Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women
- Registration Number
- NCT01923168
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 340
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + Letrozole Placebo 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. Buparlisib + Letrozole buparlisib Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily. Alpelisib + Letrozole alpelisib Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
- Primary Outcome Measures
Name Time Method Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort 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 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 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 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.
- Secondary Outcome Measures
Name Time Method 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 pCR and Objective response rate according to RECIST 1.1 per investigator assessment 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) Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR
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) 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.
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 pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment
Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Mutant Cohort After 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.
Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort After 24 weeks of treatment 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.
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 Mutant Cohort: Non-responders as Per pCR.
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) 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.
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) Summary of primary PK parameters for Letrozole plasma concentration
Buparlisib PK Parameter: Tmax at Cycle 4 Day 1 Cycle 4 Day 1 (each cycle is 28 days) Summary of primary PK parameters for buparlisib plasma concentration
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) Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: non-responders as per pCR
Alpelisib PK Parameter: Tmax at Cycle 4 Day 1 Cycle 4 Day 1 (each cycle is 28 days) Summary of primary PK parameters for alpelisib plasma concentration
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) Summary of primary PK parameters for alpelisib plasma concentration
Letrozole PK Parameter: Tmax at Cycle 4 Day 1 Cycle 4 Day 1 (each cycle is 28 days) Summary of primary PK parameters for letrozole plasma concentration
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) Summary of primary PK parameters for Buparlisib plasma concentration
Buparlisib PK Parameter: Cmax at Cycle 1 Day 1 Cycle 1 Day 1 (each cycle is 28 days) Summary of primary PK parameters for buparlisib plasma concentration
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: responders as per pCR
Alpelisib and PK Parameter: Tmax at Cycle 1 Day 1 Cycle 1 Day 1 (each cycle is 28 days) Summary of primary PK parameters for alpelisib plasma concentration
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) Summary of primary PK parameters for alpelisib plasma concentration
Alpelisib PK Parameter: Cmax at Cycle 4 Day 1 Cycle 4 Day 1 (each cycle is 28 days) Summary of primary PK parameters for alpelisib plasma concentration
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) Summary of primary PK parameters for Letrozole plasma concentration
Letrozole PK Parameter: Cmax at Cycle 1 Day 1 Cycle 1 Day 1 (each cycle is 28 days) Summary of primary PK parameters for letrozole plasma concentration
Letrozole PK Parameter: Tmax at Cycle 1 Day 1 Cycle 1 Day 1 (each cycle is 28 days) Summary of primary PK parameters for letrozole plasma concentration
Buparlisb PK Parameter: Cmax at Cycle 4 Day 1 Cycle 4 Day 1 (each cycle is 28 days) Summary of primary PK parameters for buparlisib plasma concentration
Alpelisib PK Parameter: Cmax at Cycle 1 Day 1 Cycle 1 Day 1 (each cycle is 28 days) Summary of primary PK parameters for alpelisib plasma concentration
Letrozole PK Parameter: Cmax at Cycle 4 Day 1 Cycle 4 Day 1 (each cycle is 28 days) Summary of primary PK parameters for letrozole plasma concentration
Buparlisib PK Parameter: Tmax at Cycle 1 Day 1 Cycle 1 Day 1 (each cycle is 28 days) Summary of primary PK parameters for buparlisib plasma concentration
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) Summary of primary PK parameters for Buparlisib plasma concentration
Trial Locations
- Locations (24)
Emory University School of Medicine/Winship Cancer Institute SC
🇺🇸Atlanta, Georgia, United States
Los Angeles Hematology/Oncology Medical Group Onc Dept.
🇺🇸Los Angeles, California, United States
Presbyterian Hospital of Dallas TexasOncology@PresbyterianHosp
🇺🇸Dallas, Texas, United States
University of California at Los Angeles UCLA SC
🇺🇸Los Angeles, California, United States
Mercy Medical Center Medical Oncology & Hematology
🇺🇸Baltimore, Maryland, United States
Dana Farber Cancer Institute BYL719A2201
🇺🇸Boston, Massachusetts, United States
Duke University Medical Center Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Cancer Care Centers of South Texas HOAST CCC of So. TX- San Antonio(2)
🇺🇸San Antonio, Texas, United States
Cancer Therapy & Research Center UT Health Science Center InstituteForDrugDevelopment(5)
🇺🇸San Antonio, Texas, United States
Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Highlands Oncology Group
🇺🇸Fayetteville, Arkansas, United States
University of Alabama at Birmingham/ Kirklin Clinic Univ AL - PI
🇺🇸Birmingham, Alabama, United States
University of California San Francisco BYL719A2201 - SC
🇺🇸San Francisco, California, United States
Vanderbilt Ingram Cancer Center Vanderbilt Health 100 Oaks
🇺🇸Nashville, Tennessee, United States
Northwest Cancer Specialists Vancouver Loc
🇺🇸Portland, Oregon, United States
Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Johns Hopkins Med. BYL719A2201
🇺🇸Baltimore, Maryland, United States
Mayo Clinic - Rochester BYL719A2201 - SC
🇺🇸Rochester, Minnesota, United States
Texas Oncology Houston Memorial City SC
🇺🇸Houston, Texas, United States
Texas Oncology, P.A.
🇺🇸Bedford, Texas, United States
Texas Oncology Texas Oncology - Sammons
🇺🇸Dallas, Texas, United States
Virginia Oncology Associates SC
🇺🇸Norfolk, Virginia, United States
Northwest Medical Specialties Dept.ofNW Med. Specialties
🇺🇸Tacoma, Washington, United States
Seattle Cancer Care Alliance SC-3
🇺🇸Seattle, Washington, United States
Novartis Investigative Site
🇪🇸Madrid, Spain