middle Initial & Last Name & Degree
Gabriela Hobbs, MD
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63130
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mark Schroeder, MD
Email
markschroeder@wustl.edu
First Name & Middle Initial & Last Name & Degree
Mark Schroeder, MD
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roni Tamari, MD
Email
tamarir@mskcc.org
First Name & Middle Initial & Last Name & Degree
Roni Tamari, MD
Facility Name
The Ohio State University Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sarah Wall, MD
Email
Sarah.Fortier@osumc.edu
First Name & Middle Initial & Last Name & Degree
Sarah Wall, MD
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37235
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Byrne, DO
Email
Michael.Byrne@vanderbilt.edu
First Name & Middle Initial & Last Name & Degree
Michael Byrne, DO

12. IPD Sharing Statement

Plan to Share IPD
No

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Ruxolitinib Pre-, During- and Post-HSCT for Patients With Primary or Secondary Myelofibrosis.

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