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

Primary Purpose

Chronic Graft Versus Host Disease

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ENTO
Placebo
Sponsored by
Gilead Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Graft Versus Host Disease focused on measuring Chronic Graft Versus Host Disease (cGVHD), newly diagnosed cGVHD, immune reconstitution, Immune System Diseases, allogeneic stem cell transplantation, SYK inhibitor

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Miami
  • Emory University
  • Loyola University Medical Center
  • University of Kansas Cancer Center
  • Weill Cornell Medical Center
  • Duke University Medical Center
  • Taussig Cancer Institute
  • Ohio State University, Wexner Medical Center
  • Vanderbilt University
  • Princess Margaret
  • Institut Paoli Calmettes
  • Hopital Saint Louis
  • Institut Gustave Roussy
  • Universitätsklinikum Carl Gustav Carus
  • Universitatsklinikum Frankfurt
  • Universitatsklinikum Hamburg-Eppendorf
  • Klinikum der Universitaet Regensburg
  • Pusan National University Hospital
  • Samsung Medical Center
  • Severance Hospital, Yonsei University Health System
  • Hospital Universitario Vall d'Hebron
  • Hospital General Universitario Gregorio Marañon
  • Hospital Universitario de Salamanca
  • Hospital Universitario Marques de Valdecilla
  • Hospital Universitario Virgen del Rocio
  • Hospital Universitario La Fe
  • Hospital Clinico Universitario de Valencia
  • Kings College Hospital NHS Trust
  • St Bartholomew's Hospital
  • Manchester Royal Infirmary

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ENTO

Placebo

Arm Description

ENTO 400 mg or 200 mg tablet twice daily for 48 weeks

Placebo to match tablet twice daily for 48 weeks

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities

Full Information

First Posted
February 24, 2016
Last Updated
December 5, 2018
Sponsor
Gilead Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT02701634
Brief Title
Efficacy and Tolerability of Entospletinib in Combination With Systemic Corticosteroids as First-Line Therapy in Adults With Chronic Graft Versus Host Disease (cGVHD)
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Terminated
Study Start Date
May 27, 2016 (Actual)
Primary Completion Date
December 19, 2017 (Actual)
Study Completion Date
March 6, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Graft Versus Host Disease
Keywords
Chronic Graft Versus Host Disease (cGVHD), newly diagnosed cGVHD, immune reconstitution, Immune System Diseases, allogeneic stem cell transplantation, SYK inhibitor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
66 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ENTO
Arm Type
Experimental
Arm Description
ENTO 400 mg or 200 mg tablet twice daily for 48 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo to match tablet twice daily for 48 weeks
Intervention Type
Drug
Intervention Name(s)
ENTO
Other Intervention Name(s)
GS-9973
Intervention Description
Tablets administered orally
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Tablets administered orally
Primary Outcome Measure Information:
Title
Best Overall Response Rate
Description
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
Secondary Outcome Measure Information:
Title
Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks
Description
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
Title
Change From Baseline in the Mouth Domain of the LSS at 24 Weeks
Description
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
Title
Change From Baseline in the Eyes Domain of the LSS at 24 Weeks
Description
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
Title
Change From Baseline in the Total Score of the LSS at 24 Weeks
Description
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
Title
Duration of Response
Description
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
Title
Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline
Description
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
Title
Percentage of Participants Who Initiate Second-Line Therapy for cGVHD
Description
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
Title
Failure-Free Survival
Description
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
Title
Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs)
Description
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
Title
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
Time Frame
Up to 48 weeks plus 30 days
Title
Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities
Time Frame
Up to 48 weeks plus 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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/Exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
Facility Name
University of Miami
City
Miami
State/Province
Florida
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
Country
United States
Facility Name
Loyola University Medical Center
City
Maywood
State/Province
Illinois
Country
United States
Facility Name
University of Kansas Cancer Center
City
Westwood
State/Province
Kansas
Country
United States
Facility Name
Weill Cornell Medical Center
City
New York
State/Province
New York
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
Country
United States
Facility Name
Taussig Cancer Institute
City
Cleveland
State/Province
Ohio
Country
United States
Facility Name
Ohio State University, Wexner Medical Center
City
Columbus
State/Province
Ohio
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
Country
United States
Facility Name
Princess Margaret
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
Institut Paoli Calmettes
City
Marseille, Cedex 9
Country
France
Facility Name
Hopital Saint Louis
City
Paris Cedex 10
Country
France
Facility Name
Institut Gustave Roussy
City
Villejuif
Country
France
Facility Name
Universitätsklinikum Carl Gustav Carus
City
Dresden
Country
Germany
Facility Name
Universitatsklinikum Frankfurt
City
Frankfurt am Main
ZIP/Postal Code
60590
Country
Germany
Facility Name
Universitatsklinikum Hamburg-Eppendorf
City
Hamburg
Country
Germany
Facility Name
Klinikum der Universitaet Regensburg
City
Regensburg
Country
Germany
Facility Name
Pusan National University Hospital
City
Busan
Country
Korea, Republic of
Facility Name
Samsung Medical Center
City
Seoul
Country
Korea, Republic of
Facility Name
Severance Hospital, Yonsei University Health System
City
Seoul
Country
Korea, Republic of
Facility Name
Hospital Universitario Vall d'Hebron
City
Barcelona
Country
Spain
Facility Name
Hospital General Universitario Gregorio Marañon
City
Madrid
Country
Spain
Facility Name
Hospital Universitario de Salamanca
City
Salamanca
Country
Spain
Facility Name
Hospital Universitario Marques de Valdecilla
City
Santander
ZIP/Postal Code
39008
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocio
City
Sevilla
Country
Spain
Facility Name
Hospital Universitario La Fe
City
Valencia
ZIP/Postal Code
46009
Country
Spain
Facility Name
Hospital Clinico Universitario de Valencia
City
Valencia
Country
Spain
Facility Name
Kings College Hospital NHS Trust
City
London
Country
United Kingdom
Facility Name
St Bartholomew's Hospital
City
London
Country
United Kingdom
Facility Name
Manchester Royal Infirmary
City
Manchester
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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