Ruxolitinib for Bronchiolitis Obliterans Syndrome (BOS) After Allogeneic Hematopoietic Cell Transplantation (HCT)

• ClinicalTrials.gov Identifier: NCT03674047
• Recruitment Status: Recruiting
• First Posted: September 17, 2018
• Last Update Posted: October 4, 2021
• Sponsor: Massachusetts General Hospital
• Collaborator: Incyte Corporation
• Information provided by (Responsible Party): Zachariah Michael DeFilipp, Massachusetts General Hospital

Study Description

Brief Summary:

This research study is studying a drug as a possible treatment for Bronchiolitis Obliterans Syndrome (BOS) after having an Allogeneic Hematopoietic Cell Transplantation (HCT).

Condition or disease	Intervention/treatment	Phase
Other Cancer	Drug: ruxolitinib	Phase 2

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 not approved ruxolitinib for this specific disease but it has been approved for other uses.

In this study the investigators are assessing the safety and effectiveness of ruxolitinib when given to participants who have been diagnosed with BOS after HCT. BOS is a sign/symptom of chronic Graft-vs-Host Disease (GVHD), a condition in which cells from the donor's tissue attack the organs after HCT occurs.

Ruxolitinib blocks certain proteins called tyrosine kinases. Specifically, it blocks tyrosine kinases called JAK2. The investigators believe that ruxolitinib may lower the rate of GVHD through its ability to block the JAK2 pathway since this pathway can lead to inflammation in the body.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Ruxolitinib for Bronchiolitis Obliterans Syndrome (BOS) After Allogeneic Hematopoietic Cell Transplantation (HCT)
• Actual Study Start Date: April 19, 2019
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: newly-diagnosed BOS; -Participants will take ruxolitinib twice every day	Drug: ruxolitinib; Ruxolitinib blocks certain proteins called tyrosine kinases. Specifically, it blocks tyrosine kinases called JAK2. it's believe that ruxolitinib may lower the rate of GVHD through its ability to block the JAK2 pathway since this pathway can lead to inflammation in the body; Other Name: Jakafi
Experimental: Established BOS; -Participants will take ruxolitinib twice every day	Drug: ruxolitinib; Ruxolitinib blocks certain proteins called tyrosine kinases. Specifically, it blocks tyrosine kinases called JAK2. it's believe that ruxolitinib may lower the rate of GVHD through its ability to block the JAK2 pathway since this pathway can lead to inflammation in the body; Other Name: Jakafi

Outcome Measures

Primary Outcome Measures :

1. absolute FEV1 increase [ Time Frame: 3 Months ]
   The proportion of participants with a sustained, absolute FEV1 increase by ≥ 10% after 3 months of treatment with ruxolitinib (compared to baseline measure prior to study enrollment) among participants with newly diagnosed Bronchiolitis Obliterans Syndrome BOS.
2. treatment failure, comparing 3-month FEV1 to baseline FEV1 [ Time Frame: 3 Months ]
   The proportion of participants who do not experience a sustained, absolute decrease in FEV1 by ≥ 10% after 3 months of treatment with ruxolitinib (compared to baseline measure prior to study enrollment) among participants with established Bronchiolitis Obliterans Syndrome BOS.

Secondary Outcome Measures :

1. Change scores for PFT measurements [ Time Frame: 1 Year ]
   Change in pulmonary function test (PFT) measurements.
2. Improvements in chronic GVHD organ manifestations [ Time Frame: 3 and 6 Months ]
   Improvements in chronic GVHD organ manifestations will be categorized according to the NIH chronic GVHD consensus criteria.
3. Overall survival [ Time Frame: 2 Years ]
4. cGVHD progression-free survival [ Time Frame: 2 Years ]
   cGVHD progression-free survival is defined as the time from registration to the earlier of progression of chronic GVHD or death due to any cause. Participants alive without cGVHD progression are censored at the date of last disease evaluation.
5. The incidence and types of serious adverse events [ Time Frame: From the start of treatment until 30 days after the end of treatment, up to 13 months total ]
   Adverse events are graded according to Common Terminology Criteria for Adverse Events (CTCAE v4).
6. The total systemic corticosteroid dose longitudinally over time [ Time Frame: 2 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of BOS after HCT defined when all of the following criteria are met (as defined by the 2014 NIH criteria):

  • FEV1/VC < 0.7 or the 5th percentile of predicted.
  • FEV1 = Forced Expiratory Volume in 1 second.
  • VC = Vital Capacity (Forced Vital Capacity "FVC" or Slow Vital Capacity "SVC", whichever is greater)
  • The 5th percentile of predicted is the lower limit of the 90% confidence interval.
  • For elderly patients, use the lower limits of normal defined according to NHANESIII calculations.
  • FEV1 <75% of predicted with ≥ 10% absolute decline over less than 2 years. FEV1 should not correct to >75% of predicted with albuterol, and the absolute decline for the corrected values should still remain ≥ 10% over 2 years. The remote comparator would be an evaluation of PFTs done within 2 years of the PFTs assessment being evaluated to determine eligibility.
  • Absence of active infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as chest radiographs or computed tomographic scans or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, bronchoalveolar lavage).
  • One of the two supporting features of BOS:
  • Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution chest CT OR
  • Evidence of air trapping by PFTs: RV (Residual Volume) > 120% of predicted or RV/TLC elevated outside the 90% confidence interval (RV/Total Lung Capacity).
• Life expectancy > 6 months at the time of enrollment as judged by the enrolling investigator.
• Male or female; 18-75 years old.
• ECOG Performance Status 0-2.
• At least 4 weeks since initiation of the most recent systemic therapy for cGVHD or BOS
• All females of childbearing potential must have a negative serum or urine pregnancy test < 7 days before study drug administration.
• The ability to understand and willingness to sign a written consent document

Exclusion Criteria:

• Recurrent malignancy or disease progression requiring anticancer therapy.
• Currently receiving or have previously received ruxolitinib for chronic GVHD therapy.
• Known history of allergy to ruxolitinib or its excipients.
• Pregnant females or nursing mothers.
• Hepatic dysfunction: transaminases (ALT, AST) > 5X ULN and/or total bilirubin > 3X ULN.
• Hematologic dysfunction: absolute neutrophil count <1000/μL, platelet cout <50K, and/or Hgb < 8 g/dL.
• Renal dysfunction: calculated creatinine clearance < 40 mL/min (Cockcroft-Gault formula)
• Receipt of any non-FDA approved study medication within the last 4 weeks (This does not apply to use of FDA-approved drugs for an off-label indication).
• Presence of an active uncontrolled infection. An active uncontrolled infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without signs or symptoms will not be interpreted as an active uncontrolled infection.
• Known human immunodeficiency virus infection.
• Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or at risk for HBV reactivation. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive. Subjects with previous positive serology results must have negative polymerase chain reaction results. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment.
• Severe organ dysfunction unrelated to underlying GVHD, including: Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to GVHD and ongoing organ dysfunction).
• Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy.
• Clinically active asthma (variable and recurring symptoms of airflow obstruction and bronchial hyper-responsiveness), chronic obstructive pulmonary disease, interstitial lung disease, or cryptogenic organizing pneumonia or other causes of restrictive lung disease such as neuromuscular weakness or diaphragmatic paralysis.
• Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with the study requirements.
• Uncontrolled substance abuse or psychiatric disorder.
• Deemed (by the local PI or the PFT lab) unable to reliably perform pulmonary function tests.
• Active smoker of cigarettes or marijuana.

Contacts and Locations

Contacts

Contact: Zachariah DeFilipp, MD; 617-724-4000; zdefilipp@mgh.harvard.edu

Locations

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Zachariah DeFilipp, MD 617-724-4000 zdefilipp@mgh.harvard.edu

Principal Investigator: Zachariah DeFilipp, MD

Sponsors and Collaborators

Massachusetts General Hospital

Incyte Corporation

Investigators

• Principal Investigator: Zachariah DeFilipp, MD; Massachusetts General Hospital

More Information

• Responsible Party: Zachariah Michael DeFilipp, Principal Investigator, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT03674047
• Other Study ID Numbers: 18-265
• First Posted: September 17, 2018
• Last Update Posted: October 4, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Zachariah Michael DeFilipp, Massachusetts General Hospital:

Hematopoietic Cell Transplantation

Additional relevant MeSH terms:

Bronchiolitis; Bronchiolitis Obliterans; Bronchitis; Respiratory Tract Infections; Infections; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases