Efficacy and Tolerability of Entospletinib in Combination With Systemic Corticosteroids as First-Line Therapy in Adults With Chronic Graft Versus Host Disease (cGVHD)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Tolerability of Entospletinib, a Selective SYK Inhibitor, in Combination With Systemic Corticosteroids as First-Line Therapy in Subjects With Chronic Graft Versus Host Disease (cGVHD)

Conditions
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Chronic Graft Versus Host Disease

Intervention / Treatment
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* Drug: ENTO
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ENTO<br>ENTO 400 mg or 200 mg tablet twice daily for 48 weeks | Drug: ENTO<br>* Tablets administered orally<br>* Other names: GS-9973;|
| Placebo Comparator: Placebo<br>Placebo to match tablet twice daily for 48 weeks | Drug: Placebo<br>* Tablets administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline; Week 24 | 
| 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. | Baseline; Week 24 | 
| 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. | Baseline; Week 24 | 
| 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. | Baseline; Week 24 | 
| 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. | Up to 48 weeks | 
| 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. | Baseline; Up to 48 weeks | 
| 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. | Up to 48 weeks | 
| 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. | Up to 48 weeks | 
| 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. | Up to 48 weeks plus 30 days | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SYK inhibitor, Chronic Graft Versus Host Disease (cGVHD), newly diagnosed cGVHD, immune reconstitution, Immune System Diseases, allogeneic stem cell transplantation