A Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib (ONO/GS-4059) in Combination With Other Targeted Anti-cancer Therapies in Subjects With B-cell Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 203
- 试验地点
- 15
- 主要终点
- Percentage of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The primary objectives of this study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of tirabrutinib (ONO/GS-4059) in combination with other targeted anti-cancer therapies and to evaluate the long-term safety of tirabrutinib as a monotherapy and in combination with other targeted anti-cancer therapies in adults with relapsed or refractory B-cell lymphoproliferative malignancies.
This study consists of three parts: Dose Escalation, Dose Expansion, and Long-term Safety Monitoring. During the Dose Escalation phase, participants will be sequentially enrolled in a standard 3 + 3 dose escalation study design, to receive oral tirabrutinib combined with idelalisib entospletinib +/- obinutuzumab. The Dose Expansion Phase will enroll additional participants with a single B-cell lymphoproliferative malignancy disease type to further evaluate efficacy, safety, tolerability, PK, and pharmacodynamics. The Long-term Safety Monitoring phase will evaluate the long-term safety of tirabrutinib both as a monotherapy and in combination with other anti-cancer therapies. As of Amendment 9, all participants currently on the study who have no clinical evidence of disease progression will transition into long-term safety monitoring. Participants from the ongoing Study GS-US-401-1787 and participants who came off Study GS-US-401-1757 and Study GS-US-401-1787 but continued to receive treatment via named patient use (or individual expanded use) will be enrolled into the long-term safety monitoring group (Group VI). Participants enrolled in Group VI will continue the same treatment regimen in Study GS-US-401-1787 or named patient use (or individual expanded use). As of Protocol Amendment 8, the maximum treatment duration for any participant is an additional 6 years from the date of this amendment (ie. until November 2025). As of Amendment 9, entospletinib will be provided until 31 December 2020 to participants who are currently receiving entospletinib. Participants treated with entospletinib as part of a combination regimen with tirabrutinib will stop receiving entospletinib by 31 December 2020 but may continue to be treated with tirabrutinib monotherapy. Idelalisib will be provided as 50 mg tablets until 31 December 2020 and 100 mg tablets until study completion. Participants assigned to the 50 mg tablet will be given the option, at the investigator's discretion, to switch to 100 mg once daily idelalisib dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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 follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL) (meeting International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria 2008), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), or non-germinal center B-cell lymphoma (GCB) diffuse large B-cell lymphoma (DLBCL) as documented by medical records on World Health Organization (WHO) criteria
- •Prior treatment for FL, MZL, SLL, MCL, WM with ≥ 2 or for CLL or non-GCB DLBCL ≥ 1 chemotherapy-based or immunotherapy-based regimen, and not transplant eligible and have had either progressive disease (PD) or no response to previous treatment
- •For diseases other than Waldenstrom's macroglobulinemia (WM), presence of radiographically measurable presence of ≥ 1 lesion that measures ≥ 2.0 cm in the longest dimension (LD) and ≥ 1.0 cm in the longest perpendicular dimension (LPD)
- •Eastern Cooperative Oncology Group (ECOG) ≤ 2
- •Platelets ≥ 50 x 10^9/L; Hb ≥ 8.0 g/dL; absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L
- •Without transfusion and growth factors within 7 days
- •Aspartate transaminase/alanine transaminase (AST/ALT) ≤ 2.5 x upper limit of normal (ULN)
- •Total bilirubin ≤ 1.5 x ULN
- •Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min
- •Not pregnant
- •Willingness and ability to comply with protocol-specified Pneumocystis jirovecii pneumonia (PJP) prophylaxis
- •Long-term Safety Monitoring group only (Group VI):
- •Currently enrolled in Study GS-US-401-1787 or previously enrolled in Study GS-US-401-1757 or Study GS-US-401-1787 and currently receiving continued treatment via named patient use
- •Continuing to benefit from the current treatment regimen in the opinion of the investigator/treating physician
排除标准
- •Hepatitis B surface antigen (HBsAG) positive or hepatitis B core antibody positive
- •Hepatitis C virus (HCV) antibody positive
- •History of long QT syndrome or whose corrected QT(QTc) interval measured (Fridericia method) at screening is prolonged (>450 ms)
- •Long-term Safety Monitoring group only (Group VI):
- •Evidence of clinical or radiological disease progression
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Combination I (Tirabrutinib 20 mg QD+ Idelalisib 50 mg BID)
Participants will receive tirabrutinib 20 mg tablet once daily (QD) for up to 209 weeks and idelalisib 50 mg tablet twice daily (BID) orally for up to 120 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination I (Tirabrutinib 20 mg QD+ Idelalisib 50 mg BID)
Participants will receive tirabrutinib 20 mg tablet once daily (QD) for up to 209 weeks and idelalisib 50 mg tablet twice daily (BID) orally for up to 120 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Idelalisib (Drug)
Combination I (Tirabrutinib 40 mg QD+ Idelalisib 50 mg BID)
Participants will receive tirabrutinib 40 mg tablet QD for up to 251 weeks and idelalisib 50 mg tablet BID orally, for up to 245 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination I (Tirabrutinib 40 mg QD+ Idelalisib 50 mg BID)
Participants will receive tirabrutinib 40 mg tablet QD for up to 251 weeks and idelalisib 50 mg tablet BID orally, for up to 245 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Idelalisib (Drug)
Combination I (Tirabrutinib 80 mg QD+ Idelalisib 50 mg BID)
Participants will receive tirabrutinib 80 mg tablet QD for up to 212 weeks and idelalisib 50 mg tablet BID orally, for up to 26 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination I (Tirabrutinib 80 mg QD+ Idelalisib 50 mg BID)
Participants will receive tirabrutinib 80 mg tablet QD for up to 212 weeks and idelalisib 50 mg tablet BID orally, for up to 26 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Idelalisib (Drug)
Combination I (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD)
Participants will receive tirabrutinib 80 mg tablet QD for up to 227 weeks and idelalisib 100 mg tablet QD orally, for up to 227 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination I (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD)
Participants will receive tirabrutinib 80 mg tablet QD for up to 227 weeks and idelalisib 100 mg tablet QD orally, for up to 227 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Idelalisib (Drug)
Combination I (Tirabrutinib 160 mg QD+ Idelalisib 100 mg QD)
Participants will receive tirabrutinib 160 mg tablet QD for up to 151 weeks and idelalisib 100 mg tablet QD orally, for up to 151 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination I (Tirabrutinib 160 mg QD+ Idelalisib 100 mg QD)
Participants will receive tirabrutinib 160 mg tablet QD for up to 151 weeks and idelalisib 100 mg tablet QD orally, for up to 151 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Idelalisib (Drug)
Combination I (Tirabrutinib 20 mg BID+ Idelalisib 50 mg BID)
Participants will receive tirabrutinib 20 mg tablet BID for up to 207 weeks and idelalisib 50 mg tablet BID orally, for up to 207 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination I (Tirabrutinib 20 mg BID+ Idelalisib 50 mg BID)
Participants will receive tirabrutinib 20 mg tablet BID for up to 207 weeks and idelalisib 50 mg tablet BID orally, for up to 207 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Idelalisib (Drug)
Combination II (Tirabrutinib 40 mg QD+ Entospletinib 200 mg QD)
Participants will receive tirabrutinib 40 mg tablet QD for up to 250 weeks and entospletinib 200 mg tablet QD orally, for up to 250 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination II (Tirabrutinib 40 mg QD+ Entospletinib 200 mg QD)
Participants will receive tirabrutinib 40 mg tablet QD for up to 250 weeks and entospletinib 200 mg tablet QD orally, for up to 250 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Entospletinib (Drug)
Combination II (Tirabrutinib 80 mg QD+ Entospletinib 200 mg QD)
Participants will receive tirabrutinib 80 mg tablet QD for up to 234 weeks and entospletinib 200 mg tablet QD orally, for up to 220 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination II (Tirabrutinib 80 mg QD+ Entospletinib 200 mg QD)
Participants will receive tirabrutinib 80 mg tablet QD for up to 234 weeks and entospletinib 200 mg tablet QD orally, for up to 220 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Entospletinib (Drug)
Combination II (Tirabrutinib 150 mg QD+ Entospletinib 200 mg QD)
Participants will receive tirabrutinib 150 mg tablet QD for up to 103 weeks and entospletinib 200 mg tablet QD orally, for up to 88 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination II (Tirabrutinib 150 mg QD+ Entospletinib 200 mg QD)
Participants will receive tirabrutinib 150 mg tablet QD for up to 103 weeks and entospletinib 200 mg tablet QD orally, for up to 88 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Entospletinib (Drug)
Combination II (Tirabrutinib 40 mg QD+ Entospletinib 400 mg QD)
Participants will receive tirabrutinib 40 mg tablet QD for up to 119 weeks and entospletinib 400 mg tablet QD orally, for up to 119 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination II (Tirabrutinib 40 mg QD+ Entospletinib 400 mg QD)
Participants will receive tirabrutinib 40 mg tablet QD for up to 119 weeks and entospletinib 400 mg tablet QD orally, for up to 119 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Entospletinib (Drug)
Combination II (Tirabrutinib 80 mg QD+ Entospletinib 400 mg QD)
Participants will receive tirabrutinib 80 mg tablet QD for up to 232 weeks and entospletinib 400 mg tablet QD orally, for up to 229 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination II (Tirabrutinib 80 mg QD+ Entospletinib 400 mg QD)
Participants will receive tirabrutinib 80 mg tablet QD for up to 232 weeks and entospletinib 400 mg tablet QD orally, for up to 229 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Entospletinib (Drug)
Combination II (Tirabrutinib 160 mg QD+ Entospletinib 400 mg QD)
Participants will receive tirabrutinib 160 mg tablet QD for up to 44 weeks and entospletinib 400 mg tablet QD orally, for up to 44 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination II (Tirabrutinib 160 mg QD+ Entospletinib 400 mg QD)
Participants will receive tirabrutinib 160 mg tablet QD for up to 44 weeks and entospletinib 400 mg tablet QD orally, for up to 44 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Entospletinib (Drug)
Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg)
Participants will receive tirabrutinib 80 mg tablet QD for up to 199 weeks; Idelalisib 100 mg tablet QD orally for up to 199 weeks, and single dose of obinutuzumab 1000 mg intravenously (IV) for up to 22 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg)
Participants will receive tirabrutinib 80 mg tablet QD for up to 199 weeks; Idelalisib 100 mg tablet QD orally for up to 199 weeks, and single dose of obinutuzumab 1000 mg intravenously (IV) for up to 22 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Idelalisib (Drug)
Combination III (Tirabrutinib 80 mg QD+ Idelalisib 100 mg QD+ obinutuzumab 1000 mg)
Participants will receive tirabrutinib 80 mg tablet QD for up to 199 weeks; Idelalisib 100 mg tablet QD orally for up to 199 weeks, and single dose of obinutuzumab 1000 mg intravenously (IV) for up to 22 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Obinutuzumab (Drug)
Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg)
Participants will receive tirabrutinib 80 mg tablet QD for up to 196 weeks; entospletinib 400 mg tablet QD orally for up to 196 weeks and single dose of obinutuzumab 1000 mg IV for up to 22 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Tirabrutinib (Drug)
Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg)
Participants will receive tirabrutinib 80 mg tablet QD for up to 196 weeks; entospletinib 400 mg tablet QD orally for up to 196 weeks and single dose of obinutuzumab 1000 mg IV for up to 22 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Entospletinib (Drug)
Combination IV (Tirabrutinib 80 mg QD+ entospletinib 400 mg QD+ obinutuzumab 1000 mg)
Participants will receive tirabrutinib 80 mg tablet QD for up to 196 weeks; entospletinib 400 mg tablet QD orally for up to 196 weeks and single dose of obinutuzumab 1000 mg IV for up to 22 weeks. Both drugs will be administered for 28-day cycles.
干预措施: Obinutuzumab (Drug)
Group V Single Agent Tirabrutinib
Participants will receive tirabrutinib 80 mg tablet QD orally, for each 28-day cycle up to 194 weeks.
干预措施: Tirabrutinib (Drug)
Group VI Single Agent Tirabrutinib: CLL
Participants with CLL who received tirabrutinib in this or a previous tirabrutinib study will continue to receive tirabrutinib at the original dose (between the range of 40 - 400 mg), tablet QD, for each 28-day cycle up to 441 weeks. Participants will be monitored for the long-term safety of tirabrutinib in this group.
干预措施: Tirabrutinib (Drug)
Group VI Single Agent Tirabrutinib: NHL
Participants with NHL who received tirabrutinib in this or a previous tirabrutinib study will continue to receive tirabrutinib at the original dose (between the range of 60 - 480 mg), tablet QD, for each 28-day cycle up to 441 weeks. Participants will be monitored for the long-term safety of tirabrutinib in this group.
干预措施: Tirabrutinib (Drug)
结局指标
主要结局
Percentage of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Up to 28 days
A DLT was defined as a ≥ Grade 3 AE that was assessed as related to study drug that occurred during the 28-day DLT assessment period with protocol-defined allowed exceptions. Any treatment-emergent adverse event (TEAE) that was, in the opinion of the Clinical Trial Steering Committee, of potential clinical significance such that further dosing exposed participants to unacceptable risk, was considered a DLT.
Objective Response Rate (ORR): Percentage of Participants With Complete Response (CR) or Partial Response (PR) at Week 12 in Participants With Non-Chronic Lymphocytic Leukemia (CLL) Type NHL
时间窗: Week 12
ORR for Waldenstrom Macroglobulinemia(WM):CR+VGPR+PR+MPR. CR: Absence of serum monoclonal IgM protein; normal serum IgM level: complete resolution of extramedullary disease, morphologically normal bone marrow/aspirate and trephine biopsy. Very good partial response (VGPR):Detectable monoclonal IgM; ≥90% reduction in serum IgM; Complete resolution of extramedullary disease; No new signs/symptoms. PR: Monoclonal immunoglobulin M (IgM) protein is detectable ≥50% but \<90% reduction in serum IgM level from baseline; reduction of extramedullary disease; no new signs or symptoms of active disease. Minor response (MPR):Detectable monoclonal IgM; ≥25% but \<50% reduction in serum IgM; No progression of extramedullary disease; No new signs/symptoms. Clopper-Pearson method was used in analysis. Data is reported by disease type: WM; Follicular Lymphoma (FL);Mantle Cell Lymphoma (MCL);Small Lymphocytic Lymphoma (SLL);Marginal Zone Lymphoma (MZL);Diffuse Large B-Cell Lymphoma (DLBCL) as applicable.
ORR: Percentage of Participants With CR or PR in Participants With CLL at Week 24
时间窗: Week 24
ORR was defined as the percentage of participants who achieved a complete response (CR) or partial response (PR). CR and PR are defined in outcome measure#2. Clopper-Pearson method was used in outcome measure analysis. Percentages were rounded off.
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
时间窗: First dose up to last dose date (up to 441 weeks) plus 30 days
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. TEAEs were defined as an AE that onset in the period from the first dose of study treatment to 30 days after the last dose of study treatment. Percentages were rounded off.
次要结局
- PK Parameter: Cmax of Entospletinib When Given in Combination With Tirabrutinib(Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose)
- PK Parameter: AUCtau of Entospletinib When Given in Combination With Tirabrutinib(Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose)
- ORR: Percentage of Participants With Complete Response (CR) or Partial Response (PR) in the Dose Escalation and Expansion Phase(Up to 281 weeks)
- Progression Free Survival (PFS) During the Dose Escalation Phase and Dose Expansion Phase(Up to 281 weeks)
- Duration of Response (DOR) During the Dose Escalation Phase and Dose Expansion Phase(Up to 281 weeks)
- Time to Response (TTR) During the Dose Escalation Phase and Dose Expansion Phase(Up to 281 weeks)
- Percentage of Participants Who Achieved Minimal Residual Negative Disease (< 1 Leukemia Cell/10,000 Leukocytes) During the Dose Escalation Phase and Dose Expansion Phase in Participants With CLL(Up to 281 weeks)
- Pharmacokinetic (PK) Parameter: AUCtau of Tirabrutinib 80 mg(Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose)
- PK Parameter: Cmax of Tirabrutinib 80 mg(Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose)
- PK Parameter: AUCtau of Idelalisib When Given in Combination With Tirabrutinib(Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose)
- PK Parameter: Cmax of Idelalisib When Given in Combination With Tirabrutinib(Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose)
- PK Parameter: AUCtau of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib(Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose)
- PK Parameter: Cmax of Metabolite of Idelalisib (GS-563117) When Given in Combination With Tirabrutinib(Cycle 1 Day 8: Predose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours postdose)