A Phase Ib/II, Open-Label Study Evaluating the Safety, Efficacy and Pharmacokinetics of GDC-0199 (ABT-199) in Combination With Rituximab (R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Patients With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 267
- 试验地点
- 52
- 主要终点
- Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This is a multicenter, open-label, dose-finding study of venetoclax administered orally in combination with rituximab (R) or obinutuzumab (G) and standard doses of cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP) in participants with Non-Hodgkin's Lymphoma (NHL). The study consisted of 2 stages: a dose-finding Phase Ib stage and a Phase II expansion stage. In the Phase I portion of the study, participants were randomized to one of 2 treatment arms venetoclax in combination with R-CHOP (Arm A) and venetoclax in combination with G-CHOP (Arm B) and explored the doses of venetoclax in combination with R-CHOP and G-CHOP. The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and G-CHOP was determined during the dose-finding stage. For the Phase II portion of the study, the venetoclax dose for venetoclax + R-CHOP was on a non-continuous dosing schedule as determined by the Phase Ib portion of the study based on safety and tolerability observed in participants treated in the dose escalation portion of the study. On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed through a press release that the primary endpoint of investigator-assessed PFS was not met. Given these results, Arm B (venetoclax + G-CHOP) was not expanded in Phase II in patients who are first-line with DLBCL.
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
- •General Inclusion Criteria:
- •At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as > 1.5 cm in its longest dimension, which is also FDG avid by screening PET scan.
- •Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- •Adequate hematologic function
- •For female participants of childbearing potential, agreement to use highly effective forms of contraception
- •Dose-Escalation Portion of the Study:
- •Participants must have histologically confirmed B-cell NHL, except MCL or SLL
- •Participants must have never received previous R-CHOP treatment
- •Any relapsed/refractory participants that are enrolled during the dose escalation should have received only a single previous treatment regimen
- •Expansion Portion of the Study:
- •Participants must have previously untreated CD20-positive DLBCL and IPI score must be 2-5
排除标准
- •General Exclusion Criteria:
- •History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
- •Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab
- •Prior anthracycline therapy
- •Participants with ongoing corticosteroid use >30 mg per day of prednisone or equivalent
- •CNS lymphoma or primary mediastinal DLBCL
- •Vaccination with live vaccines within 28 days prior to randomization
- •Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1
- •History of other malignancy that could affect compliance with the protocol or interpretation of results
- •Evidence of significant, uncontrolled concomitant disease
- •Significant cardiovascular disease or significant pulmonary disease
- •Left ventricular ejection fraction less than (<) 50% as defined by multiple-gated acquisition (MUGA)
- •Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1
- •Received the following agents within 7 days prior to the first dose of venetoclax: steroid therapy for anti-neoplastic intent; strong and moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers; grapefruit/grapefruit products, seville oranges or star fruit within 3 days prior to the first dose of venetoclax
- •Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
- •Recent major surgery
- •Women who are pregnant or lactating
- •Dose-Escalation Portion of the Study:
- •Participants with confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL)
- •Expansion Portion of the Study:
- •Participants with transformed lymphoma (participants with discordant bone marrow involvement (i.e., low grade histology in bone marrow) may be considered after discussion with the Medical Monitor)
- •Prior therapy for NHL
研究组 & 干预措施
Venetoclax + G-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Venetoclax (Drug)
Venetoclax + G-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Cyclophosphamide (Drug)
Venetoclax + G-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Obinutuzumab (Drug)
Venetoclax + G-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Doxorubicin (Drug)
Venetoclax + G-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Vincristine (Drug)
Venetoclax + G-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Prednisone (Drug)
Venetoclax + R-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Venetoclax (Drug)
Venetoclax + R-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Cyclophosphamide (Drug)
Venetoclax + R-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Rituximab (Drug)
Venetoclax + R-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Doxorubicin (Drug)
Venetoclax + R-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Vincristine (Drug)
Venetoclax + R-CHOP Arm
Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
干预措施: Prednisone (Drug)
结局指标
主要结局
Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days)
DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade \>/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not be attributed by the investigator to an alternative, clearly identifiable cause such as tumor progression, concurrent illness or medical condition, or concomitant medication and that occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was considered a DLT for dose-escalation purposes. Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose delay were considered DLTs.
Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Scan Using the Modified Lugano Classification Assessed by Independent Review Committee (IRC)
时间窗: Baseline up to end of treatment (up to approximately 6 months)
CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake \</= mediastinum; 3) uptake \< mediastinum but \</= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy
Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co-Expressing Both Bcl-2 and c-Myc Proteins (DE-DLBCL) Participants Assessed by IRC
时间窗: Baseline up to end of treatment (up to approximately 6 months)
CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake \</= mediastinum; 3) uptake \< mediastinum but \</= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
次要结局
- Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval(Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days))
- Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)(Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days))
- Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)(Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days))
- Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)(Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days))
- Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification Assessed by IRC(Baseline to end of treatment (up to approximately 6 months))
- Relative Dose Intensity of Venetoclax(Baseline up to Cycle 6 (cycle length = 21 days))
- Prednisone Plasma PK: AUC(Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days))
- Cyclophosphamide PK: Cmax(End of Infusion on Cycle 1 Day 1 (cycle length = 21 days))
- Prednisone Plasma PK: Cmax(Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days))
- Rituximab PK: Cmax(End of Infusion on Cycle 1 Day 1 (cycle length = 21 days))
- Percentage of Participants Who Are Alive and Without Disease Progression at Month 12(Month 12)
- Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification(Baseline up to end of treatment (approx. 6 months))
- Prednisone Plasma PK: Tmax(Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days))
- Vincristine PK: Cmax(End of Infusion on Cycle 1 Day 1 (cycle length = 21 days))
- Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy(Baseline up to Cycle 6 (cycle length = 21 days))
- Rituximab PK: Cmin Within the Dosing Interval(Pre-dose on Cycle 2 Day 1 (cycle length = 21 days))
- Obinutuzumab PK: Cmax(End of Infusion on Cycle 1 Day 1 (cycle length = 21 days))
- Doxorubicin PK: Cmax(End of Infusion on Cycle 1 Day 1 (cycle length = 21 days))
- Safety: Percentage of Participants With Adverse Events(Baseline up to approximately 36 months)