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

• Register: ClinicalTrials.gov
• Last refreshed on: 27 February 2024
• Main ID: NCT02669251
• Date of registration: 29/01/2016
• Prospective Registration: Yes
• Primary sponsor: National Cancer Institute (NCI)
• Public title: Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation
• Scientific title: A Phase 1b/2 Study of Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation
• Date of first enrolment: April 28, 2016
• Target sample size: 34
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT02669251
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

United States

Contacts

• Name: Steven Z Pavletic, M.D.

• Name: Steven Z Pavletic, M.D.
• Affiliation: National Cancer Institute (NCI)

Key inclusion & exclusion 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 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:

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 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:

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 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



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Chronic Graft vs Host Disease

Bronchiolitis Obliterans Syndrome

Chronic Graft-Versus-Host Disease

Intervention(s)

Drug: MPH966

Primary Outcome(s)

determine the safety of MPH966 [Time Frame: 8 weeks after study drug initiation]

Optimal biologic dose (OBD) based on maximal NE inhibition measured in sputum [Time Frame: 8 weeks after study drug initiation]

To determine the clinical efficacy of MPH966 at the OBD in patients with BOS after SCT [Time Frame: 6 months]

Secondary Outcome(s)

Phase 1B and 2: Determine the impact on lung inflammatory markers based on levels in blood, sputum and BAL fluid [Time Frame: Phase 1b: Baseline, 8 wees. Phase 2: Baseline, 3 months and 6 months (end of treatment).]

Phase 2: Determine effect on markers of target inhibition in sputum and blood [Time Frame: Baseline, 3 months and 6 months (end of treatment) or off study.]

Phase 2: Efficacy testing via NIH Lung Symptom Score, 6 minute walk test, survival, FEV1 slope measured from baseline, and other PFT measurements [Time Frame: Baseline, C1D1, D4D1, C7D1, c10D1, Off treatment.]

Phase 1b and 2: Pharmacokinetics of blood and sputum [Time Frame: Phase 1b: Baseline, first day of each cycle at dose escalation. Phase 2: Baseline, C1D1, C3D1, C6D1.]

Phase 1B and 2: Determine effect on patient-reported outcomes viaLee cGVHD Symptom Scale, HAP, FACT-BMT [Time Frame: Phase 1B: C1D1, D1 of continuation phase, D1 of Cycle 11+, Off treatment. Phase 2: Baseline, D1 of C7-12, Off treatment.]

Phase 1B: Correlation of NE activity in blood with sputum measurements [Time Frame: 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.]

Secondary ID(s)

160060

16-C-0060

Source(s) of Monetary Support

Please refer to primary and secondary sponsors