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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Graft Versus Host Disease
• Intervention / Treatment: Drug: Placebo; Drug: ENTO

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Princess Margaret
• France
  • Marseille, Cedex 9, France
    • Institut Paoli Calmettes
  • Paris Cedex 10, France
    • Hopital Saint Louis
  • Villejuif, France
    • Institut Gustave Roussy
• Germany
  • Dresden, Germany
    • Universitätsklinikum Carl Gustav Carus
  • Frankfurt am Main, Germany, 60590
    • Universitatsklinikum Frankfurt
  • Hamburg, Germany
    • Universitatsklinikum Hamburg-Eppendorf
  • Regensburg, Germany
    • Klinikum der Universitaet Regensburg
• Korea, Republic of
  • Busan, Korea, Republic of
    • Pusan National University Hospital
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Severance Hospital, Yonsei University Health System
• Spain
  • Barcelona, Spain
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain
    • Hospital General Universitario Gregorio Maranon
  • Salamanca, Spain
    • Hospital Universitario de Salamanca
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Sevilla, Spain
    • Hospital Universitario Virgen Del Rocio
  • Valencia, Spain, 46009
    • Hospital Universitario La Fe
  • Valencia, Spain
    • Hospital Clínico Universitario de Valencia
• United Kingdom
  • London, United Kingdom
    • St Bartholomew'S Hospital
  • London, United Kingdom
    • Kings College Hospital NHS Trust
  • Manchester, United Kingdom
    • Manchester Royal Infirmary
• United States
  • Florida
    • Miami, Florida, United States
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States
      • Emory University
  • Illinois
    • Maywood, Illinois, United States
      • Loyola University Medical Center
  • Kansas
    • Westwood, Kansas, United States
      • University of Kansas Cancer Center
  • New York
    • New York, New York, United States
      • Weill Cornell Medical Center
  • North Carolina
    • Durham, North Carolina, United States
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States
      • Taussig Cancer Institute
    • Columbus, Ohio, United States
      • Ohio State University, Wexner Medical Center
  • Tennessee
    • Nashville, Tennessee, United States
      • Vanderbilt University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2016
• Primary Completion (Actual): December 19, 2017
• Study Completion (Actual): March 6, 2018

Study Registration Dates

• First Submitted: February 24, 2016
• First Submitted That Met QC Criteria: March 2, 2016
• First Posted (Estimate): March 8, 2016

Study Record Updates

• Last Update Posted (Actual): December 26, 2018
• Last Update Submitted That Met QC Criteria: December 5, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Immune System Diseases; immune reconstitution; allogeneic stem cell transplantation; Chronic Graft Versus Host Disease (cGVHD); newly diagnosed cGVHD; SYK inhibitor
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: GS-US-406-1840; 2015-004572-30 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No