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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
44
Acute GVHD prophylaxis
Acute GVHD prophylaxis
Acute GVHD prophylaxis
100 ml saline IV infusion.
Indiana University School of Medicine
Indianapolis, Indiana, United States
The University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
Ohio State University
Columbus, Ohio, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 181 days
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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