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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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 : September 23, 2020
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

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

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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


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




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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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.


Information from the National Library of Medicine

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 Show 48 study locations
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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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: September 23, 2020
Last Verified: September 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