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The Safety and Tolerability of Pirfenidone for BOS After HCT (STOP-BOS)

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ClinicalTrials.gov Identifier: NCT03315741
Recruitment Status : Recruiting
First Posted : October 20, 2017
Last Update Posted : March 20, 2018
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Stanford University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Bronchiolitis Obliterans Graft Vs Host Disease Drug: Pirfenidone 267 MG [Esbriet] Phase 1

Detailed 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). 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: The Safety and Tolerability of Pirfenidone for Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplantation
Actual Study Start Date : March 1, 2018
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : March 31, 2020


Arm Intervention/treatment
Experimental: Patient centered approach
Drug titration of maximum dose over 3-8 weeks
Drug: Pirfenidone 267 MG [Esbriet]
Tolerability of drug




Primary Outcome Measures :
  1. The number of participants that do not require a reduction in drug dose for more than 21 days due to adverse events. [ Time Frame: 52 weeks ]
    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.


Secondary Outcome Measures :
  1. The number of participants that permanently discontinue drug due to adverse events. [ Time Frame: 52 weeks ]
    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.

  2. The number of participants that temporarily discontinue drug due to adverse events. [ Time Frame: 52 week ]
    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.

  3. The number of patients that experience treatment-emergent adverse events [ Time Frame: 56 week ]
    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).

  4. The number of patients that experience treatment-emergent serious adverse events (SAEs) [ Time Frame: 56 week ]
    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).

  5. The number of patients that experience treatment-emergent deaths during the study period and for 28 days after the last dose of study treatment. [ Time Frame: 56 week ]
    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.

  6. All-cause mortality [ Time Frame: 56 week ]
    We will count the total number of deaths during the study period and for 28 days after the last dose of study treatment

  7. The number of patients that experience treatment-emergent changes in complete blood counts. [ Time Frame: 52 week ]
    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.

  8. The number of patients that experience treatment-emergent changes in liver function testing. [ Time Frame: 52 week ]
    We will assess treatment related changes in total bilirubin (mg/dL), AST/SGOT (units/L) or ALT/SGPT (units/L), alkaline phosphatase (units/L)

  9. The number of patients that experience treatment-emergent changes in serum chemistries panel. [ Time Frame: 52 week ]
    We will assess treatment related changes in potassium (mEq/L), blood urea nitrogen (mg/dL) and serum creatinine (mg/dL).

  10. The number of patients that experience treatment-emergent changes in the corrected QT-interval on electrocardiogram. [ Time Frame: 52 week ]
    We will evaluate changes in the interval from ventricular depolarization (Q-wave) to ventricular repolarization (T-wave) corrected for by heart rate

  11. Body mass index [ Time Frame: 52 week ]
    We will measure changes in the participant's height (meters) and weight (kg) to determine changes in body mass index (kg/m^2)

  12. Oxygen saturation [ Time Frame: 52 week ]
    We will measure the participant's oxygen saturation (%) at rest on room air.

  13. Heart rate [ Time Frame: 52 week ]
    We will measure the participant's resting heart rate (beats per minute)

  14. Chronic GVHD assessment [ Time Frame: 56 week ]
    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.


Other Outcome Measures:
  1. Pulmonary function testing: spirometric change from baseline to week 52. [ Time Frame: 52 week ]
    We will measure the participant's Forced Expiratory Volume in 1 second (FEV1: L, % predicted), and Forced Vital Capacity (FVC: L, % predicted)

  2. Pulmonary function testing: diffusion capacity for carbon monoxide (DLCO) change from baseline to week 52. [ Time Frame: 52 week ]
    We will measure DLCO (ml/min/mmHg)

  3. Change from Baseline to Week 52 in % air trapping as measured by volumetric CT thorax with lung density analysis [ Time Frame: 52 week ]
    We will use lung density analysis to radiographically quantify the percent air trapping between an inspiratory and expiratory CT scan.

  4. BOS-related mortality [ Time Frame: 52 week ]
    We will count the number of participant deaths that are attributable to BOS.

  5. Change from Baseline to Week 24 and 52 in dyspnea, as measured by the University of California at San Diego Shortness-of-Breath Questionnaire (UCSD SOBQ) score [ Time Frame: 24 and 52 week ]

    Changes in dyspnea, as measured by UCSD SOBQ score, from Baseline to Week 26 and 52 will be analyzed using the same methods described in Section 5.4.2.1. Baseline UCSD SOBQ score will be the average of the measurements recorded at the Screening and Day 1 visits. The UCSD SOBQ score will be repeated at Week 26 and 52. The magnitude of the treatment effect of pirfenidone will be presented as the distribution (number and percentage) of patients across two categories of change from Baseline:

    • Increase of ≥ 25 points in the UCSD SOBQ score at Week 26 and 52 or death before Week 52
    • Decrease of ≥ 0

  6. Change from Baseline to Week 24 and 52 in Chronic GVHD (cGVHD) response [ Time Frame: 24 and 52 week ]
    The Lee cGVHD symptom scale contains 30 items in 7 subscales (skin, eye, mouth, lung, nutrition, energy and psychological), using a 5-point Likert scale. Scores are linearly transformed to a 0-100 scale with higher values representing more severe symptoms. A summary score also is calculated if 4 or more subscales are available for scoring. Change in GVHD symptoms as measured by the Lee GVHD-symptom scale from Baseline to Week 26 and 52 will be evaluated.

  7. Cumulative systemic corticosteroid exposure [ Time Frame: 52 week ]
    We will calculate the cumulative Prednisone dose (mg, or its corticosteroid equivalent) used by each participant over the trial period.

  8. Use of other immunosuppressive medications [ Time Frame: 52 week ]
    We will calculate the type and the cumulative dose (mg) of other immune suppressive medications used by each participant over the trial period.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 GVHD 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. Lack of bronchodilator response on PFT testing < 12% change and < 200 ml change in FEV1 and/or FVC
  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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03315741


Contacts
Contact: Joe L Hsu, MD, MPH 650-725-9536 joehsu@stanford.edu
Contact: Efthymia I Matthaiou, PhD 650-497-6766 ematth@stanford.edu

Locations
United States, California
Stanford University School of Medicine Recruiting
Palo Alto, California, United States, 94304
Contact: Joe L Hsu, MD, MPH    650-725-9536    joehsu@stanford.edu   
Contact: Efthymia I Matthaiou, PhD    650-497-6766    ematth@stanford.edu   
Principal Investigator: Joe L Hsu, MD, MPH         
Sponsors and Collaborators
Stanford University
Genentech, Inc.
Investigators
Principal Investigator: Joe L Hsu, MD, MPH Stanford University

Responsible Party: Stanford University
ClinicalTrials.gov Identifier: NCT03315741     History of Changes
Other Study ID Numbers: VAR0158
IRB-43319 ( Other Identifier: Stanford IRB )
First Posted: October 20, 2017    Key Record Dates
Last Update Posted: March 20, 2018
Last Verified: March 2018
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
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Stanford University:
Bronchiolitis obliterans syndrome

Additional relevant MeSH terms:
Bronchiolitis
Graft vs Host Disease
Bronchiolitis Obliterans
Bronchitis
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Infections
Immune System Diseases
Pirfenidone
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Antirheumatic Agents
Antineoplastic Agents