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

  • STATUS
    Recruiting
  • End date
    Jan 1, 2024
  • participants needed
    34
  • sponsor
    National Cancer Institute (NCI)
Updated on 21 September 2022

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.

Description

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 2 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 azithromycin for at least 3 months prior to enrollment, unless there is evidence of progression or unsatisfactory response while on azithromycin 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.

Details
Condition Chronic Graft vs Host Disease, Chronic Graft-Versus-Host Disease, Bronchiolitis Obliterans Syndrome
Treatment AZD9668, MPH966
Clinical Study IdentifierNCT02669251
SponsorNational Cancer Institute (NCI)
Last Modified on21 September 2022

Eligibility

Yes No Not Sure

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 the 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, and the absolute decline for the corrected values should still remain at greater than or equal to 10% from pre-translplant
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
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 2 years from the time of
Age greater than or equal to18 years
diagnosis. Patients may be at any time interval after SCT as long as the criteria for
Karnofsky greater than or equal to 60%
chronic GVHD and BOS are met
Patients must have normal organ and marrow function as defined below
If patients are taking systemic therapy for cGVHD at the time of enrollment, they must
leukocytes greater than or equal to 3,000/mcL
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
absolute neutrophil count greater than or equal to 1,000/mcL
platelets greater than or equal to 50,000/mcL
AST(SGOT)/ALT(SGPT) less than or equal to 2 X institutional upper limit of normal
Agree to adhere to methods of contraception and other fertility control measures
total bilirubin less than or equal to 3 X institutional upper limit of normal
unless there is a known history of Gilbert s disease
creatinine clearance greater than or equal to 60 mL/min will be calculated using
eGFR per DLM standards
Patients will be required to have received prior treatment with azithromycin for at
least 3 months prior to enrollment, unless there is evidence of progression or
unsatisfactory response while on azithromycin 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
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

Patients who are receiving any other investigational agents
Recurrent or progressive malignancy requiring anticancer treatment
Prior use of neutrophil elastase inhibitors
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)
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
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
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