Efprezimod Alfa (CD24Fc, MK-7110) for the Prevention of Acute Graft Versus Host Disease (GVHD) Following Myeloablative Hematopoietic Stem Cell Transplantation (HSCT) (MK-7110-005)

Study Overview
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Brief Summary
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The study compares two acute graft-versus-host disease (aGVHD) prophylaxis regimens: efprezimod alfa vs placebo with the standard GVHD prophylaxis of tacrolimus / methotrexate. The study compares two acute graft-versus-host disease (aGVHD) prophylaxis regimens: efprezimod alfa/tacrolimus / methotrexate (efprezimod alfa/Tac/MTX) versus placebo/tacrolimus / methotrexate (placebo/Tac/MTX) in the setting of myeloablative conditioning (MAC), matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation in participants with acute leukemia (AML/ALL) or myelodysplastic syndrome (MDS). The study agent, efprezimod alfa, will be administered through IV infusion on days -1, 14, and 28 at the dose of 480mg, 240 mg and 240mg, respectively. The placebo will be 100 ml normal saline intravenous (IV) solution.

Detailed Description
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The Sponsor decided to discontinue screening and enrollment in this study on 18 May 2021 for business reasons. This decision was not related to any new or unexpected safety or efficacy findings.

Official Title
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A Randomized, Double Blind, Placebo Controlled, Multi-center, Phase III Study of CD24Fc for Prevention of Acute Graft-Versus-Host Disease Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Hematopoietic Stem Cell Transplantation, Acute Graft Versus Host Disease, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Efprezimod alfa
* Drug: Placebo
* Drug: Methotrexate
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A prospective participant for allogeneic HCT for a malignant hematologic disorder. The donor and recipient must have a human leukocyte antigen (HLA)-8/8 allelic match at the HLA-A, -B, -C, and - DRB1 loci. High-resolution typing is required for all alleles for unmatched donors. Only matched unrelated donors are acceptable for this trial. The following diagnoses are to be included: Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) in first or second remission. Remission is defined as the absence of blasts in the peripheral circulation at the time of enrollment, < 5% blasts in the bone marrow and absence of extramedullary disease including CNS involvement. Myelodysplastic syndrome (MDS) with intermediate or high-risk International Prognostic Scoring System (IPSS) or equivalent Revised International Prognostic Scoring System (IPSS-R) score with < 10% blasts in the bone marrow. Males or non-pregnant, non-lactating females, ≥ 18 years of age. Note there is no defined upper age limited, so long as deemed appropriate candidate for myeloablative conditioning. Karnofsky Performance Status >70%. Participants must have normal or near normal organ function as defined by their treating institutions bone marrow transplant (BMT) program clinical practice guidelines. In addition, for purposes of this protocol minimum organ function criteria within 30 days of beginning conditioning include: Eligibility According to Pre HCT Organ Function: Total bilirubin ≤2.5 mg% (unless from Gilbert's disease or disease-related); Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT))/ alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SGPT)) <5.0 X institutional upper limit of normal; Estimated or actual glomerular filtration rate (GFR)>50 mL/min/1.73 m2 for participants with creatinine levels above institutional normal (GFR should be corrected for BSA); Pulmonary Function Tests include diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), forced vital capacity (FVC)> 50% DLCO should be corrected for hemoglobin; Ejection Fraction >50%; Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) ≤ 5. Item d and e may be assessed up to 10 weeks prior to the start of conditioning therapy. Ability to understand and the willingness to sign a written informed consent document. Women of child bearing potential and men must agree to use contraception prior to study entry and through day 100 post HCT (hormonal or barrier method of birth control; abstinence). Should a woman become pregnant or suspect she is pregnant while she or her partner is on treatment in this study, she should inform her study physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study until day 100 post HCT. Exclusion Criteria: Subjects may not have presence of active central nervous system (CNS) disease or extramedullary disease. Prior cytotoxic chemotherapy within 21 days from the initiation of HCT conditioning (i.e. intensive induction / consolidation for AML). Note, certain low intensity treatments not intended to induce remission but rather stabilize disease are acceptable up to 24 hrs prior to initiation of HCT conditioning (i.e. Tyrosine Kinase Inhibitor, sorafenib). Cord blood and haploidentical donors are not eligible. HLA-mismatch at the HLA-A, -B, -C, and - DRB1 loci. Note, HLA-DQ mismatches are permissible. Pregnant and nursing mothers are excluded from this study. This is because the risk to the fetus is unknown. Any physical or psychological condition that, in the opinion of the investigator, would pose unacceptable risk to the participant or raise concern that the participant would not comply with protocol procedures. Uncontrolled infections. Participants still under therapy for presumed or proven infection are eligible provided there is clear evidence (radiologic, clinical and/or culture) that the infection is well controlled. Participants seropositive or polymerase chain reaction (PCR) positive for the human immunodeficiency virus (HIV). Participants with evidence of Hepatitis B or Hepatitis C PCR positivity. Prior HCT (allograft or prior autograft). Use of T cell depletion either ex vivo or in vivo (i.e. anti-thymocyte globulin (ATG), alemtuzumab) is prohibited. Current or prior diagnosis of antecedent Myelofibrosis is excluded.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Efprezimod alfa Treatment<br>Efprezimod alfa: IV infusion, 480 mg (day -1), 240 mg (day +14) and 240 mg (day +28); Tacrolimus: begin on day -3. IV [0.03 mg/kg/day] or by mouth (PO) [0.045 mg/kg/dose] dosing is permitted; Methotrexate: given IV at a dose of 15 mg/m^2/dose once daily on Day 1 after hematopoietic cell transplantation (HCT), and at a dose of 10 mg/m^2/dose on days 3, 6, and 11 after HCT. | Drug: Efprezimod alfa<br>* IV infusion: 480 mg at Day -1, 240 mg at Day 14, 240 mg at Day 28.<br>* Other names: MK-7110;Drug: Methotrexate<br>* IV, 15 mg/m^2/dose at Day 1, then 10 mg/m2/dose at Day 3, 6, 11.<br>* Other names: Trexall;Drug: Tacrolimus<br>* Begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted<br>* Other names: Prograf;|
| Placebo Comparator: Placebo<br>Placebo (Saline solution): 100 ml IV infusion, Day -1, Day 14, Day 28. Tacrolimus: begin on day -3. IV [0.03mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted; Methotrexate: given IV at a dose of 15 mg/m^2/dose once daily on Day 1 after HCT, and at a dose of 10 mg/m^2/dose on days 3, 6, and 11 after HCT. | Drug: Placebo<br>* IV infusion, 100 ml at Day -1, Day 14, and Day 28.<br>* Other names: Saline;Drug: Methotrexate<br>* IV, 15 mg/m^2/dose at Day 1, then 10 mg/m2/dose at Day 3, 6, 11.<br>* Other names: Trexall;Drug: Tacrolimus<br>* Begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted<br>* Other names: Prograf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 180 Day Grade III-IV Acute Graft-Versus-Host Disease (GVHD)-Free Survival (aGFS) | Grade III-IV aGFS was defined as the time in days to the earlier of the first documented acute Grade III-IV GVHD or death by any cause in 180 days after hematopoietic stem cell transplantation (HCT). Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Participants who did not drop out or experience aGVHD or death were censored at the time of leukemia relapse or Day 180, whichever came first. | Up to 180 days after HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from HCT to death due to any cause. Participants who were alive at the end of the 180 days post HCT were censored at the last date they were known to be alive. | Up to 180 days after HCT | 
| Disease Free Survival (DFS) | DFS is defined as the earlier of time to leukemia relapse, or death, whichever occurred first. Subjects that were alive and did not experience disease relapse at the end of the follow-up period (180 days after HCT) were censored at the last date of evaluation. | Up to 180 days after HCT | 
| 180 Day Grade II-IV aGFS | Grade II-IV aGFS was defined as the time in days to the earlier of the first documented acute Grade II-IV GVHD or death by any cause in 180 days after HCT. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Participants who did not drop out or experience aGVHD or death were censored at the time of leukemia relapse or Day 180, whichever came first. | Up to 180 days after HCT | 
| 180 Day Grade III-IV aGVHD-free and Relapse-free Survival (aGVHD RFS) | Grade III-IV aGVHD RFS was defined as the time in days to the earlier of the first documented acute Grade III-IV aGVHD, relapse, or death by any cause in 180 days after HCT. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Participants who did not drop out, experience Grade III-IV aGVHD, relapse, or death were censored at Day 180. | Up to 180 days after HCT |