A Phase 1b Study of TAK-659 in Combination With Venetoclax for Adult Patients With Previously Treated Non-Hodgkin Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 43
- 试验地点
- 15
- 主要终点
- Percentage of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs), Grade 3 or Higher Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation
研究概览
简要总结
The purpose of this study is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of TAK-659 and venetoclax when administered in combination in participants with non-Hodgkin lymphoma (NHL) relapsed and/or refractory after at least 1 prior line of therapy and to evaluate safety and tolerability of TAK-659 and venetoclax when administered in combination.
详细描述
The drugs being tested in this study are called TAK-659 and venetoclax. TAK-659 in combination with venetoclax is being tested to treat people who have advanced NHL after at least 1 prior line of therapy. This study will look at the safety data, pharmacokinetic (PK) data and any early anti-tumor activity observed.
The study will enroll approximately 53 participants.
• TAK-659 and venetoclax doses will be escalated according to a Bayesian logistic regression model (BLRM) with overdose control escalation schema. TAK-659 60 mg + Venetoclax 400 mg is the starting dose.
Participants could also receive 40 mg, 60 mg, 80 mg or 100 mg TAK-659 during dose escalation and 200 mg, 400 mg, 800 mg, or 1200 mg of venetoclax.
Following dose escalation the safety and tolerability of the MTD/RP2D of the TAK-659+venetoclax combination will be further explored in two dose-safety expansion cohorts, Cohort A in participants with DLBCL and Cohort B in participants with FL.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 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
- •For the Dose Escalation phase, participants must have histologically confirmed diagnosis of advanced NHL of any histology (with the exception of participants with mantle cell lymphoma [MCL] or chronic lymphoma leukemia [CLL]).
- •For the Safety Expansion phase, participants must have histologically confirmed diagnosis of advanced DLBCL or FL.
- •Radiographically or clinically measurable disease with greater than or equal to (>=) 1 target lesion per IWG criteria for malignant lymphoma.
- •Refractory or relapsed after at least 1 prior line of therapy for whom no effective standard therapy is available per investigator's assessment.
- •o Participants who are either treatment-naive to, relapsed after, or refractory to ibrutinib, idelalisib, or any other investigational B cell receptor (BCR) pathway inhibitors not directly targeting spleen tyrosine kinase (SYK) are allowed.
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or
- •Life expectancy of greater than 3 months.
- •Suitable venous access for the study-required blood sampling that is, including PK and pharmacodynamic sampling.
- •Recovered (that is, less than or equal to [<=] Grade 1 toxicity) from the reversible effects of prior anticancer therapy.
排除标准
- •Central nervous system (CNS) lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology from lumbar puncture or computed tomography (CT) scan/magnetic resonance imaging (MRI).
- •History of drug-induced pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- •Participants requires the use of warfarin (use in prophylactic doses [example, deep vein thrombosis prophylaxis]) is allowed.
- •Prior exposure to targeted SYK inhibitors.
- •History of a prior intolerable toxicity, in the opinion of the investigator from another B-cell lymphoma (BCL)-2 family protein inhibitor study.
- •Participants who are relapsed after or refractory to regimens containing venetoclax or other BCL2 inhibitors.
- •Systemic anticancer treatment (including investigational agents) or radiotherapy less than 2 weeks before the first dose of study treatment (<=4 weeks for large molecule agents; <=8 weeks for cell-based therapy or anti-tumor vaccine), or not recovered from the reversible effects of prior anticancer therapy.
- •Prior autologous stem cell transplant (ASCT) within 6 months preceding Cycle 1 Day
- •Prior allogeneic stem cell transplant and/or chimeric antigen receptor T-cell therapy at any time.
- •Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications from surgery.
- •Known human immunodeficiency virus (HIV) positive or HIV-related malignancy.
- •Received a live viral vaccine within 6 months prior to the first dose of study drug.
- •Use or consumption of:
- •Medications or supplements that are known to be strong or moderate Cytochrome P4503A (CYP3A) inhibitors or strong or moderate CYP3A inducers and/or P-glycoprotein (P-gp) inhibitors or inducers within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drugs. In general, the use of these agents is not permitted during the study except in cases in which an adverse event (AE) must be managed during interruption of study drug dosing.
- •Food or beverages containing grapefruit, Seville oranges, or Star fruit within 5 days before the first dose of study drugs. Note that food and beverages containing grapefruit, Seville orange, or Star fruit are not permitted during the study.
- •Preparations containing St. John's wort within 7 days before the first dose of study drugs. Note that preparations containing St. John's wort are not permitted during the study.
研究组 & 干预措施
Dose Escalation: TAK-659 + Venetoclax
TAK-659 40, 60, 80, or 100 milligram (mg) (tablet, orally, once daily, up to 35 days in Cycle 1 or in different intermittent schedules [7 days dosing followed by 7 days off or 14 days dosing followed by 7 days off or other intermittent dosing schedules]) along with venetoclax 200, 400, 800 or 1200 mg (tablet, orally, once daily, up to 35 days in Cycle 1). After Cycle 1, TAK-659 and venetoclax will be administered once daily in a 28-day treatment cycle until disease progression, unacceptable toxicities, or discontinuation by participant.
干预措施: TAK-659 (Drug)
Dose Escalation: TAK-659 + Venetoclax
TAK-659 40, 60, 80, or 100 milligram (mg) (tablet, orally, once daily, up to 35 days in Cycle 1 or in different intermittent schedules [7 days dosing followed by 7 days off or 14 days dosing followed by 7 days off or other intermittent dosing schedules]) along with venetoclax 200, 400, 800 or 1200 mg (tablet, orally, once daily, up to 35 days in Cycle 1). After Cycle 1, TAK-659 and venetoclax will be administered once daily in a 28-day treatment cycle until disease progression, unacceptable toxicities, or discontinuation by participant.
干预措施: Venetoclax (Drug)
Safety Expansion: Diffuse Large B-cell Lymphoma (DLBCL) Cohort
TAK-659 tablet, orally, once daily along with venetoclax tablet, orally, once daily in a 28-day treatment cycle until disease progression, unacceptable toxicities, or discontinuation by participant. TAK-659 and venetoclax MTD/RP2D will be determined from the dose escalation phase.
干预措施: TAK-659 (Drug)
Safety Expansion: Diffuse Large B-cell Lymphoma (DLBCL) Cohort
TAK-659 tablet, orally, once daily along with venetoclax tablet, orally, once daily in a 28-day treatment cycle until disease progression, unacceptable toxicities, or discontinuation by participant. TAK-659 and venetoclax MTD/RP2D will be determined from the dose escalation phase.
干预措施: Venetoclax (Drug)
Safety Expansion: Follicular Lymphoma (FL) Cohort
TAK-659 tablet, orally, once daily along with venetoclax tablet, orally, once daily in a 28-day treatment cycle until disease progression, unacceptable toxicities, or discontinuation by participant. TAK-659 and venetoclax MTD/RP2D will be determined from the dose escalation phase.
干预措施: TAK-659 (Drug)
Safety Expansion: Follicular Lymphoma (FL) Cohort
TAK-659 tablet, orally, once daily along with venetoclax tablet, orally, once daily in a 28-day treatment cycle until disease progression, unacceptable toxicities, or discontinuation by participant. TAK-659 and venetoclax MTD/RP2D will be determined from the dose escalation phase.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Percentage of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs), Grade 3 or Higher Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation
时间窗: Baseline up to 13 months
AE Grades will be evaluated as per NCI CTCAE, version 5.0.
Number of Participants with a Dose Limiting Toxicity (DLT)
时间窗: Baseline up to 5 weeks
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), Version 5.0 DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications and that occur within the first cycle.
次要结局
- AUCτ: Area Under the Plasma Concentration-time Curve from Time 0 to Time Over the Dosing Interval for TAK-659 and Venetoclax(Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days))
- Oral Clearance (CL/F) for TAK-659 and Venetoclax(Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days))
- Peak-trough Ratio (PTR) for TAK-659 and Venetoclax(Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days))
- Cmax: Maximum Observed Plasma Concentration for TAK-659 and Venetoclax(Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length is equal to [=] 35 days))
- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 and Venetoclax(Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days))
- Accumulation Ratio (Rac) for TAK-659 and Venetoclax(Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days))
- Trough Concentration (C trough) for TAK-659 and Venetoclax(Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days))
- Overall Response Rate (ORR)(Up to 12 months)
- Duration of Overall Response(Up to 12 months)
- CR Rate(Up to 12 months)
- Duration of CR(Up to 12 months)
- Time to Progression (TTP)(Up to 13 months)
- Progression-free Survival (PFS)(Up to 18 months)