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

• ClinicalTrials.gov Identifier: NCT01799889
• Recruitment Status: Terminated
• First Posted: February 27, 2013
• Results First Posted: September 23, 2020
• Last Update Posted: September 23, 2020
• Sponsor: Gilead Sciences
• 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

• 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

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 :

1. 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 (Cheson, 2007) (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 (Cheson 2007) 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.
2. 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 (Cheson, 2007) (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 (Cheson 2007) 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 :

1. 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) ]
2. 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) ]
   The most severe graded abnormality was counted for each participant per test. ANC = absolute neutrophil count; Hb = hemoglobin; WBC = white blood cells
3. 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) ]
   The most severe graded abnormality was counted for each participant per test. ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase
4. Objective Response Rate (ORR), as Assessed by IRC Per Standardized Criteria (Cheson, 2007) (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 Cheson, 2007, 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.
5. Duration of Response (DOR), as Assessed by IRC Per Standardized Criteria (Cheson, 2007) (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 the earlier of first documentation of definitive disease progression or death from any cause. Per Cheson, 2007 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. Disease progression: as defined in Outcome measure 1. DOR was analyzed using KM estimates.
6. Time to Response (TTR), as Assessed by IRC Per Standardized Criteria (Cheson, 2007) (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 Cheson, 2007 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

• 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

Locations

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

• 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.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01799889
• Other Study ID Numbers: GS-US-339-0102
• First Posted: February 27, 2013
• Results First Posted: September 23, 2020
• Last Update Posted: September 23, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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