A Double-Blind, Placebo-Controlled, Randomized Phase III Study of Ipatasertib in Combination With Paclitaxel as a Treatment for Patients With PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor-Positive, HER2-Negative Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 579
- 试验地点
- 176
- 主要终点
- Cohort A: Progression-Free Survival (PFS)
研究概览
简要总结
This study will evaluate the efficacy of ipatasertib + paclitaxel versus placebo + paclitaxel in participants with histologically confirmed, locally advanced or metastatic triple-negative breast cancer (TNBC) and in participants with locally advanced or metastatic hormone receptor positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2-) breast adenocarcinoma who are not suitable for endocrine therapy.
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
- Triple (Participant, Investigator, Outcomes Assessor)
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
- •Women or men aged =>18 years with histologically documented triple-negative breast cancer (TNBC) or HR+/HER2- adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Adequate hematologic and organ function within 14 days prior to treatment initiation
- •Histologically documented TNBC or HR+/HER2- adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent
- •Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- •Eligible for taxane monotherapy, as per local investigator assessment (e.g., absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control which may require combination chemotherapy)
- •HR+/HER2- breast cancer that is not considered appropriate for endocrine-based therapy and meets one of the following: patient has recurrent disease <=5 years of being on adjuvant endocrine therapy or if patient with de novo metastatic disease have progressed within 6 months of being on first line endocrine therapy.
- •Consent to submit a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or freshly cut unstained, serial tumor slides from the most recently collected tumor tissue for central molecular analysis
- •Confirmation of biomarker eligibility using an appropriately validated molecular assay at a diagnostic laboratory, Clinically Laboratory Improvement Amendments (CLIA) or equivalently accredited i.e., valid results from either central testing or local testing of tumor tissue or blood demonstrating PIK3CA/AKT1/PTEN-altered status
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs
- •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and agreement to refrain from donating sperm
排除标准
- •Treatment with approved or investigational cancer therapy within 14 days prior to treatment initiation
- •Any previous chemotherapy for inoperable locally advanced or metastatic TNBC or HR+/HER2- adenocarcinoma of the breast (patients receiving neo/adjuvant chemotherapy eligible provided they have at least a 12 month disease-free interval)
- •History of or known presence of brain or spinal cord metastases
- •Malignancies other than breast cancer within 5 years prior to treatment initiation (except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer)
- •Prior treatment with an Akt inhibitor (prior PI3K or mTOR inhibitors are allowed)
- •History of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills
- •Active infection requiring systemic anti-microbial treatment (including antibiotics, anti-fungals, and anti-viral agents)
- •Known human immunodeficiency virus (HIV) infection
- •Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis, current drug or alcohol abuse, or cirrhosis
- •Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of treatment (or anticipated need during study)
- •Pregnant or breastfeeding, or intending to become pregnant during the study
- •Clinically significant cardiac dysfunction (including NYHA Class II/III/IV heart failure, left ventricular ejection fraction [LVEF] <50%, active ventricular arrhythmia requiring medication, history of myocardial infarction within 6 months of treatment initiation, clinically significant electrocardiogram [ECG] abnormalities).
- •Need for chronic corticosteroid therapy of >=10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease
- •Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 peripheral neuropathy
- •Uncontrolled clinical symptoms including pleural effusion, pericardial effusion, or ascites, tumor-related pain, hypercalcemia (or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy)
- •History of Type I or Type II diabetes mellitus requiring insulin
- •Grade >=2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia
- •History of or active inflammatory bowel disease or active bowel inflammation
- •Clinically significant lung disease (including pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, active infection/ history of opportunistic infections)
- •Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of treatment
- •Grade >=2 peripheral neuropathy
研究组 & 干预措施
Ipatasertib + Paclitaxel
干预措施: Ipatasertib (Drug)
Ipatasertib + Paclitaxel
干预措施: Paclitaxel (Drug)
Placebo + Paclitaxel
干预措施: Paclitaxel (Drug)
Placebo + Paclitaxel
干预措施: Placebo (Drug)
结局指标
主要结局
Cohort A: Progression-Free Survival (PFS)
时间窗: From randomization up to 27 months
PFS was defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator through the use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1), or death from any cause, whichever occurred first, assessed up to 27 months for this outcome measure. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). The appearance of one or more new lesions was also considered progression.
Cohort B: PFS
时间窗: From randomization up to 24.4 months
PFS was defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first, assessed up to 24.4 months for this outcome measure. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Abbreviation used in statistical analysis: PI3K=phosphoinositide 3-kinase and mTOR=mammalian target of rapamycin inhibitor.
Cohort C: PFS
时间窗: From enrollment up to 31 months
PFS for Cohort C was defined as the time from enrollment to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first, assessed up to 31 months for this outcome measure. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
次要结局
- Cohort C: CBR(From enrollment up to 31 months)
- Cohort A and B: Clinical Benefit Rate (CBR)(From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B)
- Cohort A and B: Objective Response Rate (ORR)(From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B)
- Cohort A and B: Duration of Response (DOR)(From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B)
- Cohort C: ORR(From enrollment up to 31 months)
- Cohort C: DOR(From enrollment up to 31 months)
- Overall Survival (OS)(From randomization/ enrollment (Cohort C) up to death from any cause, up to 45 months for Cohort A, up to 46 months for Cohort B and up to 31 months for Cohort C)
- Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30(Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 (cycle length=28 days))
- Cohorts A and B:Plasma Concentration of Ipatasertib(Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days))
- Cohort C: 1-year Event-free PFS Rate(From enrollment until the occurrence of disease progression or death from any cause, whichever occurred earlier, up to 1 year)
- Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30(Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 (cycle length=28 days))
- Number of Participants With Adverse Events (AEs)(Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C)
- Cohorts A and B: Plasma Concentration of G-037720(Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days ))
- Cohort C: 1-year Event-free OS Rate(From enrollment up to death from any cause, up to 1 year)
- Cohort B: Time to Deterioration (TTD) in Pain(Baseline up to 24.4 months)
- Cohort C: Plasma Concentration of Ipatasertib(Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days))
- Cohort C: Serum Concentration of Atezolizumab(Day 1 of Cycle 1: 30 minutes post dose, predose on Day 15 of Cycle 1 and predose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length=28 days))
- Cohort C: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab(Up to 45.5 months)
- Number of Participants With at Least One Adverse Events of Special Interest (AESI)(Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C)
- Cohort C: Plasma Concentration of G-037720(Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days ))