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
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Condition or disease | Intervention/treatment | Phase |
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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 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 |

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.
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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 |
- 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.
- 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.

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

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

Study Director: | Gilead Study Director | Gilead Sciences |
Documents provided by Gilead Sciences:
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 |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
SYK inhibitor |
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 Lymphoma, B-Cell Leukemia, B-Cell Neoplasms by Site Hematologic Diseases |