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

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.

Study Overview

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 Type

Interventional

Enrollment (Actual)

45

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • California
      • Duarte, California, United States, 91010
        • City of Hope Cancer Center
    • Florida
      • Tampa, Florida, United States, 33612
        • H. Lee Moffitt Cancer Center and Research Institute
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University Comprehensive Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Combination Therapy

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.

BMS-986004 will be administered in ascending dose cohorts in the phase I component of the trial. Based on prior PK and PD data, dose levels of 225 mg, 675 mg, and 1500 mg (3 total phase I dose levels) will be examined. BMS-986004 will be given intravenously (IV) every 2 weeks, starting from day -3 (i.e., three days prior to HCT) onward through a total of 100 days post-HCT. The maximum tolerated dose (MTD) identified in the phase I component of the trial will be carried forward as the recommended dose level in the phase 1 expansion cohort.
Other Names:
  • Anti-CD40L Domain Antibody

Sirolimus and tacrolimus (standard of care pharmacologic immune suppression) will be given according to institutional standards.

Sirolimus (SIR) will be given as a loading dose on day -1 orally, then daily as maintenance therapy with target levels of 10-14ng/mL early post-HCT, then tapered to 5-14ng/mL range.

Program standards will be used for SIR and TAC level monitoring frequency and dose adjustments, including careful attention to drug-interactions.

Other Names:
  • Standard of Care
  • SIR

Sirolimus and tacrolimus (standard of care pharmacologic immune suppression) will be given according to institutional standards.

In brief, tacrolimus (TAC) will be started on day -3 IV, and transitioned to oral TAC when oral medications are tolerated; target level is 3-7ng/mL.

Program standards will be used for SIR and TAC level monitoring frequency and dose adjustments, including careful attention to drug-interactions.

Other Names:
  • TAC
  • Standard of Care

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Grade II-IV Acute Graft-versus Host Disease
Time Frame: 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.
1 year post HCT

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Chronic Graft-versus Host Disease Through 1 Year Post HCT
Time Frame: 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).
1 year post HCT
Malignancy Relapse Post-HCT
Time Frame: 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.
1 year post HCT
Non-relapse Mortality
Time Frame: 1 year post HCT
Defined as death in the absence of malignancy relapse post-HCT.
1 year post HCT
Overall Survival (OS)
Time Frame: 1 year post HCT
Defined as time from HCT to death or censoring for last follow up.
1 year post HCT

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Glucocorticoid Exposure
Time Frame: 1 year post HCT
Systemic steroid (prednisone or equivalent) dose per kg of recipient body weight will be collected at each study visit, and overall exposure determined.
1 year post HCT
Neutrophil and Platelet Engraftment
Time Frame: 1 year post HCT
Stable engraftment is defined as a sustained absolute neutrophil count > 500 over 3 days, as well as a sustained platelet count of > 20 over 7 days without transfusion support. Time to engraftment is defined as time from day 0 to day of sustained engraftment per above criteria.
1 year post HCT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Farhad Khimani, M.D., H. Lee Moffitt Cancer Center and Research Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 15, 2019

Primary Completion (Actual)

September 1, 2023

Study Completion (Actual)

September 1, 2023

Study Registration Dates

First Submitted

July 20, 2018

First Submitted That Met QC Criteria

July 20, 2018

First Posted (Actual)

July 30, 2018

Study Record Updates

Last Update Posted (Estimated)

January 26, 2024

Last Update Submitted That Met QC Criteria

January 25, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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