This phase I trial tests the safety, side effects and effectiveness of emapalumab with post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil in preventing graft-versus-host disease (GVHD) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after reduced-intensity donor (allogeneic) hematopoietic cell transplant (HCT). Giving chemotherapy, such as fludarabine, melphalan, or busulfan, before a donor \[peripheral blood stem cell\] transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When healthy stem cells for a donor are infused into a patient (allogeneic HCT), they may help the patient's bone marrow make more healthy cells and platelets. Allogeneic HCT is an established treatment, however, GVHD continues to be a major problem of allogeneic HCT that can complicate therapy. GVHD is a disease caused when cells from a donated stem cell graft attack the normal tissue of the transplant patient. Emapalumab binds to an immune system protein called interferon gamma. This may help lower the body's immune response and reduce inflammation. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid and may kill cancer cells. It may also lower the body's immune response. Tacrolimus is a drug used to help reduce the risk of rejection by the body of organ and bone marrow transplants. Mycophenolate mofetil is a drug used to prevent GVHD after organ transplants. It is also being studied in the prevention of GVHD after stem cell transplants for cancer, and in the treatment of some autoimmune disorders. Mycophenolate mofetil is a type of immunosuppressive agent. Giving emapalumab with post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil may be safe, tolerable and/or effective in preventing GVHD in patients with AML or MDS after a reduced-intensity allogeneic HCT.
PRIMARY OBJECTIVE: I. Assess the safety and describe the toxicity profile of adding emapalumab to post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis by day 28 post reduced-intensity hematopoietic cell transplantation (HCT). SECONDARY OBJECTIVES: I. Estimate activity of emapalumab, PTCy, tacrolimus (tacro) and mycophenolate mofetil (MMF) acute GVHD (aGVHD) prophylaxis, by cumulative incidence of aGVHD (grade 2-4) at day +100. II. Estimate cumulative incidence of chronic GVHD (cGVHD) at 1-year post-HCT. III. Estimate overall survival (OS) and progression-free survival (PFS) at 1- year post-transplant. IV. Estimate GVHD-free relapse-free survival (GRFS) at 1-year post-HCT. V. Estimate cumulative incidence of relapse/disease progression, and non-relapse mortality (NRM) at day +100 and 1-year post-HCT. VI. Estimate the rate of grade 2 or higher infection at 100 days. VII. Assess time to engraftment (platelets and neutrophils). EXPLORATORY OBJECTIVES: I. Evaluate free emapalumab levels by serial blood sampling and assess association with severe aGVHD incidence. II. Determine levels of interferon gamma (IFNgamma)-related inflammatory cytokines (CXCL-9 and CXCL-10) by serial sampling and assess association with free emapalumab levels and incidence of grade 3-4 aGVHD. III. aGVHD biomarkers per Mount Sinai Acute GVHD International Consortium (MAGIC) criteria on days + 1, +7, +14 and +28. IV. Describe the kinetics of immune cell recovery (B, T, natural killer \[NK\] cells) at days 30, +100, +180 and +365 post-HCT in peripheral blood. V. Evaluate patient quality of life at baseline then on day +100, 6 months, and 1-year post-HCT using patient reported outcomes of Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). VI. Obtain a preliminary estimate of gut microbiome diversity at baseline (preferably before fludarabine administration), and then on days +14, +28, +60, and +100 after HCT. OUTLINE: Patients receive fludarabine intravenously (IV) on days -7 to -3 and melphalan IV over 1 hour on day -2 or busulfan IV on days -7 and -6 and fludarabine IV on days -7 to -2. Patients receive HCT infusion on day 0 per institutional standards of practice. Patients also receive emapalumab IV over 1 hour on days -8. -1, -7, 14 and 21, cyclophosphamide IV on days 3 and 4, tacrolimus IV or orally (PO) on days 5-95, mycophenolate mofetil IV or PO on days 5-35. Additionally, patients undergo chest computed tomography (CT) and echocardiography (ECHO) or multigated acquisition scan (MUGA) at baseline and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 100 days after HCT, then at 6 months and 1 year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Undergo blood sample collection
Given IV
Undergo chest CT
Given IV
Undergo ECHO
Given IV
Given IV
Given infusion
Given IV
Undergo MUGA
Given IV or PO
Ancillary studies
Given IV or PO
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence of grade 3 or higher adverse events (AEs)
Will be based on Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0, with the exception of infections which ill be graded based on the Report of the Bone Marrow Transplant (BMT) Clinical Trials Network (CTN) Infections Disease Technical Committee. The toxicity/AE information recorded on each subject will include type, severity, duration, and attribution/ association with the study regimen. Tables will be constructed to summarize the observed incidence, severity and type of toxicity, including infection.
Time frame: From starting the first emapalumab dose to the first observation of a primary safety endpoint (PSE) event or day 28 post-hematopoietic cell transplantation (HCT), whichever comes first
Incidence of severe infusion reaction
Will be defined as grade 4 per CTCAE v 5.0 after receiving the first or second dose of emapalumab. The toxicity/AE information recorded on each subject will include type, severity, duration, and attribution/ association with the study regimen. Tables will be constructed to summarize the observed incidence, severity and type of toxicity, including infection.
Time frame: From starting the first emapalumab dose to the first observation of a PSE event or day 28 post-HCT, whichever comes first
Incidence of primary graft failure
Will be defined as the failure to achieve an absolute neutrophil count of 500/ul or more for 3 days and donor chimerism of less than 5%. Will be calculated using the competing risk method as described by Gooley et al. (1999).
Time frame: From starting the first emapalumab dose to the first observation of a PSE event or day 28 post-HCT, whichever comes first
Non-relapse mortality (NRM)
Will be calculated using the competing risk method as described by Gooley et al. (1999).
Time frame: From starting the first emapalumab dose to the first observation of a PSE event or day 28 post-HCT, whichever comes first
Incidence of grade 2-4 acute graft-versus-host-disease (aGVHD)
Will be calculated using the competing risk method as described by Gooley et al. (1999).
Time frame: At day 100
Incidence of grade 3 or higher AEs
Will be defined by CTCAE v 5.0 with the exception of infections which will be graded based on the Report of the BMT CTN Infectious Disease Technical Committee. The toxicity/AE information recorded on each subject will include type, severity, duration, and attribution/ association with the study regimen. Tables will be constructed to summarize the observed incidence, severity and type of toxicity, including infection.
Time frame: From day 29 to day 100
Overall survival
Will be calculated using the Kaplan-Meier method.
Time frame: From the day of stem cell infusion until death, assessed up to 1 year
Progression free survival
Will be calculated using the Kaplan-Meier method.
Time frame: From the date of stem cell infusion to the date of death, disease relapse/progression, whichever occurs first, assessed up to 1 year
GVHD relapse-free survival (GRFS)
Will be calculated using the Kaplan-Meier method.
Time frame: From the start of HCT to grade III-IV aGVHD, chronic GVHD, requiring systemic treatment, relapse, or death from any cause, whichever occurs first, assessed up to 1 year
Relapse/progression
Will be calculated using the Kaplan-Meier method.
Time frame: From day of stem cell infusion (day 0) and at 100 days and at 1 year
NRM
Will be defined as death occurring in a patient from causes other than relapse or progression. The toxicity/AE information recorded on each subject will include type, severity, duration, and attribution/ association with the study regimen. Tables will be constructed to summarize the observed incidence, severity and type of toxicity, including infection.
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Time frame: From date of stem cell infusion until non-disease related death, assessed up to 1 year
Incidence of aGVHD
Will be calculated using the competing risk method as described by Gooley et al. (1999).
Time frame: From day 0 (date of stem cell infusion) through 180 days post-transplant
Incidence of chronic GVHD
Will be evaluated and scored according to National Institutes of Health Consensus Staging. Will be calculated using the competing risk method as described by Gooley et al. (1999).
Time frame: From day 80 through 1 year post-transplant
Incidence of infection
Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any, according to the Report of the BMT CTN Infectious Disease Technical Committee. The toxicity/AE information recorded on each subject will include type, severity, duration, and attribution/ association with the study regimen. Tables will be constructed to summarize the observed incidence, severity and type of toxicity, including infection.
Time frame: From day -7 to day 100 post-transplant
Absolute neutrophil count recovery
Will be defined as neutrophils \>= 0.5 x 10\^3/uL achieved and sustained for 3 consecutive lab values on different days with no subsequent decline.
Time frame: Up to 1 year
Platelet recovery
Will be defined as platelets \>= 20 K/uL independent of platelet transfusion support (date should reflect no transfusions in previous 7 days, and the first of 3 consecutive lab values on different days).
Time frame: Up to 1 year