A Phase II Randomized, Double-blind Placebo Controlled, Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women With Hormone Receptor-positive HER2-negative Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 340
- 试验地点
- 24
- 主要终点
- Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort
研究概览
简要总结
The purpose of the study was to determine whether treatment with a PI3K inhibitor plus letrozole led to an increase in pathologic clinical response and Objective Response Rate compared to treatment with placebo plus letrozole in patients with Breast cancer.
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, Care Provider, 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
- •Patient is an adult, female ≥ 18 years old at the time of informed consent
- •Patient has a histologically and/or cytologically confirmed diagnosis of breast cancer
- •Patient is postmenopausal.
- •Patient has T1c-T3, any N, M0, operable breast cancer
- •Patients must have measurable disease
- •Patient has diagnostic biopsy available for the analysis of PIK3CA mutation and Ki67 level.
- •Patient has estrogen-receptor and/or progesterone positive breast cancer as per local laboratory testing
- •Patient has HER2 negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0 or 1+ as per local laboratory testing
排除标准
- •Patient has locally recurrent or metastatic disease
- •Patient has received any systemic therapy (e.g. chemotherapy, targeted therapy, immunotherapy) or radiotherapy for current breast cancer disease before randomization.
- •Patient with type 1 diabetes mellitus or not adequately controlled type 2 diabetes mellitus
- •History of acute pancreatitis within 1 year of study entry
- •Uncontrolled hypertension
研究组 & 干预措施
Alpelisib + Letrozole
Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
干预措施: alpelisib (Drug)
Buparlisib + Letrozole
Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
干预措施: buparlisib (Drug)
Placebo + Letrozole
Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
干预措施: Placebo (Drug)
结局指标
主要结局
Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort
时间窗: After 24 weeks of treatment
Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.
Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Wild-type Cohort
时间窗: After 24 weeks of treatment
Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.
Objective Response Rate Per Investigator Assessment According to RECIST 1.1 for Alpelisib vs. Placebo - PIK3CA Mutant Cohort
时间窗: After 24 weeks of treatment
Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1. BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to \< 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline ≥ 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.
Objective Response Rate According to RECIST 1.1 Per Investigator Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort
时间窗: After 24 weeks of treatment
Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1. BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to \< 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline ≥ 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.
次要结局
- pCR and Objective Response Rate According to RECIST 1.1 Criteria Per Investigator Assessment for Alpelisib vs. Placebo in PIK3CA Wild-type Cohort Based on ctDNA(After 24 weeks of treatment)
- Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR(Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment))
- Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Mutant Cohort(At the time of surgery (expected after 24 weeks of treatment))
- pCR and Objective Response Rate According to RECIST 1.1 Criteria Per Investigator Assessment for Alpelisib vs. Placebo in PIK3CA Mutant Cohort Based on ctDNA(After 24 weeks of treatment)
- Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Mutant Cohort(After 24 weeks of treatment)
- Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort(After 24 weeks of treatment)
- Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR(Baseline, Cycle 1 Day 15 (each cycle is 28 days ) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment))
- Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort(At the time of surgery (expected after 24 weeks of treatment))
- Letrozole PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1(0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days))
- Buparlisib PK Parameter: Tmax at Cycle 4 Day 1(Cycle 4 Day 1 (each cycle is 28 days))
- Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1(0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days))
- Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Non-responders as Per pCR(Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment))
- Alpelisib PK Parameter: Tmax at Cycle 4 Day 1(Cycle 4 Day 1 (each cycle is 28 days))
- Letrozole PK Parameter: Tmax at Cycle 4 Day 1(Cycle 4 Day 1 (each cycle is 28 days))
- Buparlisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1(0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days))
- Buparlisib PK Parameter: Cmax at Cycle 1 Day 1(Cycle 1 Day 1 (each cycle is 28 days))
- Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Responders as Per pCR(Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment))
- Alpelisib and PK Parameter: Tmax at Cycle 1 Day 1(Cycle 1 Day 1 (each cycle is 28 days))
- Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1(0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days))
- Alpelisib PK Parameter: Cmax at Cycle 4 Day 1(Cycle 4 Day 1 (each cycle is 28 days))
- Letrozole and PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1(0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days))
- Letrozole PK Parameter: Cmax at Cycle 1 Day 1(Cycle 1 Day 1 (each cycle is 28 days))
- Letrozole PK Parameter: Tmax at Cycle 1 Day 1(Cycle 1 Day 1 (each cycle is 28 days))
- Buparlisb PK Parameter: Cmax at Cycle 4 Day 1(Cycle 4 Day 1 (each cycle is 28 days))
- Alpelisib PK Parameter: Cmax at Cycle 1 Day 1(Cycle 1 Day 1 (each cycle is 28 days))
- Letrozole PK Parameter: Cmax at Cycle 4 Day 1(Cycle 4 Day 1 (each cycle is 28 days))
- Buparlisib PK Parameter: Tmax at Cycle 1 Day 1(Cycle 1 Day 1 (each cycle is 28 days))
- Buparlisib PK Parameter: AUClast at Cycle 4 Day 1(0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days))