Hematopoietic Stem Cells
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in participants who receive allo-HSCT as treatment for a hematologic malignancy or myeloproliferative disorder.
Detailed description
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who are undergoing allo-HSCT transplantation. This study will look at the efficacy and safety of vedolizumab in the prophylaxis of intestinal aGvHD in participants undergoing allo-HSCT transplantation. The study will enroll approximately 558 participants. Participants will be randomly assigned (by chance, like flipping a coin) in 1:1 ratio to one of the two treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need) along with background GvHD prophylaxis regimen: * Vedolizumab 300 mg * Placebo (dummy inactive intravenous infusion) This multi-center trial will be conducted Worldwide. The overall time to participate in this study is 12 months.
Interventions
Vedolizumab placebo-matching IV infusion.
DRUGVedolizumab
Vedolizumab IV infusion.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must be \>= 18 years of age and, in selected countries, adolescents aged 12 years and greater and weighing \>=30 kilogram (kg) at time of randomization. 2. Must undergo deoxyribose nucleic acid (DNA)-based human leukocyte antigen (HLA) matching and be 8 of 8 or 7 of 8 HLA-matched (singe allele or antigen mismatch at HLA-A, -B, and -C, and HLA-DRB1 is allowable) unrelated hematopoietic stem cell transplantation (HSCT) from either peripheral blood or bone marrow stem cells for a hematologic malignancy or myeloproliferative disorder. 3. For whom a myeloablative conditioning or reduced intensity conditioning (RIC) is planned. 4. Allo-HSCT eligible (meeting institutional criteria)-participants planned medical care should include aGvHD prophylaxis with a combination of calcineurin inhibitor (CNI) (cyclosporine \[CYS\] or tacrolimus \[TAC\]) and methotrexate (MTX) or CNI and mycophenolate mofetil (MMF). With the exception of antithymocyte globulin (ATG) (antithymocyte globulin-Fresenius \[ATG-F\] or thymoglobulin), all other therapies, approved or investigational, for GvHD prophylaxis are excluded. 5. Eastern Cooperative Oncology Group (ECOG) performance status of \<= 2 for participants aged \>=18 years at randomization or \>=60 % using the Karnofsky performance status for adolescent participants aged \>=16 years at randomization or the Lansky performance status for adolescent participants aged 12 to \< 16 years at randomization.
Exclusion criteria
1. Had prior allo- HSCT. 2. Planned umbilical cord blood transplant or planned to receive posttransplant cyclophosphamide, in vivo or ex vivo T cell-depleted hematopoietic stem cells (HSCs) with the exception of ATG (ATG-F or thymoglobulin). 3. Planned allo-HSCT for nonmalignant hematological disorders (example, aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia or immunodeficiency).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intestinal aGvHD-Free Survival After Allo-HSCT by +180 Days | From the date of first dose of study drug to first documented intestinal aGvHD or death, whichever occurs first up to +180 days | Intestinal aGvHD Free Survival is the time from the date of first study drug administration (Day-1) to intestinal aGvHD event/death, where an event is defined as death due to any cause or Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria. Data was censored for participants who have not had the intestinal aGvHD event or died or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo HSCT whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intestinal aGvHD-Free and Relapse-Free Survival | From the date of first dose of study drug to first documented intestinal aGvHD, death or relapse, whichever occurs first up to Day +180 | Intestinal aGvHD and Relapse Free Survival is the time from the date of first study drug administration (Day-1) to intestinal aGvHD event/death/relapse, where an event is defined as death or Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria, or relapse. It will be censored for participants who have not had the event or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo-HSCT whichever occurs first. |
| Grade C-D aGvHD-Free Survival | From the date of first dose of study drug to first documented Grade C-D aGvHD or death, whichever occurs first up to Day +180 | Grade C-D aGvHD Free Survival is the time from the date of first study drug administration (Day-1) to GvHD event/death, where an event is defined as Grade C-D aGvHD any organ involvement per International Bone Marrow Transplant Registry Database (IBMTR) Severity Index for aGvHD or death. It will be censored for participants who have not had the event or have had the event after pre-specified timing, eg, last contact or Day +180 after allo-HSCT whichever occurs first. |
| Nonrelapse Mortality (NRM) | From the date of first dose of study drug to first documented death without relapse, up to Day +180 | Non-relapse mortality is the time from the date of first study drug administration (Day-1) to death without occurrence of a relapse. Data was censored for participants who have not had the event or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo HSCT whichever occurs first. |
| Overall Survival (OS) | From the date of first dose of study drug to first documented death up to Day +180 | Overall Survival by Days +180 is the time from the date of first study drug administration (Day-1) to death from any cause. |
| Grade B-D aGvHD-Free Survival | From the date of first dose of study drug to first documented grade B-D aGvHD or death, whichever occurs first up to Day +180 | Grade B-D aGvHD Free Survival is the time from the date of first study drug administration (Day-1) to aGvHD event or death, where an event is defined as death or grade B-D any organ involvement per IBMTR Severity Index for aGvHD. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, Norway, Poland, Portugal, Romania, Russia, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 95 investigative sites in Canada, United States, Argentina, Brazil, Belgium, France, Germany, Italy, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom, Austria, Greece, Hungary, Poland, Israel, Romania, Russia, Australia, Japan, Republic of Korea and Singapore from 6 February 2019 to 9 May 2022.
Pre-assignment details
Participants undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT) were randomized into 1:1 ratio to receive Vedolizumab 300 mg or vedolizumab-matching placebo. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Vedolizumab placebo-matching, intravenous (IV) infusion, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT up to the end of study treatment (up to 182 days). | 165 |
| Vedolizumab 300 mg Vedolizumab 300 mg, IV, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT up to the end of study treatment (up to 182 days). | 168 |
| Total | 333 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 6 |
| Overall Study | Death | 33 | 26 |
| Overall Study | Death (COVID-19-Related) | 1 | 0 |
| Overall Study | Other (COVID-19-Related) | 0 | 1 |
| Overall Study | Protocol Deviation | 3 | 0 |
| Overall Study | Reason Not Specified | 5 | 5 |
| Overall Study | Site Termination | 1 | 0 |
| Overall Study | Unsatisfactory Therapeutic Response | 5 | 3 |
| Overall Study | Withdrawal by Subject | 18 | 16 |
Baseline characteristics
| Characteristic | Vedolizumab 300 mg | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 50.8 years STANDARD_DEVIATION 14.41 | 51.4 years STANDARD_DEVIATION 14.44 | 51.9 years STANDARD_DEVIATION 14.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 25 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 133 Participants | 266 Participants | 133 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 19 Participants | 42 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 29 Participants | 65 Participants | 36 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 28 Participants | 13 Participants |
| Race (NIH/OMB) White | 121 Participants | 235 Participants | 114 Participants |
| Sex: Female, Male Female | 103 Participants | 209 Participants | 106 Participants |
| Sex: Female, Male Male | 65 Participants | 124 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 34 / 169 | 26 / 174 |
| other Total, other adverse events | 164 / 165 | 169 / 169 |
| serious Total, serious adverse events | 114 / 165 | 120 / 169 |
Outcome results
Primary
Intestinal aGvHD-Free Survival After Allo-HSCT by +180 Days
Intestinal aGvHD Free Survival is the time from the date of first study drug administration (Day-1) to intestinal aGvHD event/death, where an event is defined as death due to any cause or Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria. Data was censored for participants who have not had the intestinal aGvHD event or died or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo HSCT whichever occurs first.
Time frame: From the date of first dose of study drug to first documented intestinal aGvHD or death, whichever occurs first up to +180 days
Population: FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Intestinal aGvHD-Free Survival After Allo-HSCT by +180 Days | NA days |
| Vedolizumab 300 mg | Intestinal aGvHD-Free Survival After Allo-HSCT by +180 Days | NA days |
p-value: <0.00195% CI: [0.27, 0.73]Log Rank
Secondary
Grade B-D aGvHD-Free Survival
Grade B-D aGvHD Free Survival is the time from the date of first study drug administration (Day-1) to aGvHD event or death, where an event is defined as death or grade B-D any organ involvement per IBMTR Severity Index for aGvHD.
Time frame: From the date of first dose of study drug to first documented grade B-D aGvHD or death, whichever occurs first up to Day +180
Population: FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Grade B-D aGvHD-Free Survival | NA days |
| Vedolizumab 300 mg | Grade B-D aGvHD-Free Survival | NA days |
p-value: 0.010595% CI: [0.46, 0.91]Log Rank
Secondary
Grade C-D aGvHD-Free Survival
Grade C-D aGvHD Free Survival is the time from the date of first study drug administration (Day-1) to GvHD event/death, where an event is defined as Grade C-D aGvHD any organ involvement per International Bone Marrow Transplant Registry Database (IBMTR) Severity Index for aGvHD or death. It will be censored for participants who have not had the event or have had the event after pre-specified timing, eg, last contact or Day +180 after allo-HSCT whichever occurs first.
Time frame: From the date of first dose of study drug to first documented Grade C-D aGvHD or death, whichever occurs first up to Day +180
Population: FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Grade C-D aGvHD-Free Survival | NA days |
| Vedolizumab 300 mg | Grade C-D aGvHD-Free Survival | NA days |
p-value: 0.020495% CI: [0.39, 0.91]Log Rank
Secondary
Intestinal aGvHD-Free and Relapse-Free Survival
Intestinal aGvHD and Relapse Free Survival is the time from the date of first study drug administration (Day-1) to intestinal aGvHD event/death/relapse, where an event is defined as death or Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria, or relapse. It will be censored for participants who have not had the event or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo-HSCT whichever occurs first.
Time frame: From the date of first dose of study drug to first documented intestinal aGvHD, death or relapse, whichever occurs first up to Day +180
Population: FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Intestinal aGvHD-Free and Relapse-Free Survival | NA days |
| Vedolizumab 300 mg | Intestinal aGvHD-Free and Relapse-Free Survival | NA days |
p-value: 0.004395% CI: [0.37, 0.86]Log Rank
Secondary
Nonrelapse Mortality (NRM)
Non-relapse mortality is the time from the date of first study drug administration (Day-1) to death without occurrence of a relapse. Data was censored for participants who have not had the event or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo HSCT whichever occurs first.
Time frame: From the date of first dose of study drug to first documented death without relapse, up to Day +180
Population: FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Nonrelapse Mortality (NRM) | NA days |
| Vedolizumab 300 mg | Nonrelapse Mortality (NRM) | NA days |
p-value: 0.066895% CI: [0.22, 1.04]Log Rank
Secondary
Overall Survival (OS)
Overall Survival by Days +180 is the time from the date of first study drug administration (Day-1) to death from any cause.
Time frame: From the date of first dose of study drug to first documented death up to Day +180
Population: FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival (OS) | NA days |
| Vedolizumab 300 mg | Overall Survival (OS) | NA days |
p-value: 0.145895% CI: [0.34, 1.17]Log Rank