A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS-9973 in Subjects With Relapsed or Refractory Hematologic Malignancies
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 326
- 试验地点
- 48
- 主要终点
- PFS Rate of Participants With CLL (Including CLL, Prior BCR Inhibitor Naive Participants), FL, and Non-FL iNHL at Week 24
研究概览
简要总结
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]).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Entospletinib MM (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib MM (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib MM (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib MM (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib MM (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib SDD (Drug)
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.
干预措施: Entospletinib SDD (Drug)
结局指标
主要结局
PFS Rate of Participants With CLL (Including CLL, Prior BCR Inhibitor Naive Participants), FL, and Non-FL iNHL at Week 24
时间窗: 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
时间窗: 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.
次要结局
- 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))
- Percentage 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))
- Percentage of Participants Experiencing Treatment-Emergent Adverse Events(First dose date up to the last dose date plus 30 days (maximum: 78.4 months))
- 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))
- 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))
- 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))