This study is currently recruiting participants.
Number
16-C-0060
Sponsoring Institute
National Cancer Institute (NCI)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 18 Years Max Age: N/A
Referral Letter Required
No
Population Exclusion(s)
Pregnant Women;Fetuses;Children
Keywords
Optimal Biologic Dose; Safety; Chronic Graft-Versus-Host Disease (cGVHD); Inflammatory Lung Disease; FEV1
Recruitment Keyword(s)
None
Condition(s)
Chronic Graft vs Host Disease; Chronic Graft-Versus-Host Disease; Bronchiolitis Obliterans Syndrome
Investigational Drug(s)
Alvelestat (MPH966)
Investigational Device(s)
Intervention(s)
Drug: MPH966
Supporting Site
National Cancer Institute
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.
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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: 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
-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
--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
Principal Investigator
Referral Contact
For more information: