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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 )

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: alpelisib Drug: buparlisib Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 340 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 11, 2014
Actual Primary Completion Date : July 7, 2017
Actual Study Completion Date : July 8, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Letrozole

Arm Intervention/treatment
Experimental: Alpelisib + Letrozole
Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
Drug: alpelisib
BYL719 + Letrozole
Other Name: BYL719

Experimental: Buparlisib + Letrozole
Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
Drug: buparlisib
BKM120 + Letrozole
Other Name: BKM120

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.
Drug: Placebo
Placebo (of BYL719 or BKM120) + Letrozole
Other Name: BYL719 Placebo, BKM120 Placebo




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.


  4. 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.



Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01923168


  Show 87 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Statistical Analysis Plan  [PDF] February 7, 2017
Study Protocol  [PDF] October 18, 2016


Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01923168     History of Changes
Other Study ID Numbers: CBYL719A2201
2013-001862-41 ( EudraCT Number )
First Posted: August 15, 2013    Key Record Dates
Results First Posted: September 14, 2018
Last Update Posted: September 14, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
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


Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
BYL719
alpelisib
Breast Cancer
BKM120
buparlisib
Pathological Complete Response
neoadjuvant
hormone receptor-positive
HER2 negative
Objective Response Rate

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs