Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: alpelisib
* Drug: buparlisib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alpelisib + Letrozole<br>Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily. | Drug: alpelisib<br>* BYL719 + Letrozole<br>* Other names: BYL719;|
| Experimental: Buparlisib + Letrozole<br>Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily. | Drug: buparlisib<br>* BKM120 + Letrozole<br>* Other names: BKM120;|
| Placebo Comparator: Placebo + Letrozole<br>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. | Drug: Placebo<br>* Placebo (of BYL719 or BKM120) + Letrozole<br>* Other names: BYL719 Placebo, BKM120 Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort | 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. | After 24 weeks of treatment | 
| Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Wild-type Cohort | 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. | After 24 weeks of treatment | 
| Objective Response Rate Per Investigator Assessment According to RECIST 1.1 for Alpelisib vs. Placebo - PIK3CA Mutant Cohort | 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. | After 24 weeks of treatment | 
| Objective Response Rate According to RECIST 1.1 Per Investigator Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort | 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. | After 24 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment | 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 Wild-type Cohort Based on ctDNA | pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment | After 24 weeks of treatment | 
| Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Mutant Cohort | Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row no surgery provides the number of patients who did not undergo surgery at all for various reasons. | After 24 weeks of treatment | 
| Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort | Breast conserving surgery is defined as the percentage of participants with no mastectomy following completion of 24 weeks of treatment. Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row no surgery provides the number of patients who did not undergo surgery at all for various reasons. | 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 | 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) | 
| Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR | 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) | 
| Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Responders as Per pCR | 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) | 
| Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Non-responders as Per pCR | 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) | 
| Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Mutant Cohort | Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA mutant cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0. | At the time of surgery (expected after 24 weeks of treatment) | 
| Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort | Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA wild-type cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0. | At the time of surgery (expected after 24 weeks of treatment) | 
| Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1 | Summary of primary PK parameters for alpelisib plasma concentration | 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days) | 
| Alpelisib PK Parameter: Cmax at Cycle 1 Day 1 | Summary of primary PK parameters for alpelisib plasma concentration | Cycle 1 Day 1 (each cycle is 28 days) | 
| Alpelisib and PK Parameter: Tmax at Cycle 1 Day 1 | Summary of primary PK parameters for alpelisib plasma concentration | Cycle 1 Day 1 (each cycle is 28 days) | 
| Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1 | Summary of primary PK parameters for alpelisib plasma concentration | 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 | Summary of primary PK parameters for alpelisib plasma concentration | Cycle 4 Day 1 (each cycle is 28 days) | 
| Alpelisib PK Parameter: Tmax at Cycle 4 Day 1 | Summary of primary PK parameters for alpelisib plasma concentration | Cycle 4 Day 1 (each cycle is 28 days) | 
| Letrozole and PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1 | Summary of primary PK parameters for Letrozole plasma concentration | 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 | Summary of primary PK parameters for letrozole plasma concentration | Cycle 1 Day 1 (each cycle is 28 days) | 
| Letrozole PK Parameter: Tmax at Cycle 1 Day 1 | Summary of primary PK parameters for letrozole plasma concentration | Cycle 1 Day 1 (each cycle is 28 days) | 
| Letrozole PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1 | Summary of primary PK parameters for Letrozole plasma concentration | 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days) | 
| Letrozole PK Parameter: Cmax at Cycle 4 Day 1 | Summary of primary PK parameters for letrozole plasma concentration | Cycle 4 Day 1 (each cycle is 28 days) | 
| Letrozole PK Parameter: Tmax at Cycle 4 Day 1 | Summary of primary PK parameters for letrozole plasma concentration | Cycle 4 Day 1 (each cycle is 28 days) | 
| Buparlisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1 | Summary of primary PK parameters for Buparlisib plasma concentration | 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 | Summary of primary PK parameters for buparlisib plasma concentration | Cycle 1 Day 1 (each cycle is 28 days) | 
| Buparlisib PK Parameter: Tmax at Cycle 1 Day 1 | Summary of primary PK parameters for buparlisib plasma concentration | Cycle 1 Day 1 (each cycle is 28 days) | 
| Buparlisib PK Parameter: AUClast at Cycle 4 Day 1 | Summary of primary PK parameters for Buparlisib plasma concentration | 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days) | 
| Buparlisb PK Parameter: Cmax at Cycle 4 Day 1 | Summary of primary PK parameters for buparlisib plasma concentration | Cycle 4 Day 1 (each cycle is 28 days) | 
| Buparlisib PK Parameter: Tmax at Cycle 4 Day 1 | Summary of primary PK parameters for buparlisib plasma concentration | Cycle 4 Day 1 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neoadjuvant, BYL719, alpelisib, Breast Cancer, BKM120, buparlisib, Pathological Complete Response, hormone receptor-positive, HER2 negative, Objective Response Rate