A Phase III, Double-Blind, Placebo-Controlled, Randomized Study of Taselisib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Locally Advanced or Metastatic Breast Cancer Who Have Disease Recurrence or Progression During or After Aromatase Inhibitor Therapy
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 631
- 试验地点
- 157
- 主要终点
- PFS as Assessed by Investigator Using RECIST v1.1 at Final Analysis
研究概览
简要总结
This international, multicenter, randomized, double-blinded, placebo-controlled study is designed to compare the efficacy and safety of taselisib + fulvestrant with that of placebo + fulvestrant in postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, oncogene that encodes for phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA)-mutant, unresectable, locally advanced or metastatic breast cancer after recurrence or progression during or after an aromatase inhibitor (AI) therapy. There will be a 2:1 randomization to the taselisib arm versus the placebo arm. Enrollment will be enriched for participants with PIK3CA mutant tumors via central testing. The anticipated duration of the study is approximately 3.5 years.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Postmenopausal women with histologically or cytologically confirmed locally advanced or metastatic estrogen receptor (ER) positive breast cancer
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Participants for whom endocrine therapy (example [e.g.], fulvestrant) is recommended and treatment with cytotoxic chemotherapy is not indicated at time of entry into the study
- •Radiologic/objective evidence of recurrence or progression to the most recent systemic therapy for breast cancer
- •Radiologic/objective evidence of breast cancer recurrence or progression while on or within 12 months of the end of adjuvant treatment with an aromatase inhibitor (AI), or progression while on or within 1 month of the end of prior AI treatment for locally advanced or metastatic breast cancer
- •Measurable disease via Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) or non-measurable, evaluable disease with at least one evaluable bone lesion via RECIST v1.1
- •Consent to provide a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (preferred) or a minimum of 20 (25 preferred) freshly cut unstained tumor slides from the most recently collected, available tumor tissue for oncogene that encodes for phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA)-mutation testing
- •A valid cobas PIK3CA mutation result by central testing is required
- •Adequate hematologic and end-organ function within 28 days prior to treatment initiation
排除标准
- •Human epidermal growth factor receptor 2 (HER2)-positive disease by local laboratory testing (immunohistochemistry 3 positive [IHC 3+] staining or in situ hybridization positive)
- •Prior treatment with fulvestrant
- •Prior treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor, mammalian target of rapamycin (mTOR) inhibitor (e.g. everolimus), or protein kinase B (AKT) inhibitor
- •Prior anti-cancer therapy within 2 weeks prior to Day 1 of Cycle 1
- •Prior radiation therapy within 2 weeks prior to Day 1 of Cycle 1
- •All acute treatment-related toxicity must have resolved to Grade less than or equal to (</=) 1 or be deemed stable by the Investigator
- •Prior treatment with greater than (>) 1 cytotoxic chemotherapy regimen for metastatic breast cancer
- •Concurrent hormone replacement therapy
- •Known untreated or active central nervous system (CNS) metastases
- •Type 1 or Type 2 diabetes mellitus requiring anti-hyperglycemic medications
- •History of inflammatory bowel disease or active bowel inflammation
- •Clinically significant cardiac or pulmonary dysfunction
- •Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with human immunodeficiency virus (HIV), hepatitis B or C virus
研究组 & 干预措施
Taselisib + Fulvestrant
Participants received taselisib 4 milligrams (mg) taken orally QD beginning at Cycle 1, Day 1 and fulvestrant 500 mg by IM injection at Cycle 1, Days 1 and 15, and then on Day 1 of each subsequent 28-day cycle until disease progression, unacceptable toxicity, or study termination by the Sponsor.
干预措施: Taselisib (Drug)
Taselisib + Fulvestrant
Participants received taselisib 4 milligrams (mg) taken orally QD beginning at Cycle 1, Day 1 and fulvestrant 500 mg by IM injection at Cycle 1, Days 1 and 15, and then on Day 1 of each subsequent 28-day cycle until disease progression, unacceptable toxicity, or study termination by the Sponsor.
干预措施: Fulvestrant (Drug)
Placebo + Fulvestrant
Participants received placebo taken orally once daily (QD) beginning at Cycle 1, Day 1, and fulvestrant 500 mg administered by intramuscular (IM) injection at Cycle 1, Days 1 and 15, and then on Day 1 of each subsequent 28-day cycle until disease progression, unacceptable toxicity, or study termination by the Sponsor.
干预措施: Placebo (Drug)
Placebo + Fulvestrant
Participants received placebo taken orally once daily (QD) beginning at Cycle 1, Day 1, and fulvestrant 500 mg administered by intramuscular (IM) injection at Cycle 1, Days 1 and 15, and then on Day 1 of each subsequent 28-day cycle until disease progression, unacceptable toxicity, or study termination by the Sponsor.
干预措施: Fulvestrant (Drug)
结局指标
主要结局
PFS as Assessed by Investigator Using RECIST v1.1 at Final Analysis
时间窗: From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier (up to approximately 6.2 years)
PFS was defined as the time from randomization to disease progression as determined by the investigator with the use of RECIST v1.1 or death due to any cause, whichever occurred earlier. Disease progression 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. For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression.
Progression-Free Survival (PFS) as Assessed by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) at Primary Analysis
时间窗: From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier (up to the 15 Oct 2017 data cutoff, approximately 2.5 years)
PFS was defined as the time from randomization to disease progression as determined by the investigator with the use of RECIST v1.1 or death due to any cause, whichever occurred earlier. Disease progression 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 millimeters (mm). For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression.
次要结局
- Percentage of Participants With Objective Response (PR Plus CR), as Assessed Using RECIST v.1.1 at Final Analysis(From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier (up to approximately 6.2 years))
- PFS as Assessed by BICR Using RECIST v1.1 at Final Analysis(From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier (up to approximately 6.2 years))
- Change From Baseline in Modified EORTC Quality of Life Questionnaire Breast Cancer Module 23 (QLQ-BR23) Score(Baseline, C2D1 up to C7D1 (each cycle=28 days))
- Overall Survival (OS) at Primary Analysis(From randomization up to death from any cause (up to the 15 Oct 2017 data cutoff, approximately 2.5 years))
- OS at Final Analysis(From randomization up to death from any cause (up to approximately 6.2 years))
- Percentage of Participants With Clinical Benefit, as Assessed According to RECIST v1.1 at Primary Analysis(From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier (up to the 15 Oct 2017 data cutoff, approximately 2.5 years))
- Percentage of Participants With Clinical Benefit, as Assessed According to RECIST v1.1 at Final Analysis(From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier (up to approximately 6.2 years))
- Percentage of Participants With Objective Response (Partial Response [PR] Plus Complete Response [CR]), as Assessed Using RECIST v.1.1 at Primary Analysis(From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier (up to the 15 Oct 2017 data cutoff, approximately 2.5 years))
- Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Score(Baseline, C2D1 up to C7D1 (each cycle=28 days))
- Duration of Objective Response, as Assessed by Investigator Using RECIST v1.1 at Primary Analysis(Time from the first occurrence of a documented objective response to the time of the first documented disease progression or death from any cause, whichever occurs earlier (up to the 15 Oct 2017 data cutoff, approximately 2.5 years))
- Percentage of Participants With Adverse Events at Final Analysis(From randomization up to approximately 6.2 years)
- Minimum Observed Plasma Concentration (Cmin) of Taselisib(1 to 4 hrs post-dose on Cycle 1, Day 1; 0 to 3 hrs pre-dose and 2 to 6 hrs post dose on Cycle 2, Day 1; 0 to 3 hrs pre-dose on Cycle 6, Day 1 (each cycle=28 days))
- Duration of Objective Response, as Assessed by Investigator Using RECIST v1.1 at Final Analysis(Time from the first occurrence of a documented objective response to the time of the first documented disease progression or death from any cause, whichever occurs earlier (up to approximately 6.2 years))
- PFS as Assessed by Blinded Independent Central Review (BICR) Using RECIST v1.1 at Primary Analysis(From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier (up to the 15 Oct 2017 data cutoff, approximately 2.5 years))
- Percentage of Participants With Adverse Events at Primary Analysis(From randomization up to the 15 Oct 2017 data cutoff, approximately 2.5 years.)
- Maximum Observed Plasma Concentration (Cmax) of Taselisib(1 to 4 hours (hrs) post-dose on Cycle (C) 1, Day (D) 1; 0 to 3 hrs pre-dose and 2 to 6 hrs post dose on Cycle 2, Day 1 (each cycle=28 days))