Clinical trial NCT02663622: 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)
Official title: A Phase II Trial of CD24Fc for Prevention of Acute Graft-versus-Host Disease Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft Versus Host Disease
Hematopoietic Stem Cell Transplantation
Leukemia
Lead sponsor: Oncoimmune, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
Collaborators: name: Ohio State University
name: University of Michigan Rogel Cancer Center
name: Indiana University School of Medicine
name: Barbara Ann Karmanos Cancer Institute
name: National Cancer Institute (NCI)
First posted: 2016-01-26
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

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:

1. 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.
2. 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.
3. 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.
4. 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.

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: 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.
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: 1 day for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to approximately 30 days for the CD24Fc 960 mg arm.
measure: Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
timeFrame: 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.
measure: Open Label Expansion Arm Only: Grade III-IV Acute Graft-Versus-Host Disease (GVHD) Free Survival (AGFS)
timeFrame: Up to 181 days
Secondary outcomes:
measure: Grade II-IV Acute Graft-Versus-Host Disease (GVHD) Free Survival (AGFS)
timeFrame: 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.
measure: Percentage of Participants Experiencing Grade II to IV Acute GVHD Following HCT
timeFrame: Up to approximately 108 days
measure: Percentage of Participants Experiencing Chronic GVHD Following HCT
timeFrame: Up to 380 days
measure: Percentage of Participants Experiencing Relapse Following HCT
timeFrame: Up to 380 days
measure: Percentage of Participants Experiencing Non-Relapse Mortality (NRM) Following HCT
timeFrame: Up to 380 days
measure: Percentage of Participants Experiencing Infection Following Hematopoietic Stem Cell Transplantation (HCT)
timeFrame: Up to approximately 101 days
measure: Overall Survival (OS) Following Hematopoietic Stem Cell Transplantation (HCT)
timeFrame: 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.
measure: GVHD-Free and Relapse-Free Survival (GRFS) Following HCT
timeFrame: Up to 380 days
measure: Relapse-Free Survival (RFS) Following Hematopoietic Stem Cell Transplantation (HCT)
timeFrame: 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
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Ann Arbor
country: United States
facility: The University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
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citation: Toubai T, Hou G, Mathewson N, Liu C, Wang Y, Oravecz-Wilson K, Cummings E, Rossi C, Evers R, Sun Y, Wu J, Choi SW, Fang D, Zheng P, Liu Y, Reddy P. Siglec-G-CD24 axis controls the severity of graft-versus-host disease in mice. Blood. 2014 May 29;123(22):3512-23. doi: 10.1182/blood-2013-12-545335. Epub 2014 Apr 2.
citation: Toubai T, Mathewson ND, Magenau J, Reddy P. Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives. Front Immunol. 2016 Nov 29;7:539. doi: 10.3389/fimmu.2016.00539. eCollection 2016.
citation: Magenau J, Jaglowski S, Uberti J, Farag SS, Riwes MM, Pawarode A, Anand S, Ghosh M, Maciejewski J, Braun T, Devenport M, Lu S, Banerjee B, DaSilva C, Devine S, Zhang MJ, Burns LJ, Liu Y, Zheng P, Reddy P. A phase 2 trial of CD24Fc for prevention of graft-versus-host disease. Blood. 2024 Jan 4;143(1):21-31. doi: 10.1182/blood.2023020250.