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MPH966 for Prevention of Graft-versus-host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

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ClinicalTrials.gov Identifier: NCT03986086
Recruitment Status : Not yet recruiting
First Posted : June 14, 2019
Last Update Posted : June 14, 2019
Sponsor:
Collaborators:
Mereo BioPharma
National Center for Advancing Translational Science (NCATS)
Information provided by (Responsible Party):
Nelson Chao, Duke University

Brief Summary:
The purpose of this study is evaluate the safety and tolerability of MPH966, a neutrophil elastase inhibitor, and its ability to prevent graft-versus-host disease after hematopoietic stem cell transplant.

Condition or disease Intervention/treatment Phase
Hematologic Malignancy Drug: MPH966 Drug: Placebo Phase 1 Phase 2

Detailed Description:

Phase 1 is a 3+3 dose escalation study to determine the safety and recommended phase 2 dose (RP2D) of MPH966 in patients undergoing allogeneic hematopoietic stem cell transplantation (HCT). We will evaluate up to 4 doses: 60 mg po bid, 120 mg po bid, 180 mg po bid, and 240 mg po bid. Safety, tolerability, and efficacy will be assessed in real time and pharmacokinetics and pharmacodynamics after each dose cohort before escalating to the next cohort.

Phase 2 is a randomized, double-blind, placebo-controlled study to determine the clinical efficacy of MPH966 vs. placebo in preventing acute graft-versus-host disease (GVHD) after HCT, using the RP2D as determined by the phase 1 trial.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of MPH966, an Oral Neutrophil Elastase Inhibitor, for Prevention of Graft-versus-host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
Estimated Study Start Date : September 2021
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MPH966
Participants receive MPH966 at RP2D tablet orally twice daily from the start of conditioning chemotherapy through 45 days post transplant.
Drug: MPH966
RP2D tablet
Other Name: alvelestat

Placebo Comparator: Placebo
Participants receive MPH placebo tablet matching MPH966 orally twice daily from the start of conditioning chemotherapy through 45 days post transplant.
Drug: Placebo
MPH966 placebo table




Primary Outcome Measures :
  1. Incidence of grade 2-4 acute Graft vs Host Disease (GVHD) requiring systemic therapy [ Time Frame: day 100 ]

Secondary Outcome Measures :
  1. Incidence of grade 2-4 acute GVHD [ Time Frame: day 100 ]
  2. Incidence of grade 3-4 acute GVHD [ Time Frame: day 100 ]
  3. Incidence of grade 2-4 acute GVHD [ Time Frame: month 6 ]
  4. Incidence of grade 3-4 acute GVHD [ Time Frame: month 6 ]
  5. Kaplan-Meier analysis of time-to-event: percentage of participants who develop grade 2-4 acute GVHD by visit [ Time Frame: day 0 and 100 days, 6 months ]
  6. Kaplan-Meier analysis of time-to-event: percentage of participants who develop grade 3-4 acute GVHD by visit [ Time Frame: Day 0 and day 100, month 6 ]
  7. Incidence of chronic GVHD [ Time Frame: month 6 ]
  8. Incidence of chronic GVHD [ Time Frame: month 12 ]
  9. Kaplan-Meier analysis of time-to-event: percentage of participants who develop chronic GVHD [ Time Frame: Day 0 and month 6, 12 ]
    Time to event distributions estimated by the Kaplan-Meier method

  10. Incidence of GVHD-free survival [ Time Frame: month 6 ]
    GVHD-free survival is defined as freedom from GVHD requiring systemic steroids

  11. Incidence of GVHD-free survival [ Time Frame: month 12 ]
    GVHD-free survival is defined as freedom from GVHD requiring systemic steroids

  12. Incidence of relapse-free survival [ Time Frame: month 6 ]
    Relapse-free survival is defined as freedom from relapse

  13. Incidence of relapse-free survival [ Time Frame: month 12 ]
    Relapse-free survival is defined as freedom from relapse

  14. Incidence of bacterial infections [ Time Frame: Day 100 ]
  15. Incidence of fungal infections [ Time Frame: Day 100 ]
  16. Incidence of viral infections [ Time Frame: Day 100 ]
  17. Incidence of overall infections [ Time Frame: Day 100 ]
  18. Incidence of bacterial infections [ Time Frame: 6 months ]
  19. Incidence of fungal infections [ Time Frame: month 6 ]
  20. Incidence of viral infections [ Time Frame: month 6 ]
  21. Incidence of overall infections [ Time Frame: month 6 ]
  22. Incidence of bacterial infections [ Time Frame: month 12 ]
  23. Incidence of fungal infections [ Time Frame: month 12 ]
  24. Incidence of viral infections [ Time Frame: month 12 ]
  25. Incidence of overall infections [ Time Frame: month 12 ]
  26. Kaplan-Meier analysis of time-to-event: percentage of participants who develop bacterial infections [ Time Frame: Day 0 and day 100, month 6,12 ]
  27. Kaplan-Meier analysis of time-to-event: percentage of participants who develop fungal infections [ Time Frame: Day 0 and day 100, month 6,12 ]
  28. Kaplan-Meier analysis of time-to-event: percentage of participants who develop viral infections [ Time Frame: Day 0 and day 100, month 6,12 ]
  29. Kaplan-Meier analysis of time-to-event: percentage of participants who develop overall infections [ Time Frame: Day 0 and day 100, month 6,12 ]
  30. Incidence of relapse [ Time Frame: month 6 ]
  31. Incidence of relapse [ Time Frame: month 12 ]
  32. Kaplan-Meier analysis of time-to-event: percentage of participants who relapse [ Time Frame: Day 0 and month 6,12 ]
  33. Incidence of non-relapse mortality [ Time Frame: month 6 ]
    Non-relapse mortality is defined as death while in remission from the primary disease

  34. Incidence of non-relapse mortality [ Time Frame: month 12 ]
    Non-relapse mortality is defined as death while in remission from the primary disease

  35. Kaplan-Meier analysis of time-to-event: percentage of participants who experience non-relapse mortality [ Time Frame: Day 0 and month 6,12 ]
    Non-relapse mortality is defined as death while in remission from the primary disease

  36. Incidence of hospital re-admission [ Time Frame: Day 100 ]
  37. Incidence of hospital re-admission [ Time Frame: month 6 ]
  38. Incidence of hospital re-admission [ Time Frame: month 12 ]
  39. Kaplan-Meier analysis of time-to-event: percentage of participants who are re-admitted to the hospital [ Time Frame: Day 0 and day 100, month 6,12 ]
  40. Length of hospital re-admission [ Time Frame: Day 100 ]
  41. Length of hospital re-admission [ Time Frame: month 6 ]
  42. Length of hospital re-admission [ Time Frame: month 12 ]
  43. Incidence of intensive care unit (ICU) admission [ Time Frame: Day 100 ]
  44. Incidence of intensive care unit (ICU) admission [ Time Frame: month 6 ]
  45. Incidence of intensive care unit (ICU) admission [ Time Frame: month 12 ]
  46. Kaplan-Meier analysis of time-to-event: percentage of participants who are admitted to ICU [ Time Frame: Day 0 and month 6,12 ]
  47. Length of intensive care unit (ICU) admission [ Time Frame: Day 100 ]
  48. Length of intensive care unit (ICU) admission [ Time Frame: month 6 ]
  49. Length of intensive care unit (ICU) admission [ Time Frame: month 12 ]
  50. Length of stay in days between transplant and discharge to home [ Time Frame: Day 0 until discharge from hospital, up to 100 days ]
    To determine the length of stay between transplant (Day 0) and discharge to home for those alive to be discharged home

  51. Quality of life as measured by the FACT-BMT assessment [ Time Frame: day 30 ]
  52. Quality of life as measured by the FACT-BMT assessment [ Time Frame: day 100 ]
  53. Quality of life as measured by the EQ 5D-5L assessment [ Time Frame: Day 30 ]
  54. Quality of life as measured by the EQ 5D-5L assessment [ Time Frame: Day 100 ]
  55. Quality of life as measured by the Lorig Self-Efficacy assessment [ Time Frame: Day 30 ]
  56. Quality of life as measured by the Lorig Self-Efficacy assessment [ Time Frame: Day 100 ]
  57. Quality of life as measured by the PG-SGA (patient-generated subjective global assessment) [ Time Frame: day 30 ]
  58. Quality of life as measured by the PG-SGA (patient-generated subjective global assessment) [ Time Frame: day 100 ]
  59. Quality of life as measured by the PROMIS-Depression assessment [ Time Frame: day 30 ]
  60. Quality of life as measured by the PROMIS-Depression assessment [ Time Frame: day 100 ]
  61. Quality of life as measured by the PROMIS-Anxiety assessment [ Time Frame: Day 30 ]
  62. Quality of life as measured by the PROMIS-Anxiety assessment [ Time Frame: Day 100 ]
  63. Quality of life as measured by the PROMIS-Social Isolation assessment [ Time Frame: Day 30 ]
  64. Quality of life as measured by the PROMIS-Social Isolation assessment [ Time Frame: Day 100 ]
  65. Quality of life as measured by the PROMIS-Emotional Support assessment [ Time Frame: day 30 ]
  66. Quality of life as measured by the PROMIS-Emotional Support assessment [ Time Frame: Day 100 ]
  67. Quality of life as measured by the PROMIS-Cognitive Function assessment [ Time Frame: Day 30 ]
  68. Quality of life as measured by the PROMIS-Cognitive Function assessment [ Time Frame: Day 100 ]
  69. Quality of life as measured by the PROMIS-Physical Function assessment [ Time Frame: Day 30 ]
  70. Quality of life as measured by the PROMIS-Physical Function assessment [ Time Frame: Day 100 ]
  71. Rate of grade 2 or higher adverse events, causally related during treatment period [ Time Frame: Day 75 ]
  72. Rate of grade 2 or higher adverse events, causally related during follow up period [ Time Frame: Year 1 ]
  73. Rate of grade 2 or higher adverse events, non related during treatment period [ Time Frame: Day 75 ]
  74. Rate of grade 2 or higher adverse events, non related during follow up period [ Time Frame: Year 1 ]


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of written informed consent prior to any study specific procedures
  2. Plan to undergo allogeneic HCT for any cancer or non-cancer illness with a planned cell dose of ≥2 x 106 CD34/kg using peripheral blood stem cells.
  3. Plan to receive a myeloablative conditioning regimen (see 4.3.1).
  4. Plan to receive GVHD prophylaxis with tacrolimus and methotrexate.
  5. Having a donor who is a 10 of 10 HLA match;
  6. Karnofsky Performance Scale KPS ≥60
  7. Willing to abstain from sexual activity or use two methods of birth control while on study drug and for 5 half-lives (4 days) after last dose.

Exclusion Criteria:

  1. If female, pregnant or nursing.
  2. Life expectancy <6 months
  3. Other malignancy or neoplastic disease (i.e. aside from the malignancy for which they are undergoing HCT) within the past 5 years with the exception of treated basal/squamous cell skin carcinoma or treated cervical cancer in situ
  4. Clinically significant active infection within 1 week of starting study drug
  5. Any of the following organ system function criteria:

    1. Cardiac: Ejection fraction ≤40% or myocardial infarction within 6 months of transplant or QTc >450 msec for males and >470 msec for females or other EKG abnormality which in the opinion of the investigator may put the subject at risk or interfere with study assessments
    2. Renal: Creatinine clearance (CLcr) ≤ 60 mL/min as estimated by the Cockcroft-Gault equation
    3. Pulmonary: FEV1, FVC, or corrected DLCO ≤40% predicted (forced expiratory volume in 1 second; forced vital capacity; and diffusing capacity of the lung for carbon monoxide, respectively)
    4. Hepatic: Total bilirubin >1.5 x (in the absence of known inherited hyperbilirubinemia, e.g. Gilbert's) and/or aspartate transaminase (AST)/alanine transaminase (ALT) >3 x upper limit of institutional normal for age (grade 2 or higher) and/or INR >1.5 (unless on anticoagulant), or history or evidence of cirrhosis (e.g. esophageal varices, ascites, or hepatic encephalopathy) or other chronic liver disease (e.g. Wilson's disease, autoimmune liver disease, primary biliary cirrhosis, etc.). Abnormalities in platelet number or albumin will not be considered exclusion criteria given that these are often due to the hematologic malignancy for which the patient is undergoing HCT rather than actual liver dysfunction
    5. Uncontrolled infection, including detection of hepatitis B virus (HBV) or hepatitis C virus (HCV) by serology or nucleic acid testing or HIV by polymerase chain reaction (PCR)

    i. Treated HBV/HCV/HIV with documented clearance is ok f. Other significant organ dysfunction (cardiac, pulmonary, renal, metabolic or central nervous system) that is uncontrolled and may interfere with study completion

  6. Any significant medial history of alcohol abuse within 3 months of starting study drug and/or unwillingness to abstain for the duration of the study and follow up periods
  7. Prior (within 30 days) or concomitant use of another neutrophil elastase inhibitor (e.g. alpha-1 antitrypsin)
  8. Plan for in vivo or ex vivo T cell depletion.
  9. Participated in another clinical study involving an investigational drug or device within 30 days or 5 half-lives prior to planned start of MPH966/placebo, or scheduled to participate in another clinical study involving an investigational drug or device within Day 100 of transplant

    1. If the patient develops GVHD within the first 100 days, they are allowed to enroll on trials of investigational drugs to treat GVHD provided they come off of this study.
    2. Enrollment in biorepository or supportive care trials that do not involve investigational drugs or devices is allowed
  10. Any clinically relevant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis at visit, which in the opinion of the Investigator, may put the subject at risk because of his/her participation in the study, or may influence the results of the study, or the subject's ability to participate in the study
  11. Low or intermediate risk acute leukemia in first complete remission, chronic myeloid leukemia in first chronic phase, and any benign (non-malignant) disorders (phase 1 dose-escalation portion only)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03986086


Contacts
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Contact: Anthony Sung, MD (919) 668-6239 anthony.sung@duke.edu

Locations
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United States, North Carolina
Duke University Adult Bone Marrow Transplant Clinic Not yet recruiting
Durham, North Carolina, United States, 27705
Contact: Emily Rainero, RN    919-668-0613    emily.rainero@duke.edu   
Contact: Ivy Belski, RN    (919) 660-2077    ivy.belskie@duke.edu   
Principal Investigator: Anthony Sung, MD         
Sponsors and Collaborators
Nelson Chao
Mereo BioPharma
National Center for Advancing Translational Science (NCATS)
Investigators
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Principal Investigator: Anthony Sung, MD Duke University Health System (DUHS)

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Responsible Party: Nelson Chao, Donald D. and Elizabeth G. Cooke Cancer Research Professor, Duke University
ClinicalTrials.gov Identifier: NCT03986086     History of Changes
Other Study ID Numbers: Pro00102362
First Posted: June 14, 2019    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Proteinase Inhibitory Proteins, Secretory
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action