Ruxolitinib for Early Lung Dysfunction After Hematopoietic Stem Cell Transplant (HSCT)

Ruxolitinib for Early Lung Dysfunction After HSCT: a Phase II Study

Hematopoietic stem cell transplant (HSCT) is an effective but toxic therapy, and lung injury affects as many as 25% of children receiving HSCT. Improved transplant techniques and major improvements in survival mean that HSCT is being more widely used, and more mismatched grafts are being used. Bronchiolitis obliterans (BO) is a major limitation of pediatric HSCT success as BO is commonly diagnosed late in children, when lung injury is irreversible, leading to long term morbidity or even death. Currently, there are major gaps in our knowledge regarding incidence, etiology and optimal treatment of BO following HSCT, and important diagnostic limitations specific to children. Diagnosis of BO is usually based on performance of pulmonary function tests, which is usually impossible in ill children under 10. Even older children who feel unwell or un-cooperative may be unable to produce interpretable data. These deficiencies in diagnosis mean that BO is commonly diagnosed late, meaning fibrosis has occurred and lesions are irreversible.

The hypothesis for this interventional trial is that early treatment with standard Flovent/montelukast and steroids plus ruxolitinib will reverse lung injury and reduce the frequency of chronic pulmonary impairment or florid BO.

Study Overview

• Status: Recruiting
• Conditions: Bronchiolitis Obliterans (BO); Hematopoietic Stem Cell Transplant (HSCT)
• Intervention / Treatment: Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sara Loveless, BSN, RN; Phone Number: (513) 803-7656; Email: Sara.Loveless@cchmc.org
• Study Contact Backup: Name: Evelyn Nguyen, MS; Phone Number: (513) 636-4379; Email: Evelyn.Nguyen@cchmc.org

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota
      • Principal Investigator: Samuel Goldfarb, MD
      • Contact: Tamara Griffin; Phone Number: 612-301-0164; Email: griffint@umn.edu
      • Contact: Amanda Simmons; Phone Number: 612-626-4610; Email: simmo743@umn.edu
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Principal Investigator: Kasiani Myers, MD
      • Contact: Sara Loveless, BSN, RN; Phone Number: 513-803-7656; Email: Sara.Loveless@cchmc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Subjects ≥ 5 years and ≤ 60 years of age who have undergone allogeneic HCT AND exhibit early lung dysfunction as defined by any one of the following:

• >10% decrease in FEV1 from baseline or decrease of 25% of FEF 25-75 from baseline
• active GVHD in another organ system + pulmonary symptoms (Tachypnea without wheezing, new oxygen requirement, cough)
• Increased R5 by 50% by clinical oscillometry
• Air trapping on CT, small airway thickening, or bronchiectasis

AND - All age groups, including adults:

Adequate renal function defined as estimated Creatinine Clearance (CrCl) ≥ 30 mL/min as calculated by the cystatin c GFR or nuclear GFR

Adequate hepatic function as defined by:

• ALT and AST ≤ 5 x ULN, unless the ALT / AST increase is due to cGVHD
• Total bilirubin of ≤ 5 x ULN (unless of non-hepatic origin or due to Gilbert's Syndrome) or Total bilirubin of < 10 x ULN if due to GVHD

Adequate hematological function defined as:

• Absolute neutrophil count ≥1.0 x 10^9/L
• Platelets ≥30 x 10^9/L

PT/INR <2 x ULN and PTT (aPTT) < 2 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder)

Exclusion Criteria:

• Known hypersensitivity to any constituent of the study medication.
• Active uncontrolled pulmonary infection (preceding infectious evaluation including bronchoscopy as clinically indicated)
• Subjects who are pregnant or breastfeeding or are at risk of pregnancy or fathering a baby and are unable to use acceptable highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days for both females and males after the last dose of study drug.
• Subjects previously treated with investigational agent for GVHD within the 30 days prior to first dose of study treatment. Other non-GVHD additional investigational agents may be allowed on a case by case basis with review/approval by the study Lead PI.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ruxolitinib Treatment	Drug: Ruxolitinib; Participants will receive ruxolitinib orally twice daily for 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with ruxolitinib treatment response	Treatment response is defined by stable and/or improved lung function as defined by the National Institutes of Health Chronic GVHD Response Criteria Working Group.	6 months from early lung dysfunction diagnosis

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants with JAK inhibition	The presence of JAK inhibition will be measured by phospho stat5	24 weeks after ruxolitinib initiation
Number of participants with lung function response measured by a Xenon MRI scan	The presence of a lung function response will be measured by a Xenon MRI scan	24 weeks after ruxolitinib initiation
Number of participants with lung function response measured by home spirometry	The presence of a lung function response will be measured by home spirometry	24 weeks after ruxolitinib initiation
Number of participants with lung function response measured by oscillometry	The presence of a lung function response will be measured by oscillometry	24 weeks after ruxolitinib initiation

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Kasiani Myers, MD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2021
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: May 26, 2021
• First Submitted That Met QC Criteria: May 26, 2021
• First Posted (Actual): June 1, 2021

Study Record Updates

• Last Update Posted (Actual): January 16, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Organizing Pneumonia; Graft vs Host Disease; Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis Obliterans Syndrome
• Other Study ID Numbers: 2020-0719

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No