Acute Myeloid Leukemia, Graft Versus Host Disease, Myelodysplastic Syndrome
Conditions
Brief summary
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.
Detailed description
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.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
DRUGBusulfan
Given IV
PROCEDUREComputed Tomography
Undergo chest CT
DRUGCyclophosphamide
Given IV
PROCEDUREEchocardiography Test
Undergo ECHO
BIOLOGICALEmapalumab
Given IV
DRUGFludarabine
Given IV
PROCEDUREHematopoietic Cell Transplantation
Given infusion
DRUGMelphalan
Given IV
PROCEDUREMultigated Acquisition Scan
Undergo MUGA
DRUGMycophenolate Mofetil
Given IV or PO
OTHERQuestionnaire Administration
Ancillary studies
DRUGTacrolimus
Given IV or PO
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Documented informed consent of the participant and/or legally authorized representative * Assent, when appropriate, will be obtained per institutional guidelines * Age: ≥ 18 years and ≤ 75 years * Note: Patients \> 70 years of age must have Karnofsky performance status ≥ 80% and HCT-comorbidity index (CI) ≤ 2 * Karnofsky performance status ≥ 70% * Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in complete remission with bone marrow (BM) blast of \< 5%. AML must be negative for minimal residual disease (MRD-) * Planned to undergo reduced-intensity conditioning (RIC) with either fludarabine/melphalan (Flu/Mel) or busulfan/fludarabine (Bu/Flu) regimens prior to an allogeneic HCT using a mobilized peripheral blood stem cell (PBMC) graft from an 8/8 match related/unrelated donor (A, B, C, DR by high resolution typing) * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease) * Aspartate aminotransferase (AST) ≤ 3.0 x ULN * Alanine aminotransferase (ALT) ≤ 3.0 x ULN * Creatinine clearance of ≥ 60 mL/min per 24-hour urine test or the Cockcroft-Gault formula * Left ventricular ejection fraction (LVEF) ≥ 50% * Note: To be performed within 30 days prior to day 1 of protocol therapy * Bazett's correction formula (QTcB) ≤ 480 ms * If able to perform pulmonary function tests: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) (diffusion capacity) ≥ 50% of predicted (corrected for hemoglobin). * If unable to perform pulmonary function tests: Oxygen (O2) saturation \> 92% on room air * Seronegative for HIV antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative) OR * If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable * Meets other institutional and federal requirements for infectious disease titer requirements * Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy * QuantiFERON-TB Gold+ * Administer tuberculosis prophylaxis to patients at risk for tuberculosis, or known to have a positive purified protein derivative (PPD) test result, or positive interferon gamma (IFNγ) release assay * Women of childbearing potential (WOCBP): negative urine or serum pregnancy test * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 180 days post-HCT * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)
Exclusion criteria
* Prior allogeneic HCT * Other cancer therapies (chemotherapy, radiation, biologics) are not allowed within two weeks of starting HCT conditioning; however targeted agents for underlying hematologic malignancies may be continued up to one day before conditioning, including, but not limited to: * FLT3 inhibitors * IDH1/2 inhibitors * Menin inhibitors * ABL-BCR inhibitors * BCL-2 inhibitors * Hydroxyurea * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent * Psychological issues, no appropriate caregivers identified, or non-compliant to medication * Clinically significant uncontrolled illness * Active uncontrolled infections (bacterial, viral, fungal). Infections are considered controlled if appropriate therapy has been initiated and, at the time of screening, no signs of infection are present * Other active malignancy * Females only: Pregnant or breastfeeding * Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grade 3 or higher adverse events (AEs) | 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 | 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. |
| Incidence of severe infusion reaction | From starting the first emapalumab dose to the first observation of a PSE event or day 28 post-HCT, whichever comes first | 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. |
| Incidence of primary graft failure | From starting the first emapalumab dose to the first observation of a PSE event or day 28 post-HCT, whichever comes first | 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). |
| Non-relapse mortality (NRM) | From starting the first emapalumab dose to the first observation of a PSE event or day 28 post-HCT, whichever comes first | Will be calculated using the competing risk method as described by Gooley et al. (1999). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GVHD relapse-free survival (GRFS) | 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 | Will be calculated using the Kaplan-Meier method. |
| Relapse/progression | From day of stem cell infusion (day 0) and at 100 days and at 1 year | Will be calculated using the Kaplan-Meier method. |
| NRM | From date of stem cell infusion until non-disease related death, assessed up to 1 year | 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. |
| Incidence of aGVHD | From day 0 (date of stem cell infusion) through 180 days post-transplant | Will be calculated using the competing risk method as described by Gooley et al. (1999). |
| Incidence of grade 2-4 acute graft-versus-host-disease (aGVHD) | At day 100 | Will be calculated using the competing risk method as described by Gooley et al. (1999). |
| Incidence of infection | From day -7 to day 100 post-transplant | 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. |
| Absolute neutrophil count recovery | Up to 1 year | 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. |
| Platelet recovery | Up to 1 year | 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). |
| Incidence of chronic GVHD | From day 80 through 1 year post-transplant | 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). |
| Incidence of grade 3 or higher AEs | From day 29 to day 100 | 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. |
| Overall survival | From the day of stem cell infusion until death, assessed up to 1 year | Will be calculated using the Kaplan-Meier method. |
| Progression free survival | From the date of stem cell infusion to the date of death, disease relapse/progression, whichever occurs first, assessed up to 1 year | Will be calculated using the Kaplan-Meier method. |
Countries
United States
Outcome results
None listed