Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation

Inclusion Criteria

• - INCLUSION CRITERIA: - Patients must have undergone hematopoietic stem cell transplantation and have moderate to severe chronic GVHD as defined by the NIH consensus criteria. - Patients must have BOS as defined by either of the two following criteria (A or B): (A) BOS per NIH consensus criteria (2014 updated criteria). To meet the criteria for BOS, all of the following must be present, in addition to at least one distinctive manifestation of cGVHD: - FEV1/vital capacity <0.7 or the fifth percentile of predicted - FEV1 <75% of predicted with >= 10% decline over less than 2 years. FEV1 should not correct to >75% with albuterol - Absence of infection in the respiratory tract - One of the 2 supporting features of BOS: 1. Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution CT, or 2. Evidence of air trapping by PFTs: residual volume >120% predicted or residual volume/total lung capacity elevated outside the 90% confidence interval. If a patient carries the diagnosis of cGVHD by virtue of organ involvement elsewhere, then only the first 3 criteria above are necessary. (B) BOS, expanded NIH criteria - FEV1/vital capacity >0.7 - FEV1 <75% of predicted with >= 10% decline over less than 2 years. FEV1 should not correct to >75% with albuterol - Absence of infection in the respiratory tract - One of the supporting features of BOS: 1. Evidence of air trapping by expiratory CT 2. small airway thickening or bronchiectasis by high-resolution CT 3. Evidence of air trapping by PFTs: residual volume >120% predicted or residual volume/total lung capacity elevated outside the 90% confidence interval. - For the Phase 1b study, patients may have had the diagnosis of BOS for any period of time. For the Phase 2 study, patients must be within 5 years from the time of diagnosis. Patients may be at any time interval after SCT as long as the criteria for chronic GVHD and BOS are met. - If patients are taking systemic therapy for cGVHD at the time of enrollment, they must be receiving stable or tapering doses within the previous 4 weeks. Patients are not required to have completed a course of steroids prior to enrollment. - Age >=18 years. - Karnofsky >=60% - Patients must have adequate organ and marrow function as defined below: - Leukocytes >=3,000/mcL - Absolute neutrophil count >=1,000/mcL - Platelets >=50,000/mcL - Total bilirubin <=3 x institutional upper limit of normal, unless there is a known history of Gilbert's disease - AST(SGOT)/ALT(SGPT) <=2 x institutional upper limit of normal - Serum creatinine <=1.5 mg/dL OR Creatinine clearance >=60 mL/min as estimated by GFR per DLM standards - Patients will be required to have received prior treatment with a regimen consisting of inhaled steroids and montelukast +/- azithromycin for at least 3 months prior to enrollment, unless there is evidence of progression or unsatisfactory response while on this regimen prior to 3 months of treatment, as deemed by the treating or referring physician. Patients who are on azithromycin will need to discontinue for at least 2 weeks prior to enrollment. - Agree to adhere to methods of contraception and other fertility control measures: The effects of alvelestat (MPH966)on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study therapy. Contraception should be used up until 1 week of discontinuing study medication. -Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: - FEV1 <30% (based on absolute percent predicted using USA-ITS-NIH equation) on pulmonary function testing - Patients with clinically relevant abnormal ECG findings, including abnormal QTc>500 ms on screening ECG (Note: If a patient has a QTc interval >500 ms on screening ECG, the screening ECG may be repeated twice [at least 24 hours apart] for a total of 3 ECGs). - Patients who are receiving any other investigational agents - Recurrent or progressive malignancy requiring anticancer treatment - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, acute kidney injury, or psychiatric illness/social situations within the previous 4 weeks that would limit compliance with study requirements. - Pregnant women are excluded from this study because the teratogenic effects of alvelestat (MPH966) are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with alvelestat (MPH966), nursing should be discontinued if the mother is treated with this agent. - Prior use of neutrophil elastase inhibitors - Patients with a history of cirrhosis, esophageal varices, ascites and hepatic encephalopathy - History of other chronic diseases (i.e., metabolic associated steatohepatitis (MASH), autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson's disease, haemochromatosis) - Patients with a history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening. NOTE: Patients must also be willing to refrain from drinking alcohol during study participation, until end of study drug administration