Chronic Graft Versus Host Disease
Conditions
Keywords
Chronic Graft Versus Host Disease (cGVHD), newly diagnosed cGVHD, immune reconstitution, Immune System Diseases, allogeneic stem cell transplantation, SYK inhibitor
Brief summary
The primary objective of this study is to evaluate the effect of entospletinib (ENTO) on the best overall response rate in adults with chronic graft versus host disease (cGVHD) who are currently receiving systemic corticosteroids as part of first-line therapy for cGVHD.
Interventions
DRUGENTO
Tablets administered orally
DRUGPlacebo
Tablets administered orally
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Willing and able to provide written informed consent * Male or non-pregnant, non-lactating, females * Newly diagnosed cGVHD defined by: * At least 100 days after receiving any allogeneic hematopoietic stem cell transplant AND * Receiving a new course of systemic corticosteroids (≥ 0.5 mg/kg/day) as first-line cGVHD therapy at least 1 day and no more than 21 days prior to first dose of ENTO/Placebo AND * Moderate to severe cGVHD as assessed by NIH cGVHD Diagnosis and Staging Criteria (NCDSC) with at least three organ systems involved OR one organ system with a score of 2 OR lung organ score = 1 * Individuals who have undergone transplant for hematologic malignancy are required to be in complete remission. * Have either a normal ECG or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the Sponsor Key
Exclusion criteria
* Inability to begin systemic corticosteroids therapy at a dose of ≥ 0.5 mg/kg/day (or equivalent) * Uncontrolled infection within 4 weeks prior to randomization * History of the following therapies in the post-transplant period: * B cell depleting biologic agents * CD19 CAR-T cells based therapies * BTK/SYK/JAK/PI3K inhibitors * Phototherapy-unless administered for acute GVHD * Treatment of cGVHD with anti-thymocyte globulins (ATG), or campath within 60 days of screening visit unless used for treatment of acute GVHD * Severe organ dysfunction manifested during screening period: * Requiring supplemental oxygen at more than 2 L/min * Uncontrolled arrhythmia or heart failure Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate | Up to 24 weeks | Best overall response rate by 24 weeks was defined as the proportion of participants who achieved a complete or partial overall response as assessed by the NIH cGVHD Activity Assessment (NCAA) within 24 weeks, in the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for cGVHD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Mouth Domain of the LSS at 24 Weeks | Baseline; Week 24 | The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome. |
| Change From Baseline in the Eyes Domain of the LSS at 24 Weeks | Baseline; Week 24 | The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome. |
| Change From Baseline in the Total Score of the LSS at 24 Weeks | Baseline; Week 24 | The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. The total score was calculated by taking the average of the subscale scores. A decrease from baseline value correlates with improvement in clinical outcome. |
| Duration of Response | Up to 48 weeks | Duration of response was defined as the time from the documentation of best overall response rate to the documentation of progressive disease. Note that flare was not considered as progressive disease in this analysis. |
| Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline | Baseline; Up to 48 weeks | The percentage reduction was calculated as (systemic corticosteroid dose post baseline - baseline systemic corticosteroid dose) / baseline systemic corticosteroid dose. |
| Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks | Baseline; Week 24 | The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome. |
| Failure-Free Survival | Up to 48 weeks | Failure-free survival was defined as the time from randomization to the earliest of first documentation of systemic therapy change, nonrelapse mortality, or recurrent malignancy. |
| Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs) | Up to 48 weeks plus 30 days | Treatment-emergent adverse events are defined as 1 or both of the following: 1) any AEs with an onset on or after study drug or placebo start date and no later than earlier of 30 days after permanent discontinuation of study drug or placebo, 2) any AEs leading to premature discontinuation of study drug or placebo. |
| Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | Up to 48 weeks plus 30 days | — |
| Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities | Up to 48 weeks plus 30 days | — |
| Percentage of Participants Who Initiate Second-Line Therapy for cGVHD | Up to 48 weeks | Second-line therapy for cGVHD was defined as receiving any therapy besides systemic corticosteroids or study drug for the treatment of cGVHD. Inhaled and topical steroids are not considered second-line therapy. |
Countries
Canada, France, Germany, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Europe, Asia, Canada, and United States. The first participant was screened on 27 May 2016. The last study visit occurred on 06 Mar 2018.
Pre-assignment details
89 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| ENTO ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy | 33 |
| Placebo Placebo to match ENTO tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Investigator's Discretion | 7 | 4 |
| Overall Study | Randomized but not treated | 1 | 0 |
| Overall Study | Study terminated by Sponsor | 15 | 17 |
| Overall Study | Withdrew Consent | 6 | 7 |
Baseline characteristics
| Characteristic | ENTO | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 11.9 | 58 years STANDARD_DEVIATION 11.4 | 54 years STANDARD_DEVIATION 12.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 28 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized Asian | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized Not Permitted | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized White | 23 Participants | 29 Participants | 52 Participants |
| Region of Enrollment Canada | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment France | 5 Participants | 3 Participants | 8 Participants |
| Region of Enrollment Germany | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment South Korea | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Spain | 7 Participants | 10 Participants | 17 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment United States | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Female | 14 Participants | 13 Participants | 27 Participants |
| Sex: Female, Male Male | 19 Participants | 20 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 32 | 0 / 33 |
| other Total, other adverse events | 31 / 32 | 30 / 33 |
| serious Total, serious adverse events | 15 / 32 | 11 / 33 |
Outcome results
Primary
Best Overall Response Rate
Best overall response rate by 24 weeks was defined as the proportion of participants who achieved a complete or partial overall response as assessed by the NIH cGVHD Activity Assessment (NCAA) within 24 weeks, in the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for cGVHD.
Time frame: Up to 24 weeks
Population: ITT Analysis Set: all participants who were randomized into the study. Data was analyzed according to treatment randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO | Best Overall Response Rate | 72.7 Percentage of participants |
| Placebo | Best Overall Response Rate | 72.7 Percentage of participants |
p-value: 0.99Chi-squared
Secondary
Change From Baseline in the Eyes Domain of the LSS at 24 Weeks
The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.
Time frame: Baseline; Week 24
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ENTO | Change From Baseline in the Eyes Domain of the LSS at 24 Weeks | Baseline | 29.4 units on a scale | Standard Deviation 27.52 |
| ENTO | Change From Baseline in the Eyes Domain of the LSS at 24 Weeks | Change at Week 24 | 10.2 units on a scale | Standard Deviation 21.56 |
| Placebo | Change From Baseline in the Eyes Domain of the LSS at 24 Weeks | Baseline | 21.4 units on a scale | Standard Deviation 24.22 |
| Placebo | Change From Baseline in the Eyes Domain of the LSS at 24 Weeks | Change at Week 24 | -1.4 units on a scale | Standard Deviation 31.32 |
Secondary
Change From Baseline in the Mouth Domain of the LSS at 24 Weeks
The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.
Time frame: Baseline; Week 24
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ENTO | Change From Baseline in the Mouth Domain of the LSS at 24 Weeks | Baseline | 15.2 units on a scale | Standard Deviation 18.17 |
| ENTO | Change From Baseline in the Mouth Domain of the LSS at 24 Weeks | Change at Week 24 | -4.2 units on a scale | Standard Deviation 16.54 |
| Placebo | Change From Baseline in the Mouth Domain of the LSS at 24 Weeks | Baseline | 16.8 units on a scale | Standard Deviation 21.21 |
| Placebo | Change From Baseline in the Mouth Domain of the LSS at 24 Weeks | Change at Week 24 | -1.4 units on a scale | Standard Deviation 25.34 |
Secondary
Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks
The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.
Time frame: Baseline; Week 24
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ENTO | Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks | Baseline | 15.0 units on a scale | Standard Deviation 21.92 |
| ENTO | Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks | Change at Week 24 | -3.3 units on a scale | Standard Deviation 10.31 |
| Placebo | Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks | Baseline | 19.8 units on a scale | Standard Deviation 22.34 |
| Placebo | Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks | Change at Week 24 | -9.4 units on a scale | Standard Deviation 14.24 |
Secondary
Change From Baseline in the Total Score of the LSS at 24 Weeks
The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. The total score was calculated by taking the average of the subscale scores. A decrease from baseline value correlates with improvement in clinical outcome.
Time frame: Baseline; Week 24
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ENTO | Change From Baseline in the Total Score of the LSS at 24 Weeks | Baseline | 16.0 score on a scale | Standard Deviation 9.74 |
| ENTO | Change From Baseline in the Total Score of the LSS at 24 Weeks | Change at Week 24 | -0.5 score on a scale | Standard Deviation 8.35 |
| Placebo | Change From Baseline in the Total Score of the LSS at 24 Weeks | Baseline | 14.7 score on a scale | Standard Deviation 8.51 |
| Placebo | Change From Baseline in the Total Score of the LSS at 24 Weeks | Change at Week 24 | -5.4 score on a scale | Standard Deviation 8.54 |
Secondary
Duration of Response
Duration of response was defined as the time from the documentation of best overall response rate to the documentation of progressive disease. Note that flare was not considered as progressive disease in this analysis.
Time frame: Up to 48 weeks
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ENTO | Duration of Response | 26.3 weeks |
| Placebo | Duration of Response | 32.0 weeks |
p-value: 0.67Log Rank
Secondary
Failure-Free Survival
Failure-free survival was defined as the time from randomization to the earliest of first documentation of systemic therapy change, nonrelapse mortality, or recurrent malignancy.
Time frame: Up to 48 weeks
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ENTO | Failure-Free Survival | 99.0 Days |
| Placebo | Failure-Free Survival | 85.0 Days |
p-value: 0.895% CI: [0.55, 2.18]Log Rank
Secondary
Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline
The percentage reduction was calculated as (systemic corticosteroid dose post baseline - baseline systemic corticosteroid dose) / baseline systemic corticosteroid dose.
Time frame: Baseline; Up to 48 weeks
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO | Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline | 72.7 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline | 63.6 Percentage of participants |
p-value: 0.33t-test, 2 sided
Secondary
Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs)
Treatment-emergent adverse events are defined as 1 or both of the following: 1) any AEs with an onset on or after study drug or placebo start date and no later than earlier of 30 days after permanent discontinuation of study drug or placebo, 2) any AEs leading to premature discontinuation of study drug or placebo.
Time frame: Up to 48 weeks plus 30 days
Population: Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO | Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs) | 96.9 Percentage of participants |
| Placebo | Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs) | 97.0 Percentage of participants |
Secondary
Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities
Time frame: Up to 48 weeks plus 30 days
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO | Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities | 100.0 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities | 100.0 Percentage of participants |
Secondary
Percentage of Participants Who Initiate Second-Line Therapy for cGVHD
Second-line therapy for cGVHD was defined as receiving any therapy besides systemic corticosteroids or study drug for the treatment of cGVHD. Inhaled and topical steroids are not considered second-line therapy.
Time frame: Up to 48 weeks
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO | Percentage of Participants Who Initiate Second-Line Therapy for cGVHD | 9.1 Percentage of participants |
| Placebo | Percentage of Participants Who Initiate Second-Line Therapy for cGVHD | 15.2 Percentage of participants |
p-value: 0.49t-test, 2 sided
Secondary
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
Time frame: Up to 48 weeks plus 30 days
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO | Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | 12.5 Percentage of participants |
| Placebo | Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | 12.1 Percentage of participants |