Clinical trial NCT04328714: Interferon γ-Primed Mesenchymal Stromal Cells as Prophylaxis for Acute Graft v Host Disease
Official title: Interferon γ-Primed Mesenchymal Stromal Cells as Prophylaxis for Acute Graft v Host Disease After Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Malignancies and Myelodysplasia
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE1
Conditions: Acute Leukemia
Myelodysplastic Syndromes
Keywords: Interferon Gamma (IFN γ)
Graft versus Host Disease (GVHD)
Allogeneic Hematopoietic Cell Transplantation
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: Ossium Health, Inc.
First posted: 2020-03-31
Enrollment: 45
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This study uses a rolling 6 dose escalation design with two independently accruing expansion cohorts: adults and pediatrics. Accrual in the pediatric tier will commence after the maximum dose tolerated has been determined in adults.
Primary purpose: TREATMENT

Brief summary: The protocol is a phase I open label study evaluating the safety and feasibility of peri-transplant infusion of freshly expanded interferon gamma primed MSCs in adult and pediatric patients undergoing HCT for acute leukemia and myelodysplastic syndrome (MDS).

Detailed description: Hematopoietic cell transplantation (HCT) is an established therapeutic modality for high risk hematological malignancies in adults and children. The primary cause of morbidity and mortality after HCT is graft versus host disease (GVHD), affecting up to 70% of patients even with current prophylaxis and directly accounting for approximately a third of regimen-related death. Currently, pharmacologic prophylaxis consists of a calcineurin inhibitor and methotrexate, a drug combination introduced around 40 years ago. Despite this regimen being recognized as the standard of care, it is only partially effective, increases the risk of infection and disease relapse and imparts drug-related, short- and long-term adverse effects. Mesenchymal stromal cells (MSCs) have potent immune modulatory activity which is markedly enhanced by exposure to interferon γ. In murine models, interferon γ (IFNγ) primed MSCs (γMSCs) potently suppress GVHD without untoward adverse effects suggesting this cell therapy may markedly reduce the regimen related toxicity of HCT; however γMSCs have never been infused into patients.

This protocol is designed to test the hypothesis that freshly expanded γMSCs can be reliably produced and safely infused into patients undergoing HCT as GVHD prophylaxis.

This is an investigator-initiated Phase I study using a rolling 6, dose escalation design with two independently accruing expansion cohorts: adults and pediatrics. Accrual to the pediatric tier will commence after the maximum tolerated dose (MTD) has been determined in adults. A successful outcome of this study will lay the foundation for a future Phase II study to demonstrate efficacy and support a Phase III randomized trial.

The researchers plan to enroll a minimum of 4 and maximum of 45 subjects who are greater than 1 year old. Participants will be followed for up to 2 years after the HCT. The study will be conducted at Emory University and will recruit participants from the Winship Cancer Institute and Children's Hospital in Atlanta at Egleston.

Eligibility criteria: Inclusion Criteria:

* All transplant patients who undergo HCT with a myeloablative (MA) or Fludarabine/Melphalan (RIC) conditioning regimen and a HLA A- B- C- DR-matched unrelated donor as treatment for hematologic malignancy or MDS.
* Age ≥ 1 year at the time that the informed consent document is signed.
* Patients with acute leukemia must be in complete remission (defined as an M1 marrow -\<5% blasts- no evidence of extramedullary disease. Complete remissions without platelet recovery (CRp) will be considered remissions.
* Planned GVHD prophylaxis with a calcineurin inhibitor and methotrexate per institutional standards.
* Subject or parent/guardian must sign an informed consent document, and if appropriate, children must sign an assent document.

Exclusion Criteria:

* Patients who are to receive a non-myeloablative conditioning regimen.
* Patients receiving another investigational drug for acute GVHD prevention during the conditioning regimen or a planned investigational drug for the first year after transplant (there are no restrictions on GVHD treatment).
* Any medical or psychological condition or situation deemed by the Investigators to put the patient at increased risk of complications or non-compliance.
* Patient with a secondary malignancy who would be otherwise eligible for study, but for whom remission from the primary disease cannot be conclusively confirmed or for whom the chance of relapse of the primary disease is significant.
* Pregnancy (positive serum b-HCG) or breastfeeding.
* Estimated glomerular filtration rate (GFR) of \< 50 mL/min/1.73m2.
* Cardiac ejection fraction \< 50 (using M-Mode if assessment is done by Echocardiogram)
* T bilirubin \> 2 × upper limit of normal or alanine aminotransferase (ALT) \> 4 × upper limit of normal or aspartate aminotransferase (AST) \> 4 x upper limit of normal unresolved veno-occlusive disease
* Pulmonary disease with forced vital capacity (FVC), forced expiratory volume (FEV1) or diffusing capacity for carbon monoxide (DLCO) parameters \<45% predicted (corrected for hemoglobin) or requiring supplemental oxygen. Children who are developmentally unable to perform pulmonary function testing will be assessed solely on their need for supplemental oxygen.
* Karnofsky performance score or Lansky Play-Performance Scale score \<80
* Human leukocyte antigen (HLA) antibody screen positive for HLA antibodies specific against the MSC products.

Primary outcomes:
measure: Number of successful preparations and deliveries of investigational product
timeFrame: Day 1 (day of infusion)
measure: Number of adverse events attributed to the investigational product
timeFrame: Day 2 (day after infusion)
measure: Maximal Tolerated Dose
timeFrame: Day 2 (day after infusion)
Secondary outcomes:
measure: Primary graft failure
timeFrame: Up to Year 2
measure: Secondary graft failure
timeFrame: Up to Year 2
measure: Platelet engraftment
timeFrame: Up to Year 2
measure: Non-relapse mortality (NRM)
timeFrame: Up to Year 2
measure: Change in Acute graft-versus-host disease (aGvHD) Incidence
timeFrame: Day 30, Day 100
measure: Change in Chronic graft-versus-host disease (cGvHD) Incidence
timeFrame: Day 30, Day 100, Day 180, Day 365
measure: Disease-free survival (DFS)
timeFrame: Up to Year 2
measure: Primary cause of death
timeFrame: Up to Year 2
measure: Relapse
timeFrame: Up to Year 2
measure: Early discontinuation
timeFrame: Up to Year 2
measure: Viral activation
timeFrame: Up to Day 100
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta at Egleston
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
Study officials:
affiliation: Emory University
name: Muna Qayed, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Edwin Horwitz, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: