NCT02669251进行中（未招募）1 期
A Phase 1b/2 Study of Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- To determine the clinical efficacy of MPH966 at the OBD in patients with BOS after SCT
研究概览
简要总结
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.
...
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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:
- •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 >=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.
排除标准
- •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
研究组 & 干预措施
Phase 1b
Experimental
Phase Ib dose escalation
干预措施: MPH966 (Drug)
Phase 2
Experimental
MTD po bid on days 1-28
干预措施: MPH966 (Drug)
结局指标
主要结局
To determine the clinical efficacy of MPH966 at the OBD in patients with BOS after SCT
时间窗: 6 months
Efficacy.
Optimal biologic dose (OBD) based on maximal NE inhibition measured in sputum
时间窗: 8 weeks after study drug initiation
Dose-finding.
determine the safety of MPH966
时间窗: 8 weeks after study drug initiation
Safety.
次要结局
- 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 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: 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 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.)
- Phase 2: Determine effect on markers of target inhibition in sputum and blood(Baseline, 3 months and 6 months (end of treatment) or off study.)
研究者
研究点 (1)
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