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

Phase 2CompletedNCT01923168

Novartis Pharmaceuticals340 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

340

Conditions

Interventions

BYL719 + Letrozole

BKM120 + Letrozole

Placebo (of BYL719 or BKM120) + Letrozole

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patient is an adult, female ≥ 18 years old at the time of informed consent 2. Patient has a histologically and/or cytologically confirmed diagnosis of breast cancer 3. Patient is postmenopausal. 4. Patient has T1c-T3, any N, M0, operable breast cancer 5. Patients must have measurable disease 6. Patient has diagnostic biopsy available for the analysis of PIK3CA mutation and Ki67 level. 7. Patient has estrogen-receptor and/or progesterone positive breast cancer as per local laboratory testing 8. 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: 1. Patient has locally recurrent or metastatic disease 2. Patient has received any systemic therapy (e.g. chemotherapy, targeted therapy, immunotherapy) or radiotherapy for current breast cancer disease before randomization. 3. Patient with type 1 diabetes mellitus or not adequately controlled type 2 diabetes mellitus 4. History of acute pancreatitis within 1 year of study entry 5. Uncontrolled hypertension

Locations (86)

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: After 24 weeks of treatment

Data from ClinicalTrials.gov

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Secondary Outcomes

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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Cycle 4 Day 1 (each cycle is 28 days)

NCT01923168 - Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women | Crick | Crick