The Safety and Tolerability of Pirfenidone for BOS After HCT

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Age \> 18 years at randomization
2. Clinical symptoms (e.g., dyspnea or cough) consistent with BOS of ≥ 2 months duration
3. Presence of cGVHD in an organ other than lung
4. Subjects must have had recent pulmonary function test (PFTs) measured for at least 3 months prior to study enrollment that show:

   1. A decrease in %FVC and/or %FEV1 ≥ 20% at Screening compared with pre-transplant baseline.
   2. Bronchodilator response on PFT testing that results in an FEV1 \< 75%
5. Diagnosis of BOS by one of the following criteria:

   1. Transbronchial or surgical lung biopsy demonstrating the obliterative bronchiolitis lesion
   2. Volumetric CT scan with lung density analysis with ≥ 28% air trapping (1).
   3. NIH-based PFT criteria for the diagnosis of BOS: FEV1/FVC \<0.7 and FEV1 \< 75%
   4. Evidence of clinical improvement after treatment for BOS has been initiated.
6. No features supporting an alternative diagnosis by transbronchial biopsy, bronchoalveolar lavage (BAL), surgical lung biopsy, culture and non-culture based data, if performed
7. 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
8. Life expectancy \> 6 months
9. 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:

1. 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
2. Uncontrolled infection
3. Major surgery within the past 2 months
4. The use of another investigational drug within the previous 30 days.
5. Inability to attend scheduled clinic visits
6. Inability to perform pulmonary function testing
7. Significant clinical change in health in the past 30 days
8. Body mass index (BMI) \< 17.5
9. 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.
10. History of unstable or deteriorating cardiac or pulmonary disease (other than BOS) within the previous 6 months, including but not limited to the following:

    1. Unstable angina pectoris or myocardial infarction
    2. Congestive heart failure requiring hospitalization
    3. Uncontrolled clinically significant arrhythmias
11. Pregnancy or lactation.
12. Family or personal history of long QT syndrome
13. Investigational therapy, defined as any drug that has not been approved for marketing for any indication in cGVHD will be restricted from the study
14. 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

1. 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
2. Creatinine clearance (CrCl) \<30 mL/min, calculated using the Cockcroft-Gault formula
3. 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.