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NCT01923168

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

Completed Phase 2 Results posted Last updated 14 September 2018
What this trial tests

Phase 2 trial testing alpelisib in Breast Cancer in 340 participants. Completed in 8 July 2017.

Timeline
11 March 2014
Primary endpoint
7 July 2017
8 July 2017

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingtriple
Primary purposetreatment
Enrollment340
Start date11 March 2014
Primary completion7 July 2017
Estimated completion8 July 2017
Sites86 locations across Hong Kong, Colombia, Italy, Japan, Netherlands, Belgium, Austria, Germany

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

18 and older, female only, with Breast Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort Primary · 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.

GroupValue95% CI
Alpelisib + Letrozole1.70.2 – 6.3
Placebo + Letrozole3.00.8 – 7.7
Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Wild-type Cohort Primary · 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.

GroupValue95% CI
Alpelisib + Letrozole2.80.8 – 7.3
Placebo + Letrozole1.70.2 – 6.4
Objective Response Rate Per Investigator Assessment According to RECIST 1.1 for Alpelisib vs. Placebo - PIK3CA Mutant Cohort Primary · 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 fro

GroupValue95% CI
Alpelisib + Letrozole43.334.6 – 52.4
Placebo + Letrozole44.836.5 – 53.3
Objective Response Rate According to RECIST 1.1 Per Investigator Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort Primary · 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 fro

GroupValue95% CI
Alpelisib + Letrozole63.455.1 – 71.0
Placebo + Letrozole61.051.8 – 69.6
Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Mutant Cohort Secondary · 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.

Breast conserving surgery
GroupValue95% CI
Alpelisib + Letrozole56.747.6 – 65.4
Placebo + Letrozole50.742.2 – 59.2
No Surgery
GroupValue95% CI
Alpelisib + Letrozole15.09.3 – 22.6
Placebo + Letrozole9.04.8 – 15.2
Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort Secondary · 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.

Breast conserving surgery
GroupValue95% CI
Alpelisib + Letrozole50.742.5 – 58.9
Placebo + Letrozole62.753.6 – 71.2
No Surgery
GroupValue95% CI
Alpelisib + Letrozole18.312.5 – 25.6
Placebo + Letrozole8.54.5 – 15.2
Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR Secondary · 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

Baseline
GroupValue95% CI
Alpelisib + Letrozole5.05 – 5
Placebo + Letrozole11.05 – 17
C1D15: % change from Baseline
GroupValue95% CI
Alpelisib + Letrozole-80.0-80 – -80
Placebo + Letrozole80.080 – 80
Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR Secondary · 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.

Baseline
GroupValue95% CI
Alpelisib + Letrozole14.00 – 82
Placebo + Letrozole13.03 – 89
C1D15 % change from Baseline
GroupValue95% CI
Alpelisib + Letrozole-62.5-97 – 467
Placebo + Letrozole-60.0-96 – 733
EOT % change from Baseline
GroupValue95% CI
Alpelisib + Letrozole-51.2-94 – 400
Placebo + Letrozole-60.0-97 – 223
Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Responders as Per pCR Secondary · 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

Baseline
GroupValue95% CI
Alpelisib + Letrozole16.53 – 30
Placebo + Letrozole20.020 – 20
C1D15: % change from Baseline
GroupValue95% CI
Alpelisib + Letrozole-80.0-80 – -80
EOT % change from Baseline
GroupValue95% CI
Alpelisib + Letrozole-45.0-90 – 0
Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Non-responders as Per pCR Secondary · 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

Baseline
GroupValue95% CI
Alpelisib + Letrozole16.03 – 60
Placebo + Letrozole18.04 – 85
C1D15 % change from Baseline
GroupValue95% CI
Alpelisib + Letrozole-60.0-97 – 220
Placebo + Letrozole-52.0-93 – 50
EOT % change from Baseline
GroupValue95% CI
Alpelisib + Letrozole-60.0-90 – 190
Placebo + Letrozole-71.1-100 – 250
Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Mutant Cohort Secondary · 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.

GroupValue95% CI
Alpelisib + Letrozole1
Placebo + Letrozole0
Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort Secondary · 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.

GroupValue95% CI
Alpelisib + Letrozole1
Placebo + Letrozole1

Adverse events — posted to ClinicalTrials.gov

Time frame: All Adverse Events reported in this record are on-treatment events (from first dose of study treatment to last dose of study treatment + 30 days, duration expected to be a total of approximately 25 weeks).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Alpelisib + Letrozole
Serious: 21/130 (16%)
Deaths: 1/130
Buparlisib + Letrozole
Serious: 22/81 (27%)
Deaths: 0/81
Placebo + Letrozole
Serious: 6/125 (5%)
Deaths: 1/125

Serious adverse events (50 terms)

ReactionSystemAlpelisib + LetrozoleBuparlisib + LetrozolePlacebo + Letrozole
Alanine aminotransferase increasedInvestigations
HyperglycaemiaMetabolism and nutrition disorders
Aspartate aminotransferase increasedInvestigations
HepatotoxicityHepatobiliary disorders
RashSkin and subcutaneous tissue disorders
Atrial fibrillationCardiac disorders
ColitisGastrointestinal disorders
General physical health deteriorationGeneral disorders
PyrexiaGeneral disorders
DehydrationMetabolism and nutrition disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
PruritusSkin and subcutaneous tissue disorders
Rash maculo-papularSkin and subcutaneous tissue disorders
Cardiac disorderCardiac disorders
Cardiac failureCardiac disorders
Stress cardiomyopathyCardiac disorders
IritisEye disorders
DiarrhoeaGastrointestinal disorders
NauseaGastrointestinal disorders
StomatitisGastrointestinal disorders
VomitingGastrointestinal disorders
Disease progressionGeneral disorders
Generalised oedemaGeneral disorders
MalaiseGeneral disorders
Other adverse events (55 terms — click to expand)

ReactionSystemAlpelisib + LetrozoleBuparlisib + LetrozolePlacebo + Letrozole
HyperglycaemiaMetabolism and nutrition disorders
DiarrhoeaGastrointestinal disorders
RashSkin and subcutaneous tissue disorders
NauseaGastrointestinal disorders
FatigueGeneral disorders
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
StomatitisGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Hot flushVascular disorders
AlopeciaSkin and subcutaneous tissue disorders
HeadacheNervous system disorders
DysgeusiaNervous system disorders
VomitingGastrointestinal disorders
DizzinessNervous system disorders
PruritusSkin and subcutaneous tissue disorders
Rash maculo-papularSkin and subcutaneous tissue disorders
AstheniaGeneral disorders
Dry skinSkin and subcutaneous tissue disorders
InsomniaPsychiatric disorders
Weight decreasedInvestigations
AnxietyPsychiatric disorders
HypertensionVascular disorders
Urinary tract infectionInfections and infestations
Dry mouthGastrointestinal disorders
ConstipationGastrointestinal disorders
Viral upper respiratory tract infectionInfections and infestations
Muscle spasmsMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
PyrexiaGeneral disorders
Blood creatinine increasedInvestigations
Blood glucose increasedInvestigations
DepressionPsychiatric disorders
DyspepsiaGastrointestinal disorders
Back painMusculoskeletal and connective tissue disorders
Breast painReproductive system and breast disorders
Vision blurredEye disorders
Oedema peripheralGeneral disorders
Procedural painInjury, poisoning and procedural complications

Most-reported serious reactions: Alanine aminotransferase increased, Hyperglycaemia, Aspartate aminotransferase increased, Hepatotoxicity, Rash, Atrial fibrillation, Colitis, General physical health deterioration.

Data from ClinicalTrials.gov NCT01923168 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
    Baselga J, Im SA, Iwata H, Cortés J, et al · · 2017 · cited 420× · PMID 28576675 · DOI 10.1016/s1470-2045(17)30376-5
  2. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior.
    Jiang N, Dai Q, Su X, Fu J, et al · · 2020 · cited 419× · PMID 32333246 · DOI 10.1007/s11033-020-05435-1
  3. Breast Cancer Treatments: Updates and New Challenges.
    Burguin A, Diorio C, Durocher F. · · 2021 · cited 297× · PMID 34442452 · DOI 10.3390/jpm11080808
  4. Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer.
    Dong C, Wu J, Chen Y, Nie J, et al · · 2021 · cited 260× · PMID 33790792 · DOI 10.3389/fphar.2021.628690
  5. Recent Advances in the Treatment of Breast Cancer.
    Tong CWS, Wu M, Cho WCS, To KKW. · · 2018 · cited 239× · PMID 29963498 · DOI 10.3389/fonc.2018.00227
  6. PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects.
    Mishra R, Patel H, Alanazi S, Kilroy MK, et al · · 2021 · cited 207× · PMID 33801659 · DOI 10.3390/ijms22073464
  7. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design.
    Massacesi C, Di Tomaso E, Urban P, Germa C, et al · · 2016 · cited 171× · PMID 26793003 · DOI 10.2147/ott.s89967
  8. Efficacy of PI3K inhibitors in advanced breast cancer.
    Verret B, Cortes J, Bachelot T, Andre F, et al · · 2019 · cited 92× · PMID 31859349 · DOI 10.1093/annonc/mdz381

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