The Safety and Tolerability of Pirfenidone for BOS After HCT

Study Overview
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Brief Summary
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This is a phase 1, non-randomized, single-arm, open label, single center clinical trial to determine the tolerability and safety of pirfenidone in patients with BOS associated with lung GVHD after hematopoietic cell transplant.

Detailed Description
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This is a phase 1, non-randomized, single-arm, open label, single center clinical trial to determine the tolerability and safety of pirfenidone in patients with BOS associated with lung GVHD after hematopoietic cell transplant (HCT). Such a trial is a necessary step prior to an evaluation of efficacy, as pirfenidone is known to be associated with adverse events (AEs) of the liver, gastrointestinal system and skin, organs frequently affected in GVHD. Approximately 30 patients will be enrolled, all patients will follow the same drug titration approach. The primary endpoint will be drug tolerability as measured by: the number of patients that are able to maintain the recommended dose of pirfenidone (2403 mg/d) without dose reduction lasting more than 21 days, due to adverse events (AEs). Changes from Baseline to Week 52 will be studied using validated health-related quality of life scales. Eligible patients aged > 18 years must have a diagnosis of BOS according to pre-specified criteria. Patients will be required to have an %FEV1 or %FVC decline >20% from pre-transplant baseline and symptoms of dyspnea, or cough. Eligible patients will enter the Screening Period, which may last up to 28 days. The dose of pirfenidone will be titrated over 3-8 weeks. Patients will have a telephone assessment at Week 1 and 2. An in-clinic assessment will occur every 1-3 months as part of their usual clinical care in the Stanford University Lung GVHD clinic. Patients will complete an AE and dosing compliance diary. If patients discontinue study treatment early for any reason, they will continue with all scheduled study procedures through Week 52. All deaths will be reviewed by a Mortality Assessment Committee (MAC). An external Data Safety Monitoring Board (DSMB) will monitor patient safety during the study.

Official Title
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The Safety and Tolerability of Pirfenidone for Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplantation

Conditions
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Bronchiolitis Obliterans, Graft Vs Host Disease

Intervention / Treatment
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* Drug: Pirfenidone 267 MG [Esbriet]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years at randomization Clinical symptoms (e.g., dyspnea or cough) consistent with BOS of ≥ 2 months duration Presence of cGVHD in an organ other than lung Subjects must have had recent pulmonary function test (PFTs) measured for at least 3 months prior to study enrollment that show: A decrease in %FVC and/or %FEV1 ≥ 20% at Screening compared with pre-transplant baseline. Bronchodilator response on PFT testing that results in an FEV1 < 75% Diagnosis of BOS by one of the following criteria: Transbronchial or surgical lung biopsy demonstrating the obliterative bronchiolitis lesion Volumetric CT scan with lung density analysis with ≥ 28% air trapping (1). NIH-based PFT criteria for the diagnosis of BOS: FEV1/FVC <0.7 and FEV1 < 75% Evidence of clinical improvement after treatment for BOS has been initiated. No features supporting an alternative diagnosis by transbronchial biopsy, bronchoalveolar lavage (BAL), surgical lung biopsy, culture and non-culture based data, if performed Adequate organ and marrow function including: liver function as defined by a total bilirubin below the upper limit of normal (ULN), excluding patients with Gilbert's syndrome; AST/SGOT or ALT/SGPT < 3 x ULN; alkaline phosphatase < 2.5 x ULN; renal function as defined by a CrCl > 30 mL/min, calculated using the Cockcroft-Gault formula; cardiac electrophysiologic stability as defined by an electrocardiogram (ECG) with a QTc interval < 500 msec at Screening; and bone marrow function as defined by a white blood cell count > 3 K/µL, an absolute neutrophil count > 15 K/µL and a platelet count > 20 K/µL Life expectancy > 6 months Participants must be able to understand and sign a written informed consent form and understand the importance of adherence to study treatment and protocol. In addition, participants must demonstrate a willingness to follow all study requirements, including the concomitant medication restrictions, throughout the study Exclusion Criteria: Any condition that, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone e.g., presence of active GVHD of the gastrointestinal tract as manifested by rising liver function tests (LFTs) prior to initiation of study treatment Uncontrolled infection Major surgery within the past 2 months The use of another investigational drug within the previous 30 days. Inability to attend scheduled clinic visits Inability to perform pulmonary function testing Significant clinical change in health in the past 30 days Body mass index (BMI) < 17.5 Life expectancy < 6 months due to any condition other than BOS that, in the opinion of the investigator, is likely to result in the death of the patient. History of unstable or deteriorating cardiac or pulmonary disease (other than BOS) within the previous 6 months, including but not limited to the following: Unstable angina pectoris or myocardial infarction Congestive heart failure requiring hospitalization Uncontrolled clinically significant arrhythmias Pregnancy or lactation. Family or personal history of long QT syndrome Investigational therapy, defined as any drug that has not been approved for marketing for any indication in cGVHD will be restricted from the study The following medications may significantly increase the level of Pirfenidone and should not be taken concurrently including: fluvoxamine, ciprofloxacin > 500mg twice daily, systemically administered aminolevulinic acid, vemurafenib and enoxacin. Any other strong inhibitors of P450 isoenzymes CYP1A2, CYP2C9, 2C19, 2D6, and 2E1 should be avoided. Participants that cannot take alternative medications to those listed above will be excluded from this study. Laboratory Exclusions Any of the following LFT criteria above specified limits: total bilirubin above the upper limit of normal (ULN), excluding patients with Gilbert's syndrome; aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) >3 × ULN; alkaline phosphatase >2.5 × ULN Creatinine clearance (CrCl) <30 mL/min, calculated using the Cockcroft-Gault formula Electrocardiogram (ECG) with a QTc interval >500 msec at Screening Medication Exclusions 1. Prior use of pirfenidone or known hypersensitivity to any of the components of study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a phase 1, non-randomized, single arm, open label, single center clinical trial to determine the tolerability and safety of pirfenidone in patients with BOS associated with lung GVHD after hematopoietic cell transplant (HCT). Approximately 30 patients will be enrolled. All patients will follow the 'patient-centered' drug titration approach.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient centered approach<br>Drug titration of maximum dose over 3-8 weeks | Drug: Pirfenidone 267 MG [Esbriet]<br>* Tolerability of drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of participants that do not require a reduction in drug dose for more than 21 days due to adverse events. | We will count the number of participants that do not require a reduction in drug dose of more than 21, non-continuous days due to adverse events. Tolerability will be assessed during continuous treatment. If the medication dosage increase results in the reoccurrence of a moderate adverse event or serious adverse event, lasting more than 21 days, then the event would be defined as not tolerated. If adverse events resolve before 21 days, then participants will attempt to again up-titrate the Pirfenidone dose, as tolerated. If at least 25% of participants tolerate the drug, then investigators will deem that this study demonstrates adequate tolerability to proceed to a larger trial to examine drug efficacy. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of participants that permanently discontinue drug due to adverse events. | We will count the number of patients that permanently discontinue Pirfenidone due to adverse events. A permanent discontinuation of drug is defined as discontinuation of the drug for more than 42 days. | 52 weeks | 
| The number of participants that temporarily discontinue drug due to adverse events. | We will count the number of participants that temporarily discontinue Pirfenidone due to adverse events. A temporary discontinuation of drug is defined as discontinuation of the drug for less than or equal to 42 days. | 52 week | 
| The number of patients that experience treatment-emergent adverse events | Treatment emergent events are defined as those that start or worsen after the start of study treatment and up to 28 days after the last dose of study treatment. AEs will be summarized by treatment group, system organ class, and preferred term, and also by the event's relationship to study treatment. At each level of summation, patients will be counted only once, under the greatest severity and strongest study-drug relationship (as reported by the investigator). | 56 week | 
| The number of patients that experience treatment-emergent serious adverse events (SAEs) | Serious adverse events (SAEs) are defined as those that result in: (i) death or are life threatening; (ii) result in hospitalization or prolong hospitalization; or (iii) result in disability (disruption of the participant's ability to conduct normal daily activities). Serious adverse events will be summarized by treatment group, system organ class, and preferred term, and also by the event's relationship to study treatment. At each level of summation, patients will be counted only once, under the greatest severity and strongest study-drug relationship (as reported by the investigator). | 56 week | 
| The number of patients that experience treatment-emergent deaths during the study period and for 28 days after the last dose of study treatment. | Treatment emergent deaths are defined as those that occur after the start of study treatment and up to 28 days after the last dose of study treatment and are deemed by the investigator to be related to study treatment. | 56 week | 
| All-cause mortality | We will count the total number of deaths during the study period and for 28 days after the last dose of study treatment | 56 week | 
| The number of patients that experience treatment-emergent changes in complete blood counts. | The complete blood count measures the number white blood cells (WBCs) per liter (L) including differential counts of the type of WBCs, hemoglobin concentration (g/dL), and platelet count per liter. | 52 week | 
| The number of patients that experience treatment-emergent changes in liver function testing. | We will assess treatment related changes in total bilirubin (mg/dL), AST/SGOT (units/L) or ALT/SGPT (units/L), alkaline phosphatase (units/L) | 52 week | 
| The number of patients that experience treatment-emergent changes in serum chemistries panel. | We will assess treatment related changes in potassium (mEq/L), blood urea nitrogen (mg/dL) and serum creatinine (mg/dL). | 52 week | 
| The number of patients that experience treatment-emergent changes in the corrected QT-interval on electrocardiogram. | We will evaluate changes in the interval from ventricular depolarization (Q-wave) to ventricular repolarization (T-wave) corrected for by heart rate | 52 week | 
| Body mass index | We will measure changes in the participant's height (meters) and weight (kg) to determine changes in body mass index (kg/m^2) | 52 week | 
| Oxygen saturation | We will measure the participant's oxygen saturation (%) at rest on room air. | 52 week | 
| Heart rate | We will measure the participant's resting heart rate (beats per minute) | 52 week | 
| Chronic GVHD assessment | Chronic GVHD symptoms will be assessed according to NIH cGVHD global severity score. The global cGVHD severity score evaluates the severity of cGVHD in eight sites including the skin, mouth, eyes, gastrointestinal track, liver, lungs, joints and fascia, and genital track. Each organ is assigned a severity score and composite scores are calculated based on the number of organs involved and the severity score within each affected organ. | 56 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bronchiolitis obliterans syndrome