Allogeneic Hematopoietic Stem Cell Transplantation
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to assess the initial tolerability, safety and recommended phase 2 dose of vedolizumab intravenous (IV) administered for GvHD prophylaxis along with standard GvHD prophylaxis therapy (in participants undergoing allogeneic hematopoietic stem cell transplantation \[allo-HSCT\]).
Detailed description
The drug being tested in this study is called Vedolizumab. Vedolizumab (also called MLN0002) is approved for the treatment of adult participants with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD) who achieved an inadequate response, had a loss of response, or were intolerant to conventional and/or biologic treatments. This study will look at the tolerability and pharmacokinetics of Vedolizumab in participants undergoing allo-HSCT when added to standard GvHD prophylaxis (tacrolimus plus short-term methotrexate) for the prevention of acute GvHD (major complication in allo-HSCT). The study will enroll approximately 36 participants. Participants will be assigned to different dose-escalating cohorts in order to find out the recommended phase 2 dose (RP2D) of the study: * Cohort 1: Vedolizumab 75 mg * Cohort 2: Vedolizumab 300 mg * Cohort 3: Vedolizumab Dose 1 All participants have to receive 1 injection of Vedolizumab on Day -1 before allo-HSCT and on Days 13 and 42 after allo-HSCT. If none of the participants receiving vedolizumab at 75 mg experience dose-limiting toxicities (DLTs), dose escalation will continue to 300 mg on Day -1 before allo-HSCT and on Days +13 and +42 after allo-HSCT. If the first 3 participants at 300 mg tolerate the treatment without experiencing DLTs, then the decision on whether to increase the vedolizumab IV dose in the next cohort will be guided by the PK results. Cohorts will be escalated in same manner until the identification of RP2D. The cohort at that dose level may be expanded to include approximately 18 additional participants undergoing myeloablative conditioning or reduced-intensity conditioning (RIC) and receiving either related or unrelated allo-HSCT for the treatment of hematologic malignancies or myeloproliferative neoplasms. This group of participants will allow the further assessment of the tolerability and clinical activity of vedolizumab. This multi-center trial will be conducted in the United States. The overall time to participate in this study will be approximately 2 years. Following the treatment period, participants who remain in remission will be followed for development of acute and chronic GvHD and safety during clinic visits at 4, 5, 6, 9, and 12 months after allo-HSCT or until death or withdrawal of consent or termination of the study by the sponsor. Participants who complete the study will attend a 12-month follow-up visit. Patients who have been discontinued from treatment will attend an end of treatment visit 30 to 40 days after the last dose of study drug using all study procedures outlined for the 12-month follow-up visit.
Interventions
DRUGVedolizumab
Vedolizumab Injection.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Is undergoing matched or single-antigen mismatched unrelated-donor myeloablative transplant for the treatment of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML); Is less than or equal to (\<=) 60 years of age. For the cohort after RP2D 2. Is undergoing matched or single-antigen mismatched related or unrelated-donor transplant and receiving myeloablative conditioning or RIC for the treatment of hematologic malignancies or myeloproliferative neoplasms; Is less than or equal to (\<=) 75 years of age.
Exclusion criteria
1. Has received prior allogeneic transplants or who are planned to undergo umbilical cord blood transplant, receive ex vivo T-cell-depleted hematopoietic stem cells (HSCs), received any in vivo T-cell depleting antibodies, or non-myeloablative conditioning. 2. Has active cerebral/meningeal disease, active cytomegalovirus (CMV) colitis, or signs and symptoms of progressive multifocal leukoencephalopathy (PML) or any history of PML. 3. Is undergoing transplant for the treatment of nonmalignant hematological disorders (for example: aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities (DLTs) | Baseline up to Day 28 | DLTs was based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and was defined as any of following events: Grade 3 or higher toxicity assessed by the investigator as related to vedolizumab treatment; Grade 4 or higher regimen-related organ toxicities; and failure to engraft by Day +28. Engraftment was defined as absolute neutrophils count (ANC) greater than (\>) 500 per cubic millimeter (/mm\^3) for 3 consecutive days or \>2000/mm\^3 for 1 day. |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Up to 18 weeks after last dose of study drug | — |
| Mean Serum Concentrations of Vedolizumab That Helped the Likelihood of Alpha4Beta7 Target Saturation on Day 100 Following Allo-HSCT | Day 100 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Baseline up to Day 100 | Maximum severity of acute GvHD was assessed by using BMT CTN modified IBMTR index. The severity index are defined as: Grade A (skin stage 1: extent of rash less than \[\<\] 25%); Grade B (skin stage 2: extent of rash 25 to 50% or liver stage 1 to 2: total bilirubin 34 to 102 micromole per liter \[mcmol/L\] or intestinal tract stage 1 to 2: volume of diarrhea 550 to 1500 milliliter per day \[mL/day\]); Grade C (skin stage 3: extent of rash greater than (\>) 50% or liver stage 3: total bilirubin 103 to 255 mcmol/L or intestinal tract stage 3: volume of diarrhea \>1500 mL/day); Grade D (skin stage 4: extent of rash bullae or liver stage 4: total bilirubin \>255 or intestinal tract stage 4: volume of diarrhea severe pain and ileus). |
| Time to Neutrophil Engraftment | Baseline up to Day 100 | Time to neutrophil engraftment (recovery of ANC) was defined by an ANC \>500/mm\^3 for 3 consecutive days or \>2000/mm\^3 for 1 day. Time to neutrophil engraftment was calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. |
| Ctrough: Serum Concentration Before Dosing for Vedolizumab | Days 13 and 42 pre-dose | — |
| Percentage of Participants With Overall Grade 2 to 4 Acute Graft-Versus-Host Disease (GvHD) | Baseline up to Day 100 | GvHD grading scale was based on the modified Glucksberg criteria. The grades are defined as: Grade 1 (skin stage 1 or 2 only); Grade 2 (skin stage 3 or liver stage 1 or lower or gastrointestinal \[GI\] stage 1 or upper GI involvement); Grade 3 (skin stage 0 to 3 plus liver stage 2 to 4 or lower GI stage 2 to 3); Grade 4 (skin stage 4 or lower GI stage 4). |
| Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Baseline up to Day 100 | Maximum severity was assessed using GvHD grading scale based on the modified Glucksberg criteria. The grades are defined as: Grade 1 (skin stage 1 or 2 only); Grade 2 (skin stage 3 or liver stage 1 or lower or GI stage 1 or upper GI involvement); Grade 3 (skin stage 0 to 3 plus liver stage 2 to 4 or lower GI stage 2 to 3); Grade 4 (skin stage 4 or lower GI stage 4). |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 5 investigative sites in the United States from 15 June 2016 to 10 July 2018.
Pre-assignment details
Participants undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) were enrolled to receive vedolizumab intravenous 75 milligram (mg) or 300 mg along with standard graft-versus-host disease (GvHD) prophylaxis therapy (tacrolimus plus short team methotrexate).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Vedolizumab 75 mg Vedolizumab 75 mg, 30-minutes infusion, intravenously, once on Day -1 (before allo-HSCT on Day 1), and Days 13 and 42 (after allo-HSCT on Day 1). | 3 |
| Cohort 2: Vedolizumab 300 mg Vedolizumab 300 mg, 30-minutes infusion, intravenously once on Days -1 (before allo-HSCT on Day 1), and Days 13 and 42 (after allo-HSCT on Day 1). | 21 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Cohort 1: Vedolizumab 75 mg | Total | Cohort 2: Vedolizumab 300 mg |
|---|---|---|---|
| Age, Continuous | 30.0 years STANDARD_DEVIATION 17.44 | 49.9 years STANDARD_DEVIATION 18.27 | 52.7 years STANDARD_DEVIATION 16.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 21 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 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 | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 22 Participants | 19 Participants |
| Region of Enrollment United States | 3 Participants | 24 Participants | 21 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 17 Participants | 16 Participants |
| Weight | 92.93 kilogram (kg) STANDARD_DEVIATION 25.662 | 90.33 kilogram (kg) STANDARD_DEVIATION 25.272 | 89.96 kilogram (kg) STANDARD_DEVIATION 25.836 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 21 |
| other Total, other adverse events | 3 / 3 | 21 / 21 |
| serious Total, serious adverse events | 2 / 3 | 11 / 21 |
Outcome results
Primary
Mean Serum Concentrations of Vedolizumab That Helped the Likelihood of Alpha4Beta7 Target Saturation on Day 100 Following Allo-HSCT
Time frame: Day 100
Population: The pharmacokinetic (PK) population was defined as participants from the safety set with at least 1 PK sample collected. The PK population where data at specified time points was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Vedolizumab 75 mg | Mean Serum Concentrations of Vedolizumab That Helped the Likelihood of Alpha4Beta7 Target Saturation on Day 100 Following Allo-HSCT | 7.34 microgram per milliliter (mcg/mL) | Standard Deviation 3.762 |
| Cohort 2: Vedolizumab 300 mg | Mean Serum Concentrations of Vedolizumab That Helped the Likelihood of Alpha4Beta7 Target Saturation on Day 100 Following Allo-HSCT | 18.36 microgram per milliliter (mcg/mL) | Standard Deviation 11.043 |
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Up to 18 weeks after last dose of study drug
Population: The population of participants evaluable for vedolizumab safety was defined as all participants who received any amount of vedolizumab intravenously.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Vedolizumab 75 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 3 Participants |
| Cohort 1: Vedolizumab 75 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Cohort 2: Vedolizumab 300 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 21 Participants |
| Cohort 2: Vedolizumab 300 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 11 Participants |
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs)
DLTs was based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and was defined as any of following events: Grade 3 or higher toxicity assessed by the investigator as related to vedolizumab treatment; Grade 4 or higher regimen-related organ toxicities; and failure to engraft by Day +28. Engraftment was defined as absolute neutrophils count (ANC) greater than (\>) 500 per cubic millimeter (/mm\^3) for 3 consecutive days or \>2000/mm\^3 for 1 day.
Time frame: Baseline up to Day 28
Population: The population of participants evaluable for vedolizumab safety was defined as all participants who received any amount of vedolizumab intravenously.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Vedolizumab 75 mg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort 2: Vedolizumab 300 mg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Ctrough: Serum Concentration Before Dosing for Vedolizumab
Time frame: Days 13 and 42 pre-dose
Population: The PK population was defined as participants from the safety set with at least 1 PK sample collected. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Vedolizumab 75 mg | Ctrough: Serum Concentration Before Dosing for Vedolizumab | Day 13 | 5.87 mcg/mL | Standard Deviation 3 |
| Cohort 1: Vedolizumab 75 mg | Ctrough: Serum Concentration Before Dosing for Vedolizumab | Day 42 | 8.17 mcg/mL | Standard Deviation 5.2 |
| Cohort 2: Vedolizumab 300 mg | Ctrough: Serum Concentration Before Dosing for Vedolizumab | Day 13 | 21.34 mcg/mL | Standard Deviation 6.05 |
| Cohort 2: Vedolizumab 300 mg | Ctrough: Serum Concentration Before Dosing for Vedolizumab | Day 42 | 29.05 mcg/mL | Standard Deviation 13.04 |
Secondary
Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index
Maximum severity of acute GvHD was assessed by using BMT CTN modified IBMTR index. The severity index are defined as: Grade A (skin stage 1: extent of rash less than \[\<\] 25%); Grade B (skin stage 2: extent of rash 25 to 50% or liver stage 1 to 2: total bilirubin 34 to 102 micromole per liter \[mcmol/L\] or intestinal tract stage 1 to 2: volume of diarrhea 550 to 1500 milliliter per day \[mL/day\]); Grade C (skin stage 3: extent of rash greater than (\>) 50% or liver stage 3: total bilirubin 103 to 255 mcmol/L or intestinal tract stage 3: volume of diarrhea \>1500 mL/day); Grade D (skin stage 4: extent of rash bullae or liver stage 4: total bilirubin \>255 or intestinal tract stage 4: volume of diarrhea severe pain and ileus).
Time frame: Baseline up to Day 100
Population: The population of participants evaluable for vedolizumab safety was defined as all participants who received any amount of vedolizumab intravenously.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Grade A | 0 percentage of participants |
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Grade B | 66.7 percentage of participants |
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Grade C | 0 percentage of participants |
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Grade D | 0 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Grade D | 0 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Grade A | 19.0 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Grade C | 14.3 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index | Grade B | 14.3 percentage of participants |
Secondary
Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria
Maximum severity was assessed using GvHD grading scale based on the modified Glucksberg criteria. The grades are defined as: Grade 1 (skin stage 1 or 2 only); Grade 2 (skin stage 3 or liver stage 1 or lower or GI stage 1 or upper GI involvement); Grade 3 (skin stage 0 to 3 plus liver stage 2 to 4 or lower GI stage 2 to 3); Grade 4 (skin stage 4 or lower GI stage 4).
Time frame: Baseline up to Day 100
Population: The population of participants evaluable for vedolizumab safety was defined as all participants who received any amount of vedolizumab intravenously.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Grade 3 | 0 percentage of participants |
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Grade 2 | 0 percentage of participants |
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Grade 4 | 0 percentage of participants |
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Grade 1 | 66.7 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Grade 4 | 0 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Grade 2 | 14.3 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Grade 3 | 4.8 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria | Grade 1 | 28.6 percentage of participants |
Secondary
Percentage of Participants With Overall Grade 2 to 4 Acute Graft-Versus-Host Disease (GvHD)
GvHD grading scale was based on the modified Glucksberg criteria. The grades are defined as: Grade 1 (skin stage 1 or 2 only); Grade 2 (skin stage 3 or liver stage 1 or lower or gastrointestinal \[GI\] stage 1 or upper GI involvement); Grade 3 (skin stage 0 to 3 plus liver stage 2 to 4 or lower GI stage 2 to 3); Grade 4 (skin stage 4 or lower GI stage 4).
Time frame: Baseline up to Day 100
Population: The population of participants evaluable for vedolizumab safety was defined as all participants who received any amount of vedolizumab intravenously.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Vedolizumab 75 mg | Percentage of Participants With Overall Grade 2 to 4 Acute Graft-Versus-Host Disease (GvHD) | 0 percentage of participants |
| Cohort 2: Vedolizumab 300 mg | Percentage of Participants With Overall Grade 2 to 4 Acute Graft-Versus-Host Disease (GvHD) | 19.0 percentage of participants |
Secondary
Time to Neutrophil Engraftment
Time to neutrophil engraftment (recovery of ANC) was defined by an ANC \>500/mm\^3 for 3 consecutive days or \>2000/mm\^3 for 1 day. Time to neutrophil engraftment was calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.
Time frame: Baseline up to Day 100
Population: The population of participants evaluable for vedolizumab safety was defined as all participants who received any amount of vedolizumab intravenously.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Vedolizumab 75 mg | Time to Neutrophil Engraftment | 22 days |
| Cohort 2: Vedolizumab 300 mg | Time to Neutrophil Engraftment | 14 days |