Phase II Trial of Efprezimod Alfa (CD24Fc, MK-7110) for the Prevention of Acute Graft-Versus-Host Disease (GVHD) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) (MK-7110-002)

Study Overview
=================
Brief Summary
-----------------
This is a multicenter prospective phase IIa dose escalation and phase IIa expansion cohort clinical trial designed to evaluate the safety and tolerability of efprezimod alfa for acute GVHD prophylaxis.

Detailed Description
-----------------
The first part of this study was a phase IIa randomized, double blind, placebo controlled, multi-center study to investigate adding efprezimod alfa to standard of care tacrolimus and methotrexate in acute graft-versus host disease (GVHD) prophylaxis for allogeneic hematopoietic stem cell transplantation (HCT) with matched unrelated donors in treatment of leukemia and myelodysplastic syndrome. The primary objective was to evaluate the safety, tolerability and dose-limiting toxicities (DLTs) of efprezimod alfa in participants undergoing matched unrelated donor myeloablative allogeneic HCT for malignant hematologic disorders. Three dose cohorts were planned with 240 mg at day -1 (one day prior to HCT), 480 mg at day -1, and the multi-dose cohort of 480-240-240 mg at day -1, day 14 and day 28. The efprezimod alfa : placebo randomization ratio was 3:1. The second part was a prospective open label phase IIa expansion cohort trial investigating the addition of efprezimod alfa to standard acute graft-versus host disease (GVHD) prophylaxis for allogeneic hematopoietic stem cell transplantation (HCT). Based on the first part's safety results and the pharmacokinetic data, the phase IIa expansion dose was the multi-dose 480-240-240 mg regimen administered on day -1, day 14 and day 28, respectively. The primary objective of phase IIa expansion was to determine if the addition of efprezimod alfa to standard GVHD prophylaxis improves 180 days post-HCT grade III-IV acute GVHD-free survival (AGFS) when compared to Center for International Blood and Marrow Transplant Research (CIBMTR) database registered control participants who had standard GVHD prophylaxis alone. Eligible participants were those requiring allogeneic HCT for malignant hematologic conditions and receiving a myeloablative conditioning regimen.

Official Title
-----------------
A Phase II Trial of CD24Fc for Prevention of Acute Graft-versus-Host Disease Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplant

Conditions
-----------------
Graft Versus Host Disease, Hematopoietic Stem Cell Transplantation, Leukemia

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria 4.1.1 A prospective participant for allogeneic hematopoietic stem cell transplantation (HCT) for a malignant hematologic disorder. 4.1.2 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. 4.1.3 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 central nervous system (CNS) involvement. Chronic Myelogenous Leukemia (CML) in first or subsequent chronic phase failing to respond (or intolerant) to at least two different tyrosine kinase inhibitors. CML in accelerated or blast phase (CML-AP/BP) are eligible without requirement to fail tyrosine kinase inhibitor therapy, but must be in remission at time of enrollment. 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 IPSS (IPSS-R) score with < 10% blasts in the bone marrow. Chronic Myelomonocytic Leukemia (CMML) with < 10% blasts in the bone marrow. 4.1.4 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. 4.1.5 Karnofsky Performance Status >70%. 4.1.6 Participants must have normal or near normal organ function as defined by their treating institutions bone marrow transplantation (BMT) program clinical practice guidelines. In addition, for purposes of this protocol minimum organ function criteria within 21 days of beginning conditioning include: TABLE 1: Eligibility According to Pre HCT Organ Function Total bilirubin ≤2.5 mg% (unless from Gilbert's disease or disease-related) Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) (AST[SGOT])/ alanine aminotransferase (serum glutamic-pyruvic transaminase) (ALT[SGPT]) <3.0 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 body surface area [BSA]) Pulmonary Function Tests* diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in 1 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 *May be assessed up to 6 weeks prior to the start of conditioning therapy 4.1.7 Ability to understand and the willingness to sign a written informed consent document. 4.1.8 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: 4.2.1 Participants may not have presence of active CNS disease or extramedullary disease. 4.2.2 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). 4.2.3 Cord blood and haploidentical donors are not eligible. 4.2.4 HLA-mismatch at the HLA-A, -B, -C, and - DRB1 loci. Note, HLA-DQ mismatches are permissible. 4.2.5 Pregnant and nursing mothers are excluded from this study. This is because the risk to the fetus is unknown. 4.2.6 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. 4.2.7 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. 4.2.8 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. 4.2.9 Prior HCT (allograft or prior autograft). 4.2.10 Use of T cell depletion either ex vivo or in vivo (i.e. anti-thymocyte globulin [ATG], alemtuzumab) is prohibited. 4.2.11 Current or prior diagnosis of antecedent Myelofibrosis is excluded.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study was double blind for the first 6 participants in each arm. At that point, the recommended phase II dose (RP2D) was determined, and the selected arm enrolled additional participants in an open label fashion.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Efprezimod alfa 240 mg<br>Efprezimod alfa in 240 mg as intravenous (IV) infusion at Day -1 + Tacrolimus (begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted) + Methotrexate (given intravenously at a dose of 15 mg/square meter/dose once daily on Day 1 after HCT, and at a dose of 10 mg/square meter/dose on days 3, 6, and 11 after HCT) | Drug: Efprezimod alfa<br>* Acute GVHD prophylaxis<br>* Other names: MK-7110;Drug: Methotrexate<br>* Acute GVHD prophylaxis<br>* Other names: Trexall;Drug: Tacrolimus<br>* Acute GVHD prophylaxis<br>* Other names: Prograf;|
| Experimental: Efprezimod alfa 480 mg<br>Efprezimod alfa in 480 mg as intravenous (IV) infusion at Day -1 + Tacrolimus (begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted) + Methotrexate (given intravenously at a dose of 15 mg/square meter/dose once daily on Day 1 after HCT, and at a dose of 10 mg/square meter/dose on days 3, 6, and 11 after HCT) | Drug: Efprezimod alfa<br>* Acute GVHD prophylaxis<br>* Other names: MK-7110;Drug: Methotrexate<br>* Acute GVHD prophylaxis<br>* Other names: Trexall;Drug: Tacrolimus<br>* Acute GVHD prophylaxis<br>* Other names: Prograf;|
| Experimental: Efprezimod alfa 960 mg<br>Efprezimod alfa (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 PO [0.045 mg/kg/dose] dosing is permitted) + Methotrexate (given intravenously at a dose of 15 mg/square meter/dose once daily on Day 1 after HCT, and at a dose of 10 mg/square meter/dose on days 3, 6, and 11 after HCT) | Drug: Efprezimod alfa<br>* Acute GVHD prophylaxis<br>* Other names: MK-7110;Drug: Methotrexate<br>* Acute GVHD prophylaxis<br>* Other names: Trexall;Drug: Tacrolimus<br>* Acute GVHD prophylaxis<br>* Other names: Prograf;|
| Placebo Comparator: Placebo<br>Placebo to efprezimod alfa (saline IV injection solution) on day -1 or days -1, 14, and 28 + Tacrolimus (begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted) + Methotrexate (given intravenously at a dose of 15 mg/square meter/dose once daily on Day 1 after HCT, and at a dose of 10 mg/square meter/dose on days 3, 6, and 11 after HCT) | Drug: Methotrexate<br>* Acute GVHD prophylaxis<br>* Other names: Trexall;Drug: Tacrolimus<br>* Acute GVHD prophylaxis<br>* Other names: Prograf;Drug: Placebo<br>* 100 ml saline IV infusion.<br>* Other names: Saline Solution;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented. As described in the protocol, AEs reported after the protocol-specified timeframe were not analyzed in this outcome measure: 1 day prior to hematopoietic stem cell transplantation (HCT) through either 30 or 60 days post-HCT, depending on arm as defined in the Time Frame section. | Up to approximately 32 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to approximately 62 days for the CD24Fc 960 mg arm. | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE is presented. | 1 day for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to approximately 30 days for the CD24Fc 960 mg arm. | 
| Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT) | A DLT was defined as: any Grade III or higher non-hematologic toxicity not clearly related to the underlying malignancy, intercurrent infection, or the hematopoietic stem cell transplantation conditioning regimen; any death not related to relapse or intercurrent infection; and failure to engraft by day 30. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Hypersensitivity reactions and other infusion-related reactions were not considered DLTs. | Up to 32 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 62 days for the CD24Fc 960 mg arm. | 
| Open Label Expansion Arm Only: Grade III-IV Acute Graft-Versus-Host Disease (GVHD) Free Survival (AGFS) | AGFS was defined as the time from the date of hematopoietic stem cell transplantation (HCT) to the earliest of Grade III-IV acute GVHD or death due to any cause, whichever occurred first. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Participants were censored at 181 days. | Up to 181 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade II-IV Acute Graft-Versus-Host Disease (GVHD) Free Survival (AGFS) | AGFS was defined as the time from the date of hematopoietic stem cell transplantation (HCT) to the earliest of Grade II-IV acute GVHD or death due to any cause, whichever occurred first. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Participants were censored at 195 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms, and at 181 days for the CD24Fc 960 mg arm. | Up to 195 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 181 days for the CD24Fc 960 mg arm. | 
| Percentage of Participants Experiencing Grade II to IV Acute GVHD Following HCT | The percentage of participants who experienced grade II to IV acute GVHD is presented as cumulative incidence of Grade II to IV acute GVHD by approximately 108 days following HCT. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. The cumulative incidence (%) of acute GVHD and the 95% CI were estimated using the cumulative incidence function with death without Grade II to IV acute GVHD as a competing risk. | Up to approximately 108 days | 
| Percentage of Participants Experiencing Chronic GVHD Following HCT | The percentage of participants who experienced chronic GVHD will be presented as cumulative incidence of chronic GVHD. Chronic GVHD assessments occurred approximately quarterly beginning on Day 100 after HCT until 1 year after HCT. The cumulative incidence (%) of chronic GVHD at 1 year post-HCT and the 95% CI were estimated using the cumulative incidence function with death without chronic GVHD as a competing risk. If the maximum observed time was <Study Day 380, the cumulative incidence at the maximum observed time is presented for a treatment group. | Up to 380 days | 
| Percentage of Participants Experiencing Relapse Following HCT | The percentage of participants who experienced relapse of disease is presented as cumulative incidence of relapse. The cumulative incidence (%) of relapse at approximately 1 year following HCT and the 95% CI were estimated using the cumulative incidence function with death without relapse as a competing risk. If the maximum observed time is < Study Day 380, the cumulative incidence at the maximum observed time is presented. | Up to 380 days | 
| Percentage of Participants Experiencing Non-Relapse Mortality (NRM) Following HCT | The percentage of participants who experienced NRM is presented as cumulative incidence of NRM. The cumulative incidence (%) of NRM at approximately 1 year following HCT and the 95% CI were estimated using the cumulative incidence function with relapse as a competing risk. If the maximum observed time is < Study Day 380, the cumulative incidence at the maximum observed time will be presented. | Up to 380 days | 
| Percentage of Participants Experiencing Infection Following Hematopoietic Stem Cell Transplantation (HCT) | The percentage of participants who experienced infection by approximately 101 days following HCT is presented. | Up to approximately 101 days | 
| Overall Survival (OS) Following Hematopoietic Stem Cell Transplantation (HCT) | OS is defined as the time from HCT to death due to any cause. Participants were censored at 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms, and at 366 days for the CD24Fc 960 mg arm. | Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm. | 
| GVHD-Free and Relapse-Free Survival (GRFS) Following HCT | This GRFS following HCT is a composite endpoint in which events included Grade III to IV acute GVHD, chronic GVHD requiring systemic immunosuppressive therapy, relapse, or death from any cause | Up to 380 days | 
| Relapse-Free Survival (RFS) Following Hematopoietic Stem Cell Transplantation (HCT) | RFS is defined as the time from HCT to relapse or death due to any cause. Participants were censored at 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms, and at 366 days for the CD24Fc 960 mg arm. | Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm |