Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacodynamics of Entospletinib in Adults With Relapsed or Refractory Hematologic Malignancies

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ClinicalTrials.gov Identifier: NCT01799889

Recruitment Status : Terminated (Sponsor's decision to discontinue development of entospletinib.)

First Posted : February 27, 2013

Results First Posted : September 23, 2020

Last Update Posted : November 19, 2020

Sponsor:

Information provided by (Responsible Party):

Gilead Sciences

Study Description

Brief Summary:

The primary objective of the study is to evaluate efficacy of entospletinib in participants with relapsed or refractory hematologic malignancies. Participants with the following relapsed or refractory hematologic malignancies will be enrolled into the study: relapsed or refractory chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or non-FL indolent non-Hodgkin lymphomas (iNHL; including lymphoplasmacytoid lymphoma/ Waldenström macroglobulinemia [LPL/WM], small lymphocytic lymphoma [SLL], or marginal zone lymphoma [MZL]).

Condition or disease	Intervention/treatment	Phase
Chronic Lymphocytic Leukemia Mantle Cell Lymphoma Diffuse Large B-cell Lymphoma Non-FL Indolent Non-Hodgkin's Lymphoma Follicular Lymphoma	Drug: Entospletinib MM Drug: Entospletinib SDD	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	326 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS-9973 in Subjects With Relapsed or Refractory Hematologic Malignancies
Actual Study Start Date :	March 14, 2013
Actual Primary Completion Date :	September 14, 2017
Actual Study Completion Date :	January 30, 2020

Resource links provided by the National Library of Medicine

Genetic and Rare Diseases Information Center resources: Lymphosarcoma Follicular Lymphoma B-cell Lymphoma Diffuse Large B-Cell Lymphoma Mantle Cell Lymphoma Chronic Lymphocytic Leukemia

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: CLL, Entospletinib MM/SDD Participants with CLL, receive original formulation (mono-mesylate [MM]) of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib (spray dried dispersion [SDD]) 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib MM Entospletinib MM tablet administered orally Other Name: GS-9973 Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: FL, Entospletinib MM/SDD Participants with FL, receive original formulation of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib MM Entospletinib MM tablet administered orally Other Name: GS-9973 Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: DLBCL, Entospletinib MM/SDD Participants with DLBCL, receive original formulation of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib MM Entospletinib MM tablet administered orally Other Name: GS-9973 Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: MCL, Entospletinib MM/SDD Participants with MCL, receive original formulation of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib MM Entospletinib MM tablet administered orally Other Name: GS-9973 Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: non-FL iNHL, Entospletinib MM/SDD Participants with non-FL iNHL (ie, participants with LPL/WM, SLL, or MZL), receive original formulation of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib MM Entospletinib MM tablet administered orally Other Name: GS-9973 Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: CLL; Prior BCR Inhibitor Naive, Entospletinib SDD 100 mg Participants with CLL, who are prior B-cell receptor (BCR) inhibitor naive, receive new formulation of entospletinib 100 mg (1 × 100 mg tablet) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: CLL; Prior BCR Inhibitor Naive, Entospletinib SDD 200 mg Participants with CLL, who are prior BCR inhibitor naive, receive new formulation of entospletinib 200 mg (1 × 200 mg tablet) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: CLL; Prior BCR Inhibitor Naive, Entospletinib SDD 400 mg Participants with CLL, who are prior BCR inhibitor naive, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: CLL (Non-Richters) Prior BTK Inhibitor, Entospletinib SDD Participants with CLL and simple progression (non-Richters), who are exposed to Bruton tyrosine kinase (BTK) inhibitor, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: CLL (Non-Richters) Prior PI3K Inhibitor, Entospletinib SDD Participants with CLL and simple progression (non-Richters), who are exposed to phosphatidylinositol 3-kinase (PI3K) inhibitor, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: CLL (Richters) Prior BTK Inhibitor, Entospletinib SDD Participants with CLL, who transform to Richters or Richters-like syndrome and are exposed to BTK inhibitor, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD
Experimental: CLL (Richters) Prior PI3K Inhibitor, Entospletinib SDD Participants with CLL, who transform to Richters or Richters-like syndrome and are exposed to PI3K inhibitor, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.	Drug: Entospletinib SDD Entospletinib SDD tablet administered orally Other Name: GS-9973 SDD

Outcome Measures

Primary Outcome Measures :

Progression-Free Survival (PFS) Rate of Participants With CLL After BCR Targeted Therapy, MCL, and DLBCL at Week 16 [ Time Frame: Week 16 ]
PFS rate was assessed by Independent Review Committee (IRC) and defined per standardized criteria (2007 Cheson criteria) (for NHL) and International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria (for CLL), as the percentage of participants not experiencing definitive progression or death. Disease progression was defined per standardized criteria as: evidence of any new disease; worsening of nodal or extra-nodal index lesions; unequivocal increase in the size of non-index lesions or non-measurable disease, size of the liver, spleen, or other organ; and a ≥ 25% increase from nadir in either monoclonal immunoglobulin M (IgM) concentration or total serum IgM quantitation. Disease progression was defined per standardized IWCLL criteria as: evidence of any new disease; worsening of index lesions, spleen or liver, or non-index disease; and decrease in platelet count or hemoglobin that is attributable to CLL. PFS rate was analyzed using Kaplan-Meier (KM) estimates.
PFS Rate of Participants With CLL (Including CLL, Prior BCR Inhibitor Naive Participants), FL, and Non-FL iNHL at Week 24 [ Time Frame: Week 24 ]
PFS rate was assessed by IRC and defined per standardized criteria (2007 Cheson criteria) (for NHL) and IWCLL criteria (for CLL), as the percentage of participants not experiencing definitive progression or death. Disease progression was defined per standardized criteria (2007 Cheson criteria) as: evidence of any new disease; worsening of nodal or extra-nodal index lesions; unequivocal increase in the size of non-index lesions or non-measurable disease, size of the liver, spleen, or other organ; and a ≥ 25% increase from nadir in either monoclonal IgM concentration or total serum IgM quantitation. Disease progression was defined per standardized IWCLL criteria as: evidence of any new disease; worsening of index lesions, spleen or liver, or non-index disease; and decrease in platelet count or hemoglobin that is attributable to CLL. PFS rate was analyzed using KM estimates.

Secondary Outcome Measures :

Percentage of Participants Experiencing Treatment-Emergent Adverse Events [ Time Frame: First dose date up to the last dose date plus 30 days (maximum: 78.4 months) ]
A treatment-emergent Adverse Event (AE) was defined as an AE that occurs in the period from the first dose of study treatment to 30 days after the last dose of study treatment or leads to discontinuation of study treatment. Participants were assessed for AEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
Percentage of Participants With Hematology Postbaseline Toxicity Grade 3 or Higher [ Time Frame: First dose date up to the last dose date plus 30 days (maximum: 78.4 months) ]
Hematology toxicity at any time postbaseline was summarized according to the NCI CTCAE, version 4.03. The most severe graded abnormality was counted for each participant per test.

ANC = absolute neutrophil count; Hb = hemoglobin; WBC = white blood cells
Percentage of Participants With Serum Chemistry Toxicity Postbaseline Grade 3 or Higher [ Time Frame: First dose date up to the last dose date plus 30 days (maximum: 78.4 months) ]
Serum chemistry toxicity at anytime postbaseline was summarized according to the NCI CTCAE, version 4.03. The most severe graded abnormality was counted for each participant per test. ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase
Objective Response Rate (ORR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL) [ Time Frame: From first dose date until first occurrence of CR or PR (or VGPR or MR for participants with LPL/WM) (up to approximately 7 years) ]
ORR: percentage of participants with complete response (CR) or partial response (PR) (or very good PR [VGPR] or minor response [MR] for participants with LPL/WM). Per 2007 Cheson criteria, CR: complete resolution of all disease-related radiological abnormalities; PR: ≥50% reduction in sum of products (SPD) of the longest diameters of all index lesions, no new lesions; VGPR: >90% decrease from baseline (DFB) in IgM, and other criteria for CR met; MR: ≥25% but <50% DFB in IgM, no increase from baseline (IFB) in SPD of lesions, no new lesions. Per IWCLL, CR: lymphocytes (Ly) <4*10^9/L, no lymphadenopathy, normal spleen and liver size, absence of disease, absolute neutrophil count (ANC) >1.5*10^9/L, platelets ≥100*10^9/L, hemoglobin (Hb) >110 g/L, bone marrow at least normocellular for age; PR: ≥2 of these: ≥50% decrease in Ly, lymphadenopathy, size of liver and spleen, bone marrow infiltrates; and ≥1 of these: ANC >1500/μL, platelets ≥100,000/µL, Hb >11 g/dL.
Duration of Response (DOR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL) [ Time Frame: From the date of first documentation of CR or PR (or VGPR or MR for participants with LPL/WM) to disease progression or death from any cause (up to approximately 7 years) ]
DOR was defined as the interval from first documentation of CR or PR (or VGPR or MR for participants with LPL/WM) to earlier of first documentation of definitive disease progression or death from any cause. Per 2007 Cheson criteria, CR: complete resolution of all disease-related radiological abnormalities; PR: ≥50% reduction in SPD of longest diameters of all index lesions, no new lesions; VGPR: >90% DFB in IgM, and other criteria for CR met; MR: ≥25% but <50% DFB in IgM, no IFB in SPD of lesions, no new lesions. Per IWCLL criteria, CR: Ly <4*10^9/L, no lymphadenopathy, normal spleen and liver size, absence of disease, ANC >1.5*10^9/L, platelets ≥100*10^9/L, Hb >110 g/L, bone marrow at least normocellular for age; PR: ≥2 of these: ≥50% decrease in Ly, lymphadenopathy, size of liver and spleen, bone marrow infiltrates; and ≥1 of these: ANC>1500/μL, platelets ≥100,000/µL, Hb >11 g/dL. Disease progression: as defined in Outcome measure 1. DOR was analyzed using KM estimates.
Time to Response (TTR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL) [ Time Frame: From the first dose of study drug to the first documentation of CR or PR (or VGPR or MR for participants with LPL/WM) (up to approximately 7 years) ]
TTR was defined as the interval from the first dose of study drug to the first documentation of CR or PR (or VGPR or MR for participants with LPL/WM). Per 2007 Cheson criteria, CR: complete resolution of all disease-related radiological abnormalities; PR: ≥ 50% reduction in SPD of the longest diameters of all index lesions, no new lesions; VGPR: >90% DFB in IgM, and other criteria for CR met; MR: ≥25% but <50% DFB in IgM, no IFB in SPD of lesions, no new lesions. Per IWCLL criteria, CR: Ly <4*10^9/L, no lymphadenopathy, normal spleen and liver size, absence of disease, ANC >1.5*10^9/L, platelets ≥100*10^9/L, Hb >110 g/L, bone marrow at least normocellular for age; PR: ≥2 of these: ≥50% decrease in Ly, lymphadenopathy, size of liver and spleen, bone marrow infiltrates; and ≥1 of these: ANC >1500/μL, platelets ≥100,000/µL, Hb >11 g/dL.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Key Inclusion Criteria:

Diagnosis of B-cell iNHL, DLBCL, MCL, or CLL as documented by medical records and with histology based on criteria established by the World Health Organization
For institutions that have Phase 3 or Phase 4 protocols studying idelalisib (Zydelig®) ; individuals with malignancies being studied in these protocols must have failed screening in the respective idelalisib protocol
Prior treatment for lymphoid malignancy requiring treatment for progressive disease
Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy
All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of study drug
Karnofsky performance status of ≥ 60
Life expectancy of at least 3 months

Key Exclusion Criteria:

Known histological transformation from iNHL or CLL to an aggressive form of non-Hodgkin lymphoma (ie, Richter transformation) except if the CLL participant is enrolling in the BCR previously treated cohort
Known active central nervous system or leptomeningeal lymphoma
Presence of known intermediate- or high-grade myelodysplastic syndrome
Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of start of study drug
Ongoing liver injury
Ongoing or recent hepatic encephalopathy
Ongoing drug-induced pneumonitis
Ongoing inflammatory bowel disease
Ongoing alcohol or drug addiction
Pregnancy or breastfeeding
History of prior allogeneic bone marrow progenitor cell or solid organ transplantation
Ongoing immunosuppressive therapy
Concurrent participation in an investigational drug trial with therapeutic intent

NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01799889

Locations

Show 48 study locations

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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, Arizona
Arizona Oncology Associates
Tucson, Arizona, United States, 85710
United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010
Sharp Memorial Hospital
San Diego, California, United States, 92123
United States, Colorado
Rocky Mountain Cancer Centers, LLP
Boulder, Colorado, United States, 80303
Kaiser Permanente of Colorado
Denver, Colorado, United States, 80218
United States, Connecticut
Cancer Center of Central Connecticut
Southington, Connecticut, United States, 06489
United States, Florida
Florida Cancer - Colonial
Fort Myers, Florida, United States, 33905
Memorial Cancer Institute
Hollywood, Florida, United States, 33021
Ocala Oncology Center
Ocala, Florida, United States, 34471
United States, Georgia
Northside Hospital
Atlanta, Georgia, United States, 30341
Gwinnett Hospital System Dba The Center for Cancer Care
Lawrenceville, Georgia, United States, 30046
Northwest Georgia Oncology Center
Marietta, Georgia, United States, 30060
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
Illinois Cancer Specialists
Niles, Illinois, United States, 60714
United States, Indiana
Indiana University Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Louisiana
Hematology Oncology Clinic, PLLC
Baton Rouge, Louisiana, United States, 70809
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
United States, Michigan
University of Michigan Health System
Ann Arbor, Michigan, United States, 48109
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Minnesota
Minnesota Oncology Hematology, PA
Minneapolis, Minnesota, United States, 55404
United States, Mississippi
Hattiesburg Clinic
Hattiesburg, Mississippi, United States, 39401
United States, Nebraska
Oncology Hematology West PC dba Nebraska Cancer Specialists
Omaha, Nebraska, United States, 68130
United States, New Hampshire
One Medical Center Drive
Lebanon, New Hampshire, United States, 03756
United States, New Jersey
Summit Medical Group, P.A.
Florham Park, New Jersey, United States, 07932
United States, New York
Clinical Research Alliance
New York, New York, United States, 10021
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Gabrail Cancer Center Research
Canton, Ohio, United States, 44718
Oncology Hematology Care
Cincinnati, Ohio, United States, 45242
Cleveland Clinic
Cleveland, Ohio, United States, 44195
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Oregon
Williamette Valley Cancer Center and Research Institute
Springfield, Oregon, United States, 97477
United States, South Dakota
Prairie Lakes Health Care System, Inc.
Watertown, South Dakota, United States, 57201
United States, Tennessee
Jones Clinic PC
Germantown, Tennessee, United States, 38138
Tennessee Oncology, PLLC
Nashville, Tennessee, United States, 37203
United States, Texas
Texas Oncology-Austin Midtown
Austin, Texas, United States, 78705
Texas Oncology-Medical City Dallas
Dallas, Texas, United States, 75230
Center for Cancer and Blood Disorders
Fort Worth, Texas, United States, 76104
Cancer Care Network of South Texas
San Antonio, Texas, United States, 78217
Cancer Care Center of South Texas
San Antonio, Texas, United States, 78229
United States, Virginia
Virginia Cancer Specialists, PC
Fairfax, Virginia, United States, 22031
Virginia Cancer Institute
Richmond, Virginia, United States, 23226
United States, Washington
Columbia Basin Hematology and Oncology
Kennewick, Washington, United States, 99336
University of Washington
Seattle, Washington, United States, 98109
Northwest Cancer Specialists, PC
Vancouver, Washington, United States, 98684
Yakima Valley Memorial Hospital North Star Lodge
Yakima, Washington, United States, 98902
Canada, Ontario
Royal Victoria Regional Health Centre
Barrie, Ontario, Canada, L4M 6M2
Canada, Quebec
Sir Mortimer B. Davis-Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2

Sponsors and Collaborators

Gilead Sciences

Investigators

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Study Director:	Gilead Study Director	Gilead Sciences

Study Documents (Full-Text)

Documents provided by Gilead Sciences:

Study Protocol [PDF] March 31, 2017

Statistical Analysis Plan [PDF] September 16, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Sharman J, Hawkins M, Kolibaba K, Boxer M, Klein L, Wu M, Hu J, Abella S, Yasenchak C. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2015 Apr 9;125(15):2336-43. doi: 10.1182/blood-2014-08-595934. Epub 2015 Feb 18.

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Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT01799889
Other Study ID Numbers:	GS-US-339-0102
First Posted:	February 27, 2013 Key Record Dates
Results First Posted:	September 23, 2020
Last Update Posted:	November 19, 2020
Last Verified:	November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Gilead Sciences:


SYK inhibitor

Additional relevant MeSH terms:

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Lymphoma Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Mantle-Cell Lymphoma, Large B-Cell, Diffuse Hematologic Neoplasms Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases	Immunoproliferative Disorders Immune System Diseases Lymphoma, Non-Hodgkin Leukemia, Lymphoid Leukemia Leukemia, B-Cell Lymphoma, B-Cell Neoplasms by Site Hematologic Diseases

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