Clinical trial NCT03986086: MPH966 for Prevention of Graft-versus-host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Hematologic Malignancy
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Mereo BioPharma
name: National Center for Advancing Translational Sciences (NCATS)
First posted: 2019-06-14
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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)

Primary outcomes:
measure: Incidence of grade 2-4 acute Graft vs Host Disease (GVHD) requiring systemic therapy
timeFrame: day 100
Secondary outcomes:
measure: Incidence of grade 2-4 acute GVHD
timeFrame: day 100
measure: Incidence of grade 3-4 acute GVHD
timeFrame: day 100
measure: Incidence of grade 2-4 acute GVHD
timeFrame: month 6
measure: Incidence of grade 3-4 acute GVHD
timeFrame: month 6
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who develop grade 2-4 acute GVHD by visit
timeFrame: day 0 and 100 days, 6 months
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who develop grade 3-4 acute GVHD by visit
timeFrame: Day 0 and day 100, month 6
measure: Incidence of chronic GVHD
timeFrame: month 6
measure: Incidence of chronic GVHD
timeFrame: month 12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who develop chronic GVHD
timeFrame: Day 0 and month 6, 12
measure: Incidence of GVHD-free survival
timeFrame: month 6
measure: Incidence of GVHD-free survival
timeFrame: month 12
measure: Incidence of relapse-free survival
timeFrame: month 6
measure: Incidence of relapse-free survival
timeFrame: month 12
measure: Incidence of bacterial infections
timeFrame: Day 100
measure: Incidence of fungal infections
timeFrame: Day 100
measure: Incidence of viral infections
timeFrame: Day 100
measure: Incidence of overall infections
timeFrame: Day 100
measure: Incidence of bacterial infections
timeFrame: 6 months
measure: Incidence of fungal infections
timeFrame: month 6
measure: Incidence of viral infections
timeFrame: month 6
measure: Incidence of overall infections
timeFrame: month 6
measure: Incidence of bacterial infections
timeFrame: month 12
measure: Incidence of fungal infections
timeFrame: month 12
measure: Incidence of viral infections
timeFrame: month 12
measure: Incidence of overall infections
timeFrame: month 12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who develop bacterial infections
timeFrame: Day 0 and day 100, month 6,12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who develop fungal infections
timeFrame: Day 0 and day 100, month 6,12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who develop viral infections
timeFrame: Day 0 and day 100, month 6,12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who develop overall infections
timeFrame: Day 0 and day 100, month 6,12
measure: Incidence of relapse
timeFrame: month 6
measure: Incidence of relapse
timeFrame: month 12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who relapse
timeFrame: Day 0 and month 6,12
measure: Incidence of non-relapse mortality
timeFrame: month 6
measure: Incidence of non-relapse mortality
timeFrame: month 12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who experience non-relapse mortality
timeFrame: Day 0 and month 6,12
measure: Incidence of hospital re-admission
timeFrame: Day 100
measure: Incidence of hospital re-admission
timeFrame: month 6
measure: Incidence of hospital re-admission
timeFrame: month 12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who are re-admitted to the hospital
timeFrame: Day 0 and day 100, month 6,12
measure: Length of hospital re-admission
timeFrame: Day 100
measure: Length of hospital re-admission
timeFrame: month 6
measure: Length of hospital re-admission
timeFrame: month 12
measure: Incidence of intensive care unit (ICU) admission
timeFrame: Day 100
measure: Incidence of intensive care unit (ICU) admission
timeFrame: month 6
measure: Incidence of intensive care unit (ICU) admission
timeFrame: month 12
measure: Kaplan-Meier analysis of time-to-event: percentage of participants who are admitted to ICU
timeFrame: Day 0 and month 6,12
measure: Length of intensive care unit (ICU) admission
timeFrame: Day 100
measure: Length of intensive care unit (ICU) admission
timeFrame: month 6
measure: Length of intensive care unit (ICU) admission
timeFrame: month 12
measure: Length of stay in days between transplant and discharge to home
timeFrame: Day 0 until discharge from hospital, up to 100 days
measure: Quality of life as measured by the FACT-BMT assessment
timeFrame: day 30
measure: Quality of life as measured by the FACT-BMT assessment
timeFrame: day 100
measure: Quality of life as measured by the EQ 5D-5L assessment
timeFrame: Day 30
measure: Quality of life as measured by the EQ 5D-5L assessment
timeFrame: Day 100
measure: Quality of life as measured by the Lorig Self-Efficacy assessment
timeFrame: Day 30
measure: Quality of life as measured by the Lorig Self-Efficacy assessment
timeFrame: Day 100
measure: Quality of life as measured by the PG-SGA (patient-generated subjective global assessment)
timeFrame: day 30
measure: Quality of life as measured by the PG-SGA (patient-generated subjective global assessment)
timeFrame: day 100
measure: Quality of life as measured by the PROMIS-Depression assessment
timeFrame: day 30
measure: Quality of life as measured by the PROMIS-Depression assessment
timeFrame: day 100
measure: Quality of life as measured by the PROMIS-Anxiety assessment
timeFrame: Day 30
measure: Quality of life as measured by the PROMIS-Anxiety assessment
timeFrame: Day 100
measure: Quality of life as measured by the PROMIS-Social Isolation assessment
timeFrame: Day 30
measure: Quality of life as measured by the PROMIS-Social Isolation assessment
timeFrame: Day 100
measure: Quality of life as measured by the PROMIS-Emotional Support assessment
timeFrame: day 30
measure: Quality of life as measured by the PROMIS-Emotional Support assessment
timeFrame: Day 100
measure: Quality of life as measured by the PROMIS-Cognitive Function assessment
timeFrame: Day 30
measure: Quality of life as measured by the PROMIS-Cognitive Function assessment
timeFrame: Day 100
measure: Quality of life as measured by the PROMIS-Physical Function assessment
timeFrame: Day 30
measure: Quality of life as measured by the PROMIS-Physical Function assessment
timeFrame: Day 100
measure: Rate of grade 2 or higher adverse events, causally related during treatment period
timeFrame: Day 75
measure: Rate of grade 2 or higher adverse events, causally related during follow up period
timeFrame: Year 1
measure: Rate of grade 2 or higher adverse events, non related during treatment period
timeFrame: Day 75
measure: Rate of grade 2 or higher adverse events, non related during follow up period
timeFrame: Year 1
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Adult Bone Marrow Transplant Clinic
state: North Carolina
Study officials:
affiliation: Duke University Health System (DUHS)
name: Anthony Sung, MD
role: PRINCIPAL_INVESTIGATOR
References: