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

Nelson Chao

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Conditions

Hematologic Malignancy

Interventions

MPH966DRUG

RP2D tablet

PlaceboDRUG

MPH966 placebo table

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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)

Locations (1)

Duke University Adult Bone Marrow Transplant Clinic

Durham, North Carolina, United States

Outcomes

Primary Outcomes

Incidence of grade 2-4 acute Graft vs Host Disease (GVHD) requiring systemic therapy

Time frame: day 100

Secondary Outcomes

Incidence of grade 2-4 acute GVHD

Time frame: day 100

Incidence of grade 3-4 acute GVHD

Time frame: day 100

Incidence of grade 2-4 acute GVHD

Time frame: month 6

Incidence of grade 3-4 acute GVHD

Time frame: month 6

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

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

Incidence of chronic GVHD

Time frame: month 6

Incidence of chronic GVHD

Time frame: month 12

Kaplan-Meier analysis of time-to-event: percentage of participants who develop chronic GVHD

Time to event distributions estimated by the Kaplan-Meier method

Time frame: Day 0 and month 6, 12

Incidence of GVHD-free survival

GVHD-free survival is defined as freedom from GVHD requiring systemic steroids

Data from ClinicalTrials.gov

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Incidence of GVHD-free survival

GVHD-free survival is defined as freedom from GVHD requiring systemic steroids

Time frame: month 12

Incidence of relapse-free survival

Relapse-free survival is defined as freedom from relapse

Time frame: month 6

Incidence of relapse-free survival

Relapse-free survival is defined as freedom from relapse

Time frame: month 12

Incidence of bacterial infections

Time frame: Day 100

Incidence of fungal infections

Time frame: Day 100

Incidence of viral infections

Time frame: Day 100

Incidence of overall infections

Time frame: Day 100

Incidence of bacterial infections

Time frame: 6 months

Incidence of fungal infections

Time frame: month 6

Incidence of viral infections

Time frame: month 6

Incidence of overall infections

Time frame: month 6

Incidence of bacterial infections

Time frame: month 12

Incidence of fungal infections

Time frame: month 12

Incidence of viral infections

Time frame: month 12

Incidence of overall infections

Time frame: month 12

Kaplan-Meier analysis of time-to-event: percentage of participants who develop bacterial infections

Time frame: Day 0 and day 100, month 6,12

Kaplan-Meier analysis of time-to-event: percentage of participants who develop fungal infections

Time frame: Day 0 and day 100, month 6,12

Kaplan-Meier analysis of time-to-event: percentage of participants who develop viral infections

Time frame: Day 0 and day 100, month 6,12

Kaplan-Meier analysis of time-to-event: percentage of participants who develop overall infections

Time frame: Day 0 and day 100, month 6,12

Incidence of relapse

Time frame: month 6

Incidence of relapse

Time frame: month 12

Kaplan-Meier analysis of time-to-event: percentage of participants who relapse

Time frame: Day 0 and month 6,12

Incidence of non-relapse mortality

Non-relapse mortality is defined as death while in remission from the primary disease

Time frame: month 6

Incidence of non-relapse mortality

Non-relapse mortality is defined as death while in remission from the primary disease

Time frame: month 12

Kaplan-Meier analysis of time-to-event: percentage of participants who experience non-relapse mortality

Non-relapse mortality is defined as death while in remission from the primary disease

Time frame: Day 0 and month 6,12

Incidence of hospital re-admission

Time frame: Day 100

Incidence of hospital re-admission

Time frame: month 6

Incidence of hospital re-admission

Time frame: month 12

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

Length of hospital re-admission

Time frame: Day 100

Length of hospital re-admission

Time frame: month 6

Length of hospital re-admission

Time frame: month 12

Incidence of intensive care unit (ICU) admission

Time frame: Day 100

Incidence of intensive care unit (ICU) admission

Time frame: month 6

Incidence of intensive care unit (ICU) admission

Time frame: month 12

Kaplan-Meier analysis of time-to-event: percentage of participants who are admitted to ICU

Time frame: Day 0 and month 6,12

Length of intensive care unit (ICU) admission

Time frame: Day 100

Length of intensive care unit (ICU) admission

Time frame: month 6

Length of intensive care unit (ICU) admission

Time frame: month 12

Length of stay in days between transplant and discharge to home

To determine the length of stay between transplant (Day 0) and discharge to home for those alive to be discharged home

Time frame: Day 0 until discharge from hospital, up to 100 days

Quality of life as measured by the FACT-BMT assessment

Time frame: day 30

Quality of life as measured by the FACT-BMT assessment

Time frame: day 100

Quality of life as measured by the EQ 5D-5L assessment

Time frame: Day 30

Quality of life as measured by the EQ 5D-5L assessment

Time frame: Day 100

Quality of life as measured by the Lorig Self-Efficacy assessment

Time frame: Day 30

Quality of life as measured by the Lorig Self-Efficacy assessment

Time frame: Day 100

Quality of life as measured by the PG-SGA (patient-generated subjective global assessment)

Time frame: day 30

Quality of life as measured by the PG-SGA (patient-generated subjective global assessment)

Time frame: day 100

Quality of life as measured by the PROMIS-Depression assessment

Time frame: day 30

Quality of life as measured by the PROMIS-Depression assessment

Time frame: day 100

Quality of life as measured by the PROMIS-Anxiety assessment

Time frame: Day 30

Quality of life as measured by the PROMIS-Anxiety assessment

Time frame: Day 100

Quality of life as measured by the PROMIS-Social Isolation assessment

Time frame: Day 30

Quality of life as measured by the PROMIS-Social Isolation assessment

Time frame: Day 100

Quality of life as measured by the PROMIS-Emotional Support assessment

Time frame: day 30

Quality of life as measured by the PROMIS-Emotional Support assessment

Time frame: Day 100

Quality of life as measured by the PROMIS-Cognitive Function assessment

Time frame: Day 30

Quality of life as measured by the PROMIS-Cognitive Function assessment

Time frame: Day 100

Quality of life as measured by the PROMIS-Physical Function assessment

Time frame: Day 30

Quality of life as measured by the PROMIS-Physical Function assessment

Time frame: Day 100

Rate of grade 2 or higher adverse events, causally related during treatment period

Time frame: Day 75

Rate of grade 2 or higher adverse events, causally related during follow up period

Time frame: Year 1

Rate of grade 2 or higher adverse events, non related during treatment period

Time frame: Day 75

Rate of grade 2 or higher adverse events, non related during follow up period

Time frame: Year 1