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Completed

NCT Number: NCT01923168

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

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.

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Key information

Conditions

Breast Cancer Breast Diseases Breast Neoplasms Neoplasms Neoplasms by Site Skin Diseases Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 2

Primary location

Novartis Investigative Site, Kingswood, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Alpelisib

Drug

BYL719 + Letrozole

Other names: BYL719

Buparlisib

Drug

BKM120 + Letrozole

Other names: BKM120

Placebo

Drug

Placebo (of BYL719 or BKM120) + Letrozole

Other names: BYL719 Placebo, BKM120 Placebo

Primary outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study 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

Important dates

Study start
2014
Primary completion
2017
Study completion
2017
First posted
Aug 15, 2013
Registry last updated
Sep 14, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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