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AZD9668, an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 9, 2017 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT02669251
First received: January 29, 2016
Last updated: January 26, 2017
Last verified: January 9, 2017
  Purpose

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 AZD9668 may help.

Objectives:

To test the safety of AZD9668 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.


Condition Intervention Phase
Chronic Graft vs Host Disease
Chronic Graft-Versus-Host-Disease
Bronchiolitis Obliterans Syndrome
Drug: AZD9668
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of AZD9668, an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 AZD9668 at the OBD in patients with BOS after SCT [ Time Frame: 6 months ]
  • determine the safety of AZD9668 [ Time Frame: 8 weeks after study drug initiation ]

Estimated Enrollment: 34
Study Start Date: January 20, 2016
Estimated Study Completion Date: September 30, 2018
Estimated Primary Completion Date: September 30, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase 1b
Phase Ib dose escalation
Drug: AZD9668

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

Experimental: Phase 2
MTD po bid on days 1-28
Drug: AZD9668

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


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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% over 2 years
    • 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.

  • 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 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 normal 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
    • creatinine clearance greater than or equal to 50 mL/min/1.73 m(2) (Cockroft-Gault formula)
  • 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
  • Agree to adhere to methods of contraception and other fertility control measures:

The effects of AZD9668 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 AZD9668 are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9668, breastfeeding should be discontinued if the mother is treated with this agent.
  • Prior use of neutrophil elastase inhibitors
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02669251

Contacts
Contact: Steven Z Pavletic, M.D. (240) 760-6174 sp326h@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Steven Z Pavletic, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02669251     History of Changes
Other Study ID Numbers: 160060
16-C-0060
Study First Received: January 29, 2016
Last Updated: January 26, 2017

Keywords provided by National Institutes of Health Clinical Center (CC):
Optimal Biologic Dose
Safety
Chronic Graft-Versus-Host Disease (cGVHD)
Inflammatory Lung Disease
FEV1

Additional relevant MeSH terms:
Syndrome
Graft vs Host Disease
Bronchiolitis
Bronchiolitis Obliterans
Disease
Pathologic Processes
Immune System Diseases
Bronchitis
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Infections
Proteinase Inhibitory Proteins, Secretory
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on March 29, 2017