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

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ClinicalTrials.gov Identifier: NCT01923168
Recruitment Status : Completed
First Posted : August 15, 2013
Results First Posted : September 14, 2018
Last Update Posted : September 14, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

August 13, 2013
August 15, 2013
July 4, 2018
September 14, 2018
September 14, 2018
March 11, 2014
July 7, 2017   (Final data collection date for primary outcome measure)
  • Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

Pathological Complete Response [ Time Frame: After 24 weeks of treatment ]
Measure Pathological complete Response after 24 weeks of treatment
Complete list of historical versions of study NCT01923168 on ClinicalTrials.gov Archive Site
  • 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 [ Time Frame: After 24 weeks of treatment ]
    pCR and Objective response rate according to RECIST 1.1 per investigator assessment 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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: 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: 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 Mutant Cohort: Non-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: 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) ]
    Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: non-responders as per pCR
  • Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Mutant Cohort [ 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 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.
  • Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort [ 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. 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.
  • Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1 [ Time Frame: 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
  • Alpelisib PK Parameter: Cmax at Cycle 1 Day 1 [ Time Frame: Cycle 1 Day 1 (each cycle is 28 days) ]
    Summary of primary PK parameters for alpelisib plasma concentration
  • Alpelisib and PK Parameter: Tmax at Cycle 1 Day 1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Cycle 4 Day 1 (each cycle is 28 days) ]
    Summary of primary PK parameters for alpelisib plasma concentration
  • Alpelisib PK Parameter: Tmax at Cycle 4 Day 1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Cycle 1 Day 1 (each cycle is 28 days) ]
    Summary of primary PK parameters for letrozole plasma concentration
  • Letrozole PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1 [ Time Frame: 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
  • Letrozole PK Parameter: Cmax at Cycle 4 Day 1 [ Time Frame: Cycle 4 Day 1 (each cycle is 28 days) ]
    Summary of primary PK parameters for letrozole plasma concentration
  • Letrozole PK Parameter: Tmax at Cycle 4 Day 1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Cycle 1 Day 1 (each cycle is 28 days) ]
    Summary of primary PK parameters for buparlisib plasma concentration
  • Buparlisib PK Parameter: Tmax at Cycle 1 Day 1 [ Time Frame: 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 [ Time Frame: 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
  • Buparlisb PK Parameter: Cmax at Cycle 4 Day 1 [ Time Frame: Cycle 4 Day 1 (each cycle is 28 days) ]
    Summary of primary PK parameters for buparlisib plasma concentration
  • Buparlisib PK Parameter: Tmax at Cycle 4 Day 1 [ Time Frame: Cycle 4 Day 1 (each cycle is 28 days) ]
    Summary of primary PK parameters for buparlisib plasma concentration
  • Objective response rate according to RECIST 1.1 criteria [ Time Frame: After 24 weeks of treatment ]
    Objective response rate according to RECIST 1.1 criteria after 24 weeks of treatment
  • Frequency and severity, of AEs and lab abnormalties [ Time Frame: During 24 weeks of treatment ]
    To evaluate the safety and tolerability of study treatment based on the frequency, severity AEs, lab abnormalities
  • Rate breast conserving surgery [ Time Frame: After 24 weeks of treatment ]
    Rate of breast conserving surgery, following completion of 24 weeks of treatment
  • Molecular markers and correlation with response [ Time Frame: Baseline, Day 15 and 24 weeks of treatment ]
    Correlation between pCR and change in Ki67 from baseline to day 15 and baseline to surgery
  • PEPI (preoperative endocrine prognostic index) score [ Time Frame: After 24 weeks of treatment ]
    To assess the Preoperative endocrine prognostic index (PEPI) score after 24 weeks of treatment
  • Plasma concentration of BYL719/buparlisib and letrozole when given in combination [ Time Frame: Cycle 1 (Day 1, 2, 8, 15, 22), Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4(Day 1 and Day 2), Cycle 5 Day 1 and Cycle 6 Day 1 ]
    Plasma concentration time profiles of BYL719/buparlisib and appropriate individual PK parameters Plasma concentration time profiles of letrozole and appropriate individual PK parameters
Not Provided
Not Provided
 
Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women
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
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.
Not Provided
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Breast Cancer
  • Drug: alpelisib
    BYL719 + Letrozole
    Other Name: BYL719
  • Drug: buparlisib
    BKM120 + Letrozole
    Other Name: BKM120
  • Drug: Placebo
    Placebo (of BYL719 or BKM120) + Letrozole
    Other Name: BYL719 Placebo, BKM120 Placebo
  • Experimental: Alpelisib + Letrozole
    Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
    Intervention: Drug: alpelisib
  • Experimental: Buparlisib + Letrozole
    Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
    Intervention: Drug: buparlisib
  • Placebo Comparator: 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.
    Intervention: Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
340
372
July 8, 2017
July 7, 2017   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: Female
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Canada,   Colombia,   Czechia,   Germany,   Hong Kong,   Israel,   Italy,   Japan,   Lebanon,   Netherlands,   Spain,   United States
Czech Republic,   France,   South Africa
 
NCT01923168
CBYL719A2201
2013-001862-41 ( EudraCT Number )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP