Hematologic Malignancy
Conditions
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.
Interventions
DRUGMPH966
RP2D tablet
DRUGPlacebo
MPH966 placebo table
Sponsors
Mereo BioPharma
National Center for Advancing Translational Sciences (NCATS)
Nelson Chao
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of grade 2-4 acute Graft vs Host Disease (GVHD) requiring systemic therapy | day 100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of grade 2 or higher adverse events, causally related during treatment period | Day 75 | — |
| Rate of grade 2 or higher adverse events, causally related during follow up period | Year 1 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who are admitted to ICU | Day 0 and month 6,12 | — |
| Length of intensive care unit (ICU) admission | Day 100 | — |
| Quality of life as measured by the PROMIS-Depression assessment | day 30 | — |
| Incidence of grade 2-4 acute GVHD | day 100 | — |
| Incidence of grade 3-4 acute GVHD | day 100 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who develop grade 2-4 acute GVHD by visit | 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 | Day 0 and day 100, month 6 | — |
| Incidence of chronic GVHD | month 6 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who develop chronic GVHD | Day 0 and month 6, 12 | Time to event distributions estimated by the Kaplan-Meier method |
| Incidence of GVHD-free survival | month 6 | GVHD-free survival is defined as freedom from GVHD requiring systemic steroids |
| Incidence of relapse-free survival | month 6 | Relapse-free survival is defined as freedom from relapse |
| Incidence of bacterial infections | Day 100 | — |
| Incidence of fungal infections | Day 100 | — |
| Incidence of viral infections | Day 100 | — |
| Incidence of overall infections | Day 100 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who develop bacterial infections | Day 0 and day 100, month 6,12 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who develop fungal infections | Day 0 and day 100, month 6,12 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who develop viral infections | Day 0 and day 100, month 6,12 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who develop overall infections | Day 0 and day 100, month 6,12 | — |
| Incidence of relapse | month 6 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who relapse | Day 0 and month 6,12 | — |
| Incidence of non-relapse mortality | month 6 | Non-relapse mortality is defined as death while in remission from the primary disease |
| Kaplan-Meier analysis of time-to-event: percentage of participants who experience non-relapse mortality | Day 0 and month 6,12 | Non-relapse mortality is defined as death while in remission from the primary disease |
| Incidence of hospital re-admission | Day 100 | — |
| Kaplan-Meier analysis of time-to-event: percentage of participants who are re-admitted to the hospital | Day 0 and day 100, month 6,12 | — |
| Length of hospital re-admission | Day 100 | — |
| Incidence of intensive care unit (ICU) admission | Day 100 | — |
| Length of stay in days between transplant and discharge to home | 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 |
| Quality of life as measured by the FACT-BMT assessment | day 30 | — |
| Quality of life as measured by the EQ 5D-5L assessment | Day 30 | — |
| Quality of life as measured by the Lorig Self-Efficacy assessment | Day 30 | — |
| Quality of life as measured by the PG-SGA (patient-generated subjective global assessment) | day 30 | — |
| Quality of life as measured by the PROMIS-Anxiety assessment | Day 30 | — |
| Quality of life as measured by the PROMIS-Social Isolation assessment | Day 30 | — |
| Quality of life as measured by the PROMIS-Emotional Support assessment | day 30 | — |
| Quality of life as measured by the PROMIS-Cognitive Function assessment | Day 30 | — |
| Quality of life as measured by the PROMIS-Physical Function assessment | Day 30 | — |
| Rate of grade 2 or higher adverse events, non related during treatment period | Day 75 | — |
| Rate of grade 2 or higher adverse events, non related during follow up period | Year 1 | — |
Countries
United States
Outcome results
None listed