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

Study Overview
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Brief Summary
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Background: Bronchiolitis obliterans syndrome (BOS) is a complication people can experience after hematopoietic stem cell transplant. It usually affects people with chronic graft versus host disease (cGVHD). This occurs when donor stem cells attack the cells of the person who received them. BOS reduces airflow and oxygen levels in the body. It may be caused by neutrophil elastase in the body. Researchers believe the new drug alvelestat (MPH966) may help. Objectives: To test the safety of alvelestat (MPH966) and see what dose best inhibits neutrophil elastase in people with BOS after a stem cell transplant. To study how well the best dose improves lung function in those people. Eligibility: Adults 18 and older who have had a hematopoietic stem cell transplant and have cGVHD and BOS. Design: Participants will be screened with a medical history, physical exam, and blood and urine tests. They will have lung function and heart function tests. They will have computed tomography scans of the chest. Study part 1: Participants will take the starting dose of the study drug by mouth twice a day for 14 days. This is 1 cycle. They will get different doses, for up to 4 cycles. Study part 2: Participants will take the study drug twice a day by mouth at the dose set in part 1, for up to 12 months. Participants will keep medicine diaries. Participants will have several study visits. These may include: Repeats of the screening tests. Bronchoscopy with bronchoalveolar lavage. Sputum samples taken. 6-minute walking test. cGVHD assessment and answer questions. Participants will be contacted after the study for up to 24 months.

Detailed Description
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Background: Chronic graft-versus-host disease (cGVHD) is the leading cause of non-relapse morbidity and mortality in persons after allogeneic hematopoietic stem cell transplantation (SCT). Bronchiolitis obliterans syndrome (BOS) is a complication of cGVHD associated with a high morbidity and mortality, and treatment options are limited. Neutrophil elastase (NE) is a protease released by neutrophils in the setting of inflammation, and has been implicated in the pathogenesis of BOS. Alvelestat (MPH966) (Formerly known as AZD9668) is a potent and selective inhibitor of NE that has demonstrated evidence of target inhibition and a good safety profile in patients with inflammatory lung diseases, but has not been evaluated in BOS. Objectives: Phase 1b: To determine the optimal biologic dose (OBD) based on maximal NE inhibition measured in blood, and to determine the safety of alvelestat (MPH966) in patients with BOS after SCT Phase 2: To determine the clinical efficacy of alvelestat (MPH966) at the OBD in patients with BOS after SCT, based on the proportion of patients with stable or improved forced expiratory volume in 1 second (FEV1) on pulmonary function testing Eligibility: Inclusion criteria: Age greater than or equal to 18 years BOS after SCT and moderate to severe cGVHD as defined by the NIH consensus criteria Within 5 years from the time of diagnosis (Phase 2 only) Karnofsky performance status greater than or equal to 60% If on systemic cGVHD therapy, must be receiving stable or tapering doses in the preceding 4 weeks Patients will be required to have received prior treatment with a regimen consisting of inhaled steroids and montelukast plus or minus 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, an antibiotic used in the treatment of BOS, will need to discontinue for at least 2 weeks prior to enrollment Exclusion criteria: FEV1 < 30% (based on absolute percent predicted using USA-ITS-NIH equation) on pulmonary function testing Prior use of neutrophil elastase inhibitors Progressive malignancy Uncontrolled infection or any major organ dysfunction as defined by the protocol Design: Phase 1b: This is a Phase 1b trial to determine the OBD and safety of alvelestat (MPH966) in patients with BOS after SCT. This trial will use an intra-patient dose escalation schedule. The starting dose will be 60mg twice daily for 2 weeks, and the dose will be increased by 60mg with each escalation every 2 weeks until a maximum dose of 240mg twice daily is reached for a total treatment period of 8 weeks. After completion of the dose escalation phase, patients will have the option to continue the dose at which maximal NE inhibition and safety are demonstrated for up to 6 additional months. The co-primary endpoint of OBD will be defined as the dose level at which the maximal NE inhibition occurs, and at which no more than 1/3 of patients experience a DLT. NE activity will be measured in the blood at baseline and with each dose escalation, and will be compared between dose levels to determine the OBD. The co-primary endpoint of safety will be determined by monitoring adverse events and dose limiting toxicities (DLT) as defined by the protocol. Further dose escalation will cease in a patient who experiences a DLT. In addition, no subsequent patients will be treated at or beyond the dose in which 1/3 of patients have experienced a DLT. A total of 10 patients will be enrolled in the Phase 1b trial. Phase 2: This is a Phase 2 trial to determine the efficacy of alvelestat (MPH966) at the OBD in patients with BOS after SCT, as measured by stabilization or improvement of FEV1 (based on absolute percent predicted) after 6 months of treatment. Patients will receive alvelestat (MPH966) using an intra-patient dose escalation schedule. The starting dose will be 60 mg twice daily for 2 weeks, and the dose will be increased by 60 mg twice daily with each dose escalation every 2 weeks until a maximum dose of 240 mg twice daily is reached for a total treatment period of 18 weeks (total of 6 cycles). There is an optional continuation phase for 24 more weeks (cycles 7-12) with each cycle being 28 days and pulmonary function testing with measurement of FEV1 will be performed to determine the primary endpoint. Response assessments will occur every 3 months with primary efficacy endpoint evaluated at 6 months. Patients with stable or responding disease will have the option to continue therapy for another 6 months. As an early stopping rule for futility, if 0-2 of the first 8 patients enrolled have responded, then no further patients will be accrued. A total of 20 patients may be needed for evaluation in phase II. In order to allow for a small number of inevaluable patients, the accrual ceiling will be set at 34 patients across both phases.

Official Title
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A Phase 1b/2 Study of Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Chronic Graft vs Host Disease, Chronic Graft-Versus-Host Disease, Bronchiolitis Obliterans Syndrome

Intervention / Treatment
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* Drug: MPH966


Participation Criteria
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Eligibility Criteria
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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 greater than or equal to 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: Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution CT, or 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 greater than or equal to 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: Evidence of air trapping by expiratory CT Small airway thickening or bronchiectasis by high-resolution CT 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 greater than or equal to18 years. Karnofsky greater than or equal to 60% Patients must have adequate organ and marrow function as defined below: Leukocytes greater than or equal to 3,000/mcL Absolute neutrophil count greater than or equal to 1,000/mcL Platelets greater than or equal to 50,000/mcL Total bilirubin less than or equal to 3 x institutional upper limit of normal, unless there is a known history of Gilbert s disease AST(SGOT)/ALT(SGPT) less than or equal to 2 x institutional upper limit of normal Serum creatinine less than or equal to 1.5 mg/dL OR Creatinine clearance greater than or equal to 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 plus or minus 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. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, or if a man s partner becomes pregnant or suspects she is pregnant while he is participating in this study, she or he should inform their treating physician immediately. -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), breastfeeding 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 Patients with non-alcoholic fatty liver disease (NAFLD) or use of drugs associated with NAFLD for more than 2 weeks in the year prior to screening 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

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b<br>Phase Ib dose escalation | Drug: MPH966<br>* Phase 1b Cycle= 14 days: Each dose level will increase by 60mg PO BID, up to a maximum of 240mg PO BID Phase 2 Cycle=28 days: MTD PO BID<br>|
| Experimental: Phase 2<br>MTD po bid on days 1-28 | Drug: MPH966<br>* Phase 1b Cycle= 14 days: Each dose level will increase by 60mg PO BID, up to a maximum of 240mg PO BID Phase 2 Cycle=28 days: MTD PO BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal biologic dose (OBD) based on maximal NE inhibition measured in sputum | Dose-finding. | 8 weeks after study drug initiation | 
| To determine the clinical efficacy of MPH966 at the OBD in patients with BOS after SCT | Efficacy. | 6 months | 
| determine the safety of MPH966 | Safety. | 8 weeks after study drug initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b and 2: Pharmacokinetics of blood and sputum | Pharmacokinetics of study drug. | Phase 1b: Baseline, first day of each cycle at dose escalation. Phase 2: Baseline, C1D1, C3D1, C6D1. | 
| Phase 1B: Correlation of NE activity in blood with sputum measurements | Efficacy/drug effect on laboratory values. | Phase 1b: Pre/post dose on day 1 of each dose level and at start of continuation phase. Phase 2: Pre/post dose on day one of each dose level. | 
| Phase 1B and 2: Determine the impact on lung inflammatory markers based on levels in blood, sputum and BAL fluid | Efficacy/drug effect on laboratory values. | Phase 1b: Baseline, 8 wees. Phase 2: Baseline, 3 months and 6 months (end of treatment). | 
| Phase 2: Efficacy testing via NIH Lung Symptom Score, 6 minute walk test, survival, FEV1 slope measured from baseline, and other PFT measurements | Efficacy. | Baseline, C1D1, D4D1, C7D1, c10D1, Off treatment. | 
| Phase 1B and 2: Determine effect on patient-reported outcomes viaLee cGVHD Symptom Scale, HAP, FACT-BMT | Analysis of patient-reported outcomes. | Phase 1B: C1D1, D1 of continuation phase, D1 of Cycle 11+, Off treatment. Phase 2: Baseline, D1 of C7-12, Off treatment. | 
| Phase 2: Determine effect on markers of target inhibition in sputum and blood | Efficacy/drug effect on laboratory values. | Baseline, 3 months and 6 months (end of treatment) or off study. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Optimal Biologic Dose, Safety, Chronic Graft-Versus-Host Disease (cGVHD), Inflammatory Lung Disease, FEV1