Steroid-Refractory Acute Graft Versus Host Disease
Conditions
Keywords
T-Guard, Ruxolitinib, Steroid-Refractory, GVHD, Acute GVHD, aGVHD, Grade III, Grade IV, Complete Response (CR), Transplant, Hematopoietic Stem Cell Transplant (HSCT)
Brief summary
This is an open-label, randomized, Phase 3, multicenter trial, which has been designed to compare the efficacy and safety of T-Guard to ruxolitinib in patients with Grade III or IV Steroid-Refractory acute Graft-Versus-Host Disease (SR-aGVHD). The primary hypothesis is that T-Guard treatment will improve the Day 28 complete response (CR) rate in patients with Grades III and IV SR-aGVHD compared to ruxolitinib.
Detailed description
Graft-vs-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) patients; it occurs when the new cells from a transplant attack the recipient's body. Acute GVHD (aGVHD) typically develops within the first three months after HSCT and is typically treated with steroid therapy. A significant fraction of the aGVHD population (10-50%) fail to respond to treatment and are deemed steroid-refractory (SR). Participants that develop Grade III or IV SR aGVHD will be randomized to receive T-Guard or ruxolitinib and will be followed for approximately 180 days. Participants will be stratified by center region (US vs. Europe) and age group (at least 55 years vs. under 55). Participants randomized to the T-Guard arm will receive 4 doses administered intravenously as four 4-hour infusions, and participants randomized to the ruxolitinib arm will receive one dose administered orally twice a day. The primary analysis will include all participants that are randomized.
Interventions
DRUGT-Guard
T-Guard will be administered intravenously inpatient over 4 hours every 2 calendar days on Days 0, 2, 4, and 6, at a dose of 4mg/m2 Body Surface Area (BSA).
DRUGRuxolitinib
Ruxolitinib will be administered orally twice a day starting on Day 0 through Day 56, at a dose of 10mg. Ruxolitinib taper can be initiated starting on Day 56 for participants responding to treatment, tapering will be done according to institutional practices.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Xenikos
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be randomized at a ratio of 1:1 between the treatment arms
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be eligible to participate in this study, patients must meet the following: 1. Patients must be at least 18.0 years of age at the time of consent. 2. Patient has undergone first allo-HSCT from any donor source or graft source. Recipients of nonmyeloablative, reduced intensity, and myeloablative conditioning regimens are eligible. 3. Patients diagnosed with Grade III/IV SR-aGVHD after allo-HSCT. SR includes aGVHD initially treated at a lower steroid dose, but must meet one of the following criteria: * Progressed or new organ involvement after 3 days of treatment with methylprednisolone (or equivalent) of greater than or equal to 2 mg/kg/day * No improvement after 7 days of primary treatment with methylprednisolone (or equivalent) of greater than or equal to 2mg/kg/day * Patients with visceral (GI and/or liver) plus skin aGVHD at methylprednisolone (or equivalent) initiation with improvement in skin GVHD without any improvement in visceral GVHD after 7 days of primary treatment with methylprednisolone (or equivalent) of greater than or equal to 2mg/kg/day * Patients who have skin GVHD alone and develop visceral aGVHD during treatment with methylprednisolone (or equivalent) of greater than or equal to 1mg/kg/day and do not improve after 3 days of greater than or equal to 2mg/kg/day Improvement or progression in organs is determined by comparing current organ staging to staging at initiation of methylprednisolone (or equivalent) treatment. 4. Patients must have evidence of myeloid engraftment (e.g., absolute neutrophil count greater than or equal to 0.5 × 109/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor supplementation is allowed. 5. Patients or an impartial witness (in case the patient is capable of providing verbal consent but not capable of signing the informed consent form (ICF)) should have given written informed consent.
Exclusion criteria
Patients will be excluded from study entry if they meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) | Day 28 | The primary objective of this trial is to assess the rate of CR on Day 28 post-randomization in Grades III and IV SR-aGVHD patients treated with T-Guard treatment in comparison to ruxolitinib. Participants were classified as Day 28 CR if these three conditions were satisfied: 1\. Stage 0 aGVHD (no remaining symptoms) in the three target organs skin, bowel and liver, 2 . The participant is still alive at Day 28, 3 . No additional systemic treatment for aGVHD has been administered through Day 28. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Day 180 | OS is defined as survival of death from any cause. The time from randomization until death from any cause will be described for each arm. |
| Duration of Complete Response (DoCR) | Day 28 | DoCR will be evaluated only in the set of participants who are in CR at Day 28 post-randomization. The primary definition of DoCR is the time from Day 28 until an aGVHD target organ worsens by at least 1 stage and requires a significant escalation in treatment, or death. |
Countries
Belgium, Croatia, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| T-Guard Participants will be administered four doses of T-Guard intravenously for a 4-hour period every other day
T-Guard: T-Guard will be administered intravenously inpatient over 4 hours every 2 calendar days on Days 0, 2, 4, and 6, at a dose of 4mg/m2 Body Surface Area (BSA). | 7 |
| Ruxolitinib Participants will take ruxolitinib twice daily for continuous daily dosing
Ruxolitinib: Ruxolitinib will be administered orally twice a day starting on Day 0 through Day 56, at a dose of 10mg. Ruxolitinib taper can be initiated starting on Day 56 for participants responding to treatment, tapering will be done according to institutional practices. | 5 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 0 |
| Overall Study | Lost to Follow-up | 1 | 4 |
Baseline characteristics
| Characteristic | Total | Ruxolitinib | T-Guard |
|---|---|---|---|
| Absolute neutrophil count (ANC) at or below 1000/µL | 1 Participants | 0 Participants | 1 Participants |
| Age 65 or above | 4 Participants | 1 Participants | 3 Participants |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 4 Participants | 4 Participants |
| Baseline serum albumin levels below 2 mg/dL | 7 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 4 Participants | 4 Participants |
| Grade IV steroid-refractory aGVHD (SR-aGVHD) at randomization | 1 Participants | 0 Participants | 1 Participants |
| Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) above 3 | 4 Participants | 1 Participants | 3 Participants |
| Region of Enrollment France | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Germany | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Netherlands | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 3 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 10 Participants | 4 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 7 | 1 / 5 |
| other Total, other adverse events | 7 / 7 | 5 / 5 |
| serious Total, serious adverse events | 5 / 7 | 2 / 5 |
Outcome results
Primary
Complete Response (CR)
The primary objective of this trial is to assess the rate of CR on Day 28 post-randomization in Grades III and IV SR-aGVHD patients treated with T-Guard treatment in comparison to ruxolitinib. Participants were classified as Day 28 CR if these three conditions were satisfied: 1\. Stage 0 aGVHD (no remaining symptoms) in the three target organs skin, bowel and liver, 2 . The participant is still alive at Day 28, 3 . No additional systemic treatment for aGVHD has been administered through Day 28.
Time frame: Day 28
Population: Intention to treat (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-Guard | Complete Response (CR) | 2 Participants |
| Ruxolitinib | Complete Response (CR) | 0 Participants |
Secondary
Duration of Complete Response (DoCR)
DoCR will be evaluated only in the set of participants who are in CR at Day 28 post-randomization. The primary definition of DoCR is the time from Day 28 until an aGVHD target organ worsens by at least 1 stage and requires a significant escalation in treatment, or death.
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-Guard | Duration of Complete Response (DoCR) | 2 Participants |
| Ruxolitinib | Duration of Complete Response (DoCR) | 0 Participants |
Secondary
Overall Survival (OS)
OS is defined as survival of death from any cause. The time from randomization until death from any cause will be described for each arm.
Time frame: Day 180
Population: Participants randomized to the treatment arms were analyzed. For both treatment arms, the number of participants who died are reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-Guard | Overall Survival (OS) | 4 Participants |
| Ruxolitinib | Overall Survival (OS) | 1 Participants |