Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacodynamics of Entospletinib in Adults With Relapsed or Refractory Hematologic Malignancies
- Conditions
- Mantle Cell LymphomaDiffuse Large B-cell LymphomaNon-FL Indolent Non-Hodgkin's LymphomaFollicular LymphomaChronic Lymphocytic Leukemia
- Interventions
- Registration Number
- NCT01799889
- Lead Sponsor
- 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 \[MZL\]).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 326
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description MCL, Entospletinib MM/SDD Entospletinib MM 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. MCL, Entospletinib MM/SDD Entospletinib 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. CLL; Prior BCR Inhibitor Naive, Entospletinib SDD 200 mg Entospletinib SDD 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. CLL (Non-Richters) Prior BTK Inhibitor, Entospletinib SDD 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. CLL, Entospletinib MM/SDD Entospletinib 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. FL, Entospletinib MM/SDD Entospletinib 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. non-FL iNHL, Entospletinib MM/SDD Entospletinib MM 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. DLBCL, Entospletinib MM/SDD Entospletinib 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. non-FL iNHL, Entospletinib MM/SDD Entospletinib 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. CLL; Prior BCR Inhibitor Naive, Entospletinib SDD 100 mg Entospletinib SDD 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. CLL (Richters) Prior PI3K Inhibitor, Entospletinib SDD 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. CLL (Non-Richters) Prior PI3K Inhibitor, Entospletinib SDD 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. CLL (Richters) Prior BTK Inhibitor, Entospletinib SDD 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. CLL, Entospletinib MM/SDD Entospletinib MM 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. FL, Entospletinib MM/SDD Entospletinib MM 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. CLL; Prior BCR Inhibitor Naive, Entospletinib SDD 400 mg Entospletinib SDD 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. DLBCL, Entospletinib MM/SDD Entospletinib MM 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.
- Primary Outcome Measures
Name Time Method PFS Rate of Participants With CLL (Including CLL, Prior BCR Inhibitor Naive Participants), FL, and Non-FL iNHL at Week 24 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.
Progression-Free Survival (PFS) Rate of Participants With CLL After BCR Targeted Therapy, MCL, and DLBCL at Week 16 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Hematology Postbaseline Toxicity Grade 3 or Higher 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 cellsPercentage of Participants With Serum Chemistry Toxicity Postbaseline Grade 3 or Higher 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
Percentage of Participants Experiencing Treatment-Emergent Adverse Events 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.
Objective Response Rate (ORR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL) 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) 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) 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.
Trial Locations
- Locations (48)
Memorial Cancer Institute
🇺🇸Hollywood, Florida, United States
Northside Hospital
🇺🇸Atlanta, Georgia, United States
University of Chicago
🇺🇸Chicago, Illinois, United States
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
Hematology Oncology Clinic, PLLC
🇺🇸Baton Rouge, Louisiana, United States
Hattiesburg Clinic
🇺🇸Hattiesburg, Mississippi, United States
Sir Mortimer B. Davis-Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Arizona Oncology Associates
🇺🇸Tucson, Arizona, United States
Cancer Center of Central Connecticut
🇺🇸Southington, Connecticut, United States
Rocky Mountain Cancer Centers, LLP
🇺🇸Boulder, Colorado, United States
Florida Cancer - Colonial
🇺🇸Fort Myers, Florida, United States
Ocala Oncology Center
🇺🇸Ocala, Florida, United States
Northwest Georgia Oncology Center
🇺🇸Marietta, Georgia, United States
Gwinnett Hospital System Dba The Center for Cancer Care
🇺🇸Lawrenceville, Georgia, United States
Illinois Cancer Specialists
🇺🇸Niles, Illinois, United States
Summit Medical Group, P.A.
🇺🇸Florham Park, New Jersey, United States
Clinical Research Alliance
🇺🇸New York, New York, United States
Gabrail Cancer Center Research
🇺🇸Canton, Ohio, United States
Williamette Valley Cancer Center and Research Institute
🇺🇸Springfield, Oregon, United States
Jones Clinic PC
🇺🇸Germantown, Tennessee, United States
Texas Oncology-Austin Midtown
🇺🇸Austin, Texas, United States
Texas Oncology-Medical City Dallas
🇺🇸Dallas, Texas, United States
Center for Cancer and Blood Disorders
🇺🇸Fort Worth, Texas, United States
Virginia Cancer Specialists, PC
🇺🇸Fairfax, Virginia, United States
Virginia Cancer Institute
🇺🇸Richmond, Virginia, United States
Columbia Basin Hematology and Oncology
🇺🇸Kennewick, Washington, United States
Yakima Valley Memorial Hospital North Star Lodge
🇺🇸Yakima, Washington, United States
Northwest Cancer Specialists, PC
🇺🇸Vancouver, Washington, United States
Royal Victoria Regional Health Centre
🇨🇦Barrie, Ontario, Canada
Kaiser Permanente of Colorado
🇺🇸Denver, Colorado, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
University of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States
Sharp Memorial Hospital
🇺🇸San Diego, California, United States
Indiana University Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Oncology Hematology Care
🇺🇸Cincinnati, Ohio, United States
Cancer Care Network of South Texas
🇺🇸San Antonio, Texas, United States
Minnesota Oncology Hematology, PA
🇺🇸Minneapolis, Minnesota, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Oncology Hematology West PC dba Nebraska Cancer Specialists
🇺🇸Omaha, Nebraska, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Tennessee Oncology, PLLC
🇺🇸Nashville, Tennessee, United States
Cancer Care Center of South Texas
🇺🇸San Antonio, Texas, United States
University of Washington
🇺🇸Seattle, Washington, United States
One Medical Center Drive
🇺🇸Lebanon, New Hampshire, United States
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
Prairie Lakes Health Care System, Inc.
🇺🇸Watertown, South Dakota, United States