Ruxolitinib Phosphate in Treating Patients with Bronchiolitis Obliterans Syndrome after Donor Stem Cell Transplant

Status: Active

Description

This phase II trial studies how well ruxolitinib phosphate works in treating patients with bronchiolitis obliterans syndrome after donor stem cell transplant. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Diagnosis of BOS after HCT. The definition can be made following either the NIH diagnostic criteria for BOS OR diagnostic criteria for atypical BOS.
  • NIH diagnostic criteria - All of the following must be met: * 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 The Third National Health and Nutrition Examination Survey (NHANES III) 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 computed tomography (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/total lung capacity (TLC) elevated outside the 90% confidence interval (RV/total lung capacity)
  • Atypical BOS diagnostic criteria – All of the following criteria must be met: * FEV1 < 80% of predicted with >= 10% absolute decline over the last 2 years or since transplant. The remote comparator can be an evaluation of PFTs done within 2 years of the PFTs assessment being evaluated to determine eligibility or the PFT assessment done prior to transplant. * VC < 80% of predicted. * FEV1/VC > 0.7. * 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).
  • Life expectancy > 6 months at the time of enrollment as judged by the enrolling investigator
  • Eastern Cooperative Oncology Group (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
  • Transaminases (alanine aminotransferase [ALT], alanine aminotransferase [AST]) > 5 x upper limit of normal (ULN) and/or total bilirubin > 3 x ULN
  • Absolute neutrophil count < 1000/uL, platelet count < 50K, and/or hemoglobin (Hgb) < 8 g/dL
  • Calculated creatinine clearance < 40 mL/min (Cockcroft-Gault formula)
  • Receipt of any non-Food and Drug Administration (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 principal investigator [PI] or the PFT lab) unable to reliably perform pulmonary function tests
  • Active smoker of cigarettes or marijuana

Locations & Contacts

Massachusetts

Boston
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Zachariah Michael DeFilipp
Email: zdefilipp@mgh.harvard.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To evaluate the treatment effect of ruxolitinib phosphate (ruxolitinib) in patients who develop bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplant (HCT).

SECONDARY OBJECTIVES:

I. To longitudinally assess changes in forced expiratory flow at 25-75% of the pulmonary volume (FEF25-75), residual volume (RV), diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio and FEV1/slow vital capacity (SVC) ratio on pulmonary function test (PFT) testing.

II. To longitudinally assess changes in six-minute walk test.

III. To longitudinally assess the proportion of subjects with improvements in other chronic graft versus host disease (GVHD) organ manifestations (using the National Institutes of Health [NIH] consensus criteria).

IV. To longitudinally assess the change in systemic corticosteroid dose (as compared to baseline steroid dose) after starting therapy with ruxolitinib.

V. To longitudinally assess changes in patient-reported quality of life (Functional Assessment of Cancer Therapy- Bone Marrow Transplant [FACT-BMT]), functional capacity (Human Activity Profile [HAP]), and dyspnea (Modified Medical Research Council Dyspnea Scale) in patients on ruxolitinib therapy compared to baseline measures prior to study enrollment.

VI. To longitudinally assess patient-reported chronic GVHD symptoms (Lee Symptom Scale) in patients on ruxolitinib therapy compared to baseline measures prior to study enrollment.

VII. To describe the incidence and types of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version [v]4.03) Grade 3-5 serious adverse events (SAEs), any unanticipated problems (UPs) or infectious complications that are possibly or probably attributable to ruxolinitib.

VIII. To assess chronic (c) GVHD progression-free survival at months 3, 6 and 12 after enrollment.

IX. To assess overall survival at months 3, 6 and 12 after enrollment.

EXPLORATORY OBJECTIVES:

I. To longitudinally assess changes cytokines, cGVHD biomarkers and immune cell subsets.

OUTLINE:

Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, then every 3 months for 12 months.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Zachariah Michael DeFilipp

Trial IDs

Primary ID 18-265
Secondary IDs NCI-2018-03559
Clinicaltrials.gov ID NCT03674047