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

NCT02669251 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 16006016-C-0060
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Chronic Graft vs Host Disease; Chronic Graft-Versus-Host Disease; Bronchiolitis Obliterans Syndrome

Keywords

Optimal Biologic Dose; Safety; Chronic Graft-Versus-Host Disease (cGVHD); Inflammatory Lung Disease; FEV1

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (6)

• Phase 1b and 2: Pharmacokinetics of blood and sputum

  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

  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

  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

  Baseline, C1D1, D4D1, C7D1, c10D1, Off treatment.

• Phase 1B and 2: Determine effect on patient-reported outcomes viaLee cGVHD Symptom Scale, HAP, FACT-BMT

  Phase 1B: C1D1, D1 of continuation phase, D1 of Cycle 11+, Off treatment. Phase 2: Baseline, D1 of C7-12, Off treatment.

Study Arms (2)

Phase 1b

EXPERIMENTAL

Phase Ib dose escalation

Drug: MPH966

Phase 2

EXPERIMENTAL

MTD po bid on days 1-28

Drug: MPH966

Interventions

MPH966 DRUG

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

Phase 1b; Phase 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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 \>= 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:

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Study Officials

• Najla El Jurdi, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2016
• First Posted: February 1, 2016
• Study Start: April 28, 2016
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: April 20, 2026

Record last verified: 2026-04-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)