CD40-L Blockade for Prevention of Acute Graft-Versus-Host Disease

Phase 1

Completed

• Conditions: GVHD, Acute; Graft-versus-host-disease; GVHD
• Interventions: Drug: BMS-986004; Drug: Sirolimus; Drug: Tacrolimus

• Registration Number: NCT03605927
• Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Brief Summary

The purpose of this study is to examine the safety and efficacy of the addition of BMS-986004 to standard of care Sirolimus (SIR)-based immune suppression.

Detailed Description

The approach builds upon extensive evidence supporting the benefit of CD40L blockade in disrupting key signaling events associated with immune activation. The trial addresses a pressing clinical need, namely prevention of Graft-Versus-Host Disease (GVHD) after hematopoietic cell transplantation (HCT) and promotion of donor-recipient immune tolerance. The safety profile of this anti-CD40L antibody overcomes major prior limitations, and the planned biologic studies will provide significant mechanistic insight.

Study Timeline

• Study First Submitted: 2018-07-20
• Study First Submitted QC: 2018-07-20
• Study First Posted: 2018-07-30
• Study Start: 2019-02-15
• Primary Completion: 2023-09-01
• Study Completion: 2023-09-01
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-11
• Last Update Posted: 2025-02-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

Inclusion Criteria

• Hematologic malignancy or blood disorder requiring allogeneic HCT
• Adequate vital organ function as defined per protocol
• Karnofsky Performance Status Score (KPS) ≥ 80%
• Participants must have an available 8/8 HLA-A, -B, -C, and -DRB1 matched-related or unrelated donor

Exclusion Criteria

• Active infection not controlled with appropriate antimicrobial therapy
• HIV, hepatitis B or C infection or known history of HIV, hepatitis B or C(all patients will be tested for HIV, hepatitis B and C as part of standard pre-transplant testing, and will be excluded from this trial if positive)
• Anti-thymocyte globulin, or cyclophosphamide administered within 14 days before or planned to receive with HCT conditioning or as part of GVHD prophylaxis in the 14 days after HCT
• Known allergic reactions to components of the study drug
• Concurrent treatment with another investigational drug
• History of thromboembolism, transient ischemic attack, stroke, myocardial infarction within 3 months preceding the transplant, or uncontrolled congestive heart failure or cardiac arrhythmias.
• Post-transplant maintenance therapies such as FLT3 inhibitor, tyrosine kinase inhibitor, JAK inhibitors etc. are not allowed if plan is to initiate such therapies <90 days post-transplant. Patient will be eligible if plan to initiate maintenance therapy is after day 90 post-transplant.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Combination Therapy	BMS-986004	BMS-986004: From day 13, intravenously (IV) every 2 week through day 100 post HCT. Tacrolimus: From day -3 as standard of care. Sirolimus: From day -1 as standard of care.
Combination Therapy	Tacrolimus	BMS-986004: From day 13, intravenously (IV) every 2 week through day 100 post HCT. Tacrolimus: From day -3 as standard of care. Sirolimus: From day -1 as standard of care.
Combination Therapy	Sirolimus	BMS-986004: From day 13, intravenously (IV) every 2 week through day 100 post HCT. Tacrolimus: From day -3 as standard of care. Sirolimus: From day -1 as standard of care.

Primary Outcome Measures

Name	Time	Method
Incidence of Grade II-IV Acute Graft-versus Host Disease	1 year post HCT	Cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) by day 100 after hematopoietic cell transplantation (HCT). Acute GVHD severity will be determined by standard Consensus Criteria, and the cumulative incidence of grade II-IV acute GVHD will be reported through day 100 post-HCT, with relapse and death as competing risk events.

Secondary Outcome Measures

Name	Time	Method
Chronic Graft-versus Host Disease Through 1 Year Post HCT	1 year post HCT	NIH criteria defined chronic graft-versus-host disease through 1 year post-HCT. Chronic GVHD will be defined by the presence of chronic GVHD defining features, regardless of time post-HCT, in keeping with the NIH Consensus Criteria on diagnosis and staging of chronic GVHD. Individual affected organs are staged on 0-3 severity scale, and summarized for an overall global severity score. The presence of acute GVHD features defines the following subgroups: (1) late acute GVHD (sole presence of acute GVHD features after day 100 post-HCT), (2) overlap subtype of chronic GVHD (co-occurrence of chronic and acute GVHD features, and (3) classic chronic GVHD (absence of concurrent acute GVHD features).
Malignancy Relapse Post-HCT	1 year post HCT	Defined as hematologic relapse or any unplanned intervention (including withdrawal of immune suppression) to prevent progression of disease in patients with evidence (molecular, cytogenetic, flow cytometric, radiographic) of malignant disease after HCT.
Non-relapse Mortality	1 year post HCT	Defined as death in the absence of malignancy relapse post-HCT.
Overall Survival (OS)	1 year post HCT	Defined as time from HCT to death or censoring for last follow up.

Trial Locations

Locations (3)

Ohio State University Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

City of Hope Cancer Center; 🇺🇸 Duarte, California, United States

H. Lee Moffitt Cancer Center and Research Institute; 🇺🇸 Tampa, Florida, United States