Back to resultsCD40-L Blockade for Prevention of Acute Graft-Versus-Host Disease
Primary Purpose
Graft-versus-host-disease, GVHD, GVHD, Acute
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
BMS-986004
Sirolimus
Tacrolimus
Sponsored by
About this trial
This is an interventional prevention trial for Graft-versus-host-disease focused on measuring HCT, hematopoietic cell transplantation, antibody therapy
Eligibility Criteria
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.
Sites / Locations
- City of Hope Cancer Center
- H. Lee Moffitt Cancer Center and Research Institute
- Ohio State University Comprehensive Cancer Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Combination Therapy
Arm Description
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.
Outcomes
Primary Outcome Measures
Incidence of Grade II-IV Acute Graft-versus Host Disease
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
Chronic Graft-versus Host Disease Through 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
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
Defined as death in the absence of malignancy relapse post-HCT.
Overall Survival (OS)
Defined as time from HCT to death or censoring for last follow up.
Full Information
NCT ID
NCT03605927
First Posted
July 20, 2018
Last Updated
August 7, 2023
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Bristol-Myers Squibb
1. Study Identification
Unique Protocol Identification Number
NCT03605927
Brief Title
CD40-L Blockade for Prevention of Acute Graft-Versus-Host Disease
Official Title
CD40-L Blockade for Prevention of Acute Graft-Versus-Host Disease
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
February 15, 2019 (Actual)
Primary Completion Date
November 28, 2022 (Actual)
Study Completion Date
November 28, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Bristol-Myers Squibb
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft-versus-host-disease, GVHD, GVHD, Acute
Keywords
HCT, hematopoietic cell transplantation, antibody therapy
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
45 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Combination Therapy
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
BMS-986004
Other Intervention Name(s)
Anti-CD40L Domain Antibody
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Standard of Care, SIR
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
Standard of Care, TAC
Intervention Description
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.
Primary Outcome Measure Information:
Title
Incidence of Grade II-IV Acute Graft-versus Host Disease
Description
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.
Time Frame
1 year post HCT
Secondary Outcome Measure Information:
Title
Chronic Graft-versus Host Disease Through 1 Year Post HCT
Description
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).
Time Frame
1 year post HCT
Title
Malignancy Relapse Post-HCT
Description
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.
Time Frame
1 year post HCT
Title
Non-relapse Mortality
Description
Defined as death in the absence of malignancy relapse post-HCT.
Time Frame
1 year post HCT
Title
Overall Survival (OS)
Description
Defined as time from HCT to death or censoring for last follow up.
Time Frame
1 year post HCT
Other Pre-specified Outcome Measures:
Title
Glucocorticoid Exposure
Description
Systemic steroid (prednisone or equivalent) dose per kg of recipient body weight will be collected at each study visit, and overall exposure determined.
Time Frame
1 year post HCT
Title
Neutrophil and Platelet Engraftment
Description
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.
Time Frame
1 year post HCT
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Farhad Khimani, M.D.
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Cancer Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
H. Lee Moffitt Cancer Center and Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
12. IPD Sharing Statement
Links:
URL
https://www.moffitt.org/clinical-trials-research/clinical-trials/
Description
Moffitt Cancer Center Clinical Trials website
Learn more about this trial
CD40-L Blockade for Prevention of Acute Graft-Versus-Host Disease
We'll reach out to this number within 24 hrs