Breast Cancer
Conditions
Keywords
advanced breast cancer, PIK3CA, CDK 4/6 inhibitor, fulvestrant, letrozole, HR+, HER2-negative, post menopausal, pre-menopausal, aromatase inhibitor, endocrine treatment, AI, ET
Brief summary
This was a Phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in subjects (pre- and post-menopausal women and men) with HR-positive, HER2-negative aBC harboring PIK3CA mutation(s) in the tumor, whose disease had progressed on or after prior treatments.
Detailed description
The study comprised two phases: 1. Core Phase: included a treatment phase for all subjects from first subject first treatment (FSFT) until disease progression, unacceptable toxicity, or death until 18 months post last subject first treatment (LSFT) + 1 month safety follow-up (total 19 months post LSFT), discontinuation from the study treatment for any other reason, or sponsor terminates the study. At the start of the Core Phase, subjects were assigned to Cohort A, Cohort B, or Cohort C based on previous therapy as follows: * Cohort A: alpelisib (300 mg oral QD) + fulvestrant (500 mg intramuscular (IM)) to subjects whose last prior treatment was a CDK4/6i plus any AI; * Cohort B: alpelisib (300 mg oral QD) + letrozole (2.5 mg oral QD) to subjects whose last prior treatment was a CDK4/6i plus fulvestrant; * Cohort C: alpelisib (300 mg oral QD)+ fulvestrant (500 mg IM) to subjects who failed prior AI based therapy and whose last prior treatment was systemic chemotherapy or endocrine therapy (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI). Endocrine therapy included letrozole, fulvestrant and CDK 4/6 inhibitor plus fulvestrant. 2. Extension Phase: included a treatment phase starting at the end of the treatment Core Phase until last subject last visit(LSLV) (up to 36 months). Following the end of the Core Phase, subjects continuing to derive benefit from study treatment who were not eligible for Post-Study Drug Supply (PSDS) in their country based on local regulations were re-consented and transitioned to the Extension Phase. Subjects continued on their existing study treatment assigned in the Core Phase until disease progression/lack of clinical benefit or any other reason for which the subject may have been discontinued from study treatment. If PSDS became available for a subject, the subject was to be discontinued from the study and to access treatment via PSDS. When subjects discontinued treatment for any reason, the end of treatment visit was performed after discontinuation of the medication , followed by safety follow-up 30 days after last dose. A total of 340 subjects were planned to be enrolled, with approximately 112 subjects in each cohort. In the Core Phase, 379 subjects were analyzed, with 127 subjects in Cohort A, 126 subjects in Cohort B, and 126 subjects in Cohort C. In the Extension Phase, 11 subjects were analyzed, with 1 subject in Cohort A and 10 subjects in Cohort C.
Interventions
DRUGAlpelisib
300 mg of alpelisib film-coated tablets administered orally once daily
DRUGFulvestrant
500 mg of fulvestrant via intramuscular injection administered on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days
DRUGLetrozole
2.5 mg of letrozole film-coated tablets administered orally once daily
DRUGGoserelin
3.6 mg of goserelin via injectable subcutaneous implant administered every 28 days. Only for men in Cohort B and premenopausal women.
DRUGLeuprolide
7.5 mg of leuprolide via injectable intramuscular depot administered every 28 days. Only for men in cohort B and premenopausal women.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Subjects eligible for inclusion in the Core Phase of the study fulfilled the following key inclusion criteria: * Subject was an adult male or female ≥ 18 years of age. * Subjects with histologically and/or cytologically confirmed diagnosis of estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive breast cancer by local laboratory. * Subjects with a confirmed human epidermal growth factor receptor-2 (HER2)-negative aBC. * Subjects with gene encoding the p110alpha catalytic subunit of PI3K (phosphatidylinositol-3-kinase) (PIK3CA) mutation. * In case of women, both premenopausal and postmenopausal subjects were allowed to be included in this study. * Subjects with documented evidence of tumor progression on or after: i. Cyclin-Dependent Kinase 4 and 6 inhibitor (CDK4/6i) treatment as last treatment regimen in Cohorts A and B. ii. aromatase inhibitor (AI) treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET (monotherapy or combination except CDK4/6i + AI) as last treatment regimen in Cohort C. Upon completion of enrollment of Cohort B, subjects who received CDK4/6i + fulvestrant as immediate prior therapy were eligible for Cohort C. iii. No more than 2 prior anticancer therapies for aBC. iv. Received no more than 1 prior regimen of chemotherapy for the treatment of advanced/metastatic disease was permitted. v. Recovered to grade 1 or better from any adverse events (AEs) related to previous anticancer therapy prior to study entry (except alopecia or other toxicities not considered a safety risk for the subject at the investigator's discretion). * Subjects with: i. Measurable disease, i.e., at least 1 measurable lesion as per RECIST v1.1 criteria; or ii. If no measurable disease was present, at least 1 predominantly lytic bone lesion had to be present. * Subjects with adequate bone marrow and coagulation function, liver function and renal function as shown by laboratory values. * Subjects with Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2. Key
Exclusion criteria
were: * Subjects with a known hypersensitivity to alpelisib, fulvestrant, letrozole, goserelin, or leuprolide or to any of their excipients. * Subjects with prior treatment with any PI3K inhibitor (PI3Ki). * Subjects with central nervous system (CNS) involvement unless they met all of the following criteria: i. At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment, ii. Clinically stable CNS tumor at the time of screening untreated or without evidence of progressions for at least 4 weeks after treatment as determined by clinical examination and brain imaging (magnetic resonance imaging (MRI) or computed tomography (CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment. * Subjects with an established diagnosis of diabetes mellitus type I or uncontrolled type II. * Any concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, contraindicate subject participation in the study (e.g., chronic active hepatitis, severe hepatic impairment, etc.). * Subjects with a history of noncompliance to medical regimens. * Subjects with impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of the study drugs based on investigator discretion. * Subjects with documented pneumonitis/interstitial lung disease which was active and requiring treatment. * Subjects concurrently using other anticancer therapy. All anticancer therapy had to be discontinued prior to Day 1 of study treatment. * Subjects who had major surgery within 14 days prior to starting treatment with alpelisib, or did not recover from major side effects. * Subjects with significant cardiac abnormalities. * History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis. * Subjects who did not use highly effective contraception while on alpelisib and through the duration after the final dose of alpelisib (not applicable to postmenopausal women). * Subjects with unresolved osteonecrosis of the jaw. Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months | At 6 months | Percentage of participants who were alive without disease progression at 6-month follow-up based on local investigator assessment per RECIST v1.1 in Cohort A, Cohort B and Cohort C. Participants who progressed, died, or discontinued study before 6 months were counted as a failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Core Phase: Progression Free Survival on Next Line Treatment (PFS2) | From date of first dose to date of first documented progression on next-line therapy or death, up to approximately 55 months | PFS2 is defined as time from the date of first dose of study medication to the date of first documented progression on next-line therapy or death from any cause. The first documented progression on next-line treatment is based on investigator assessment of progressive disease. PFS2 was estimated using the Kaplan-Meier method. |
| Core Phase: Overall Response Rate (ORR) | Up to 46 months | ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1 in each cohort. CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm and all lymph nodes assigned as non-target lesions must be non-pathological in size (\<10 mm short axis) PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Core Phase: Clinical Benefit Rate (CBR) | Up to 46 months | CBR is defined as the percentage of participants with a BOR of CR or PR or an overall lesion response of stable disease (SD) or Non-CR/ Non-PD lasting ≥ 24 weeks based on local investigator's assessment according to RECIST v1.1. CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm and all lymph nodes assigned as non-target lesions must be non-pathological in size (\<10 mm short axis) PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. |
| Core Phase: Progression Free Survival (PFS) | From date of first dose to date of first documented progression or death, up to 46 months | PFS is defined as the time from the date of first dose of study medication to the date of the first documented progression or death due to any cause occurring in the study. PFS was assessed based on local investigator's assessment according to RECIST v1.1. PFS was censored if no PFS event was observed before the cut-off date. The censoring date was the date of last adequate tumor assessment before the cut-off date. If a PFS event was observed after two or more missing or non-adequate tumor assessments, then PFS was censored at the last adequate tumor assessment. PFS was estimated using the Kaplan-Meier method. |
| Core Phase: Overall Survival (OS) | From date of first dose and up to approximately 55 months | OS is defined as the time of start of treatment to date of death or lost to follow-up. If a subject was not known to have died, then the OS data was censored at the date of the last known alive status for the patient. |
| Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Day 1 of each extension cycle up to Cycle 29 (each cycle lasting 28 days); median duration of exposure to study treatment (alpelisib or fulvestrant) = 41 months | Clinical Benefit Rate, as assessed by the Investigator during the Extension Phase, was defined as the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR), or an overall lesion response of Stable Disease (SD) or non-complete response/non-progressive disease that lasted at least 24 weeks, based on the local investigator's assessment according to Response Evaluation Criteria in Solid Tumors version 1.1. |
| Core Phase: Duration of Response (DOR) | From date of first documented response to first documented progression or death, up to 33.3 months | DOR is the time from the date of first documented response (confirmed CR or PR based on local investigator's assessment according to RECIST v1.1) to the date of first documented progression or death due to underlying cancer. Subjects continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. DOR was estimated using the Kaplan-Meier method. |
Countries
Argentina, Belgium, Canada, Chile, Denmark, France, Germany, India, Israel, Italy, Japan, Mexico, Netherlands, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted in 92 centers across 19 countries
Pre-assignment details
Screening assessments occurred before 21 days of the start of treatment.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI Participants who received any CDK 4/6i plus AI as immediate prior treatment will receive alpelisib + fulvestrant | 127 |
| Cohort B: Pre-treated With CDK 4/6i + Fulvestrant Patients who received any CDK 4/6i plus fulvestrant as immediate prior treatment will receive alpelisib + letrozole | 126 |
| Cohort C: Pre-treated With Systemic Chemotherapy or ET Participants who received systemic chemotherapy or ET (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib + fulvestrant. | 126 |
| Total | 379 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Phase | Adverse Event | 20 | 14 | 13 |
| Core Phase | Death | 3 | 2 | 4 |
| Core Phase | Physician Decision | 7 | 13 | 5 |
| Core Phase | Progressive disease | 89 | 88 | 90 |
| Core Phase | Protocol deviation | 1 | 1 | 0 |
| Core Phase | Subject/guardian decision | 5 | 8 | 4 |
| Core Phase | Technical problems | 1 | 0 | 0 |
| Extension Phase | Adverse Event | 0 | 0 | 1 |
| Extension Phase | Physician Decision | 1 | 0 | 3 |
| Extension Phase | Subject/guardian decision | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort A: Pre-treated With CDK 4/6i + AI | Cohort B: Pre-treated With CDK 4/6i + Fulvestrant | Cohort C: Pre-treated With Systemic Chemotherapy or ET | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 32 Participants | 46 Participants | 43 Participants | 121 Participants |
| Age, Categorical Between 18 and 65 years | 95 Participants | 80 Participants | 83 Participants | 258 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants | 8 Participants | 28 Participants | 48 Participants |
| Race/Ethnicity, Customized Black | 6 Participants | 1 Participants | 1 Participants | 8 Participants |
| Race/Ethnicity, Customized Caucasian | 81 Participants | 85 Participants | 83 Participants | 249 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 7 Participants | 3 Participants | 13 Participants |
| Race/Ethnicity, Customized Pacific islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 23 Participants | 24 Participants | 11 Participants | 58 Participants |
| Sex: Female, Male Female | 127 Participants | 126 Participants | 125 Participants | 378 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 78 / 127 | 76 / 126 | 67 / 126 | 0 / 1 | 0 / 0 | 1 / 10 |
| other Total, other adverse events | 126 / 127 | 126 / 126 | 124 / 126 | 1 / 1 | 0 / 0 | 10 / 10 |
| serious Total, serious adverse events | 37 / 127 | 48 / 126 | 38 / 126 | 0 / 1 | 0 / 0 | 3 / 10 |
Outcome results
Primary
Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months
Percentage of participants who were alive without disease progression at 6-month follow-up based on local investigator assessment per RECIST v1.1 in Cohort A, Cohort B and Cohort C. Participants who progressed, died, or discontinued study before 6 months were counted as a failure.
Time frame: At 6 months
Population: Subjects who have been assigned and received at least one dose of the study treatment. They must have a confirmed PI3KCA mutation from a Novartis designated laboratory.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI | Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months | 53.8 Percentage of participants |
| Cohort B: Pre-treated With CDK 4/6i + Fulvestrant | Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months | 46.5 Percentage of participants |
| Cohort C: Pre-treated With Systemic Chemotherapy or ET | Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months | 53.0 Percentage of participants |
Secondary
Core Phase: Clinical Benefit Rate (CBR)
CBR is defined as the percentage of participants with a BOR of CR or PR or an overall lesion response of stable disease (SD) or Non-CR/ Non-PD lasting ≥ 24 weeks based on local investigator's assessment according to RECIST v1.1. CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm and all lymph nodes assigned as non-target lesions must be non-pathological in size (\<10 mm short axis) PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time frame: Up to 46 months
Population: Subjects who have been assigned and received at least one dose of the study treatment. They must have a confirmed PI3KCA mutation from a Novartis designated laboratory.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI | Core Phase: Clinical Benefit Rate (CBR) | 46.2 Percentage of participants |
| Cohort B: Pre-treated With CDK 4/6i + Fulvestrant | Core Phase: Clinical Benefit Rate (CBR) | 35.1 Percentage of participants |
| Cohort C: Pre-treated With Systemic Chemotherapy or ET | Core Phase: Clinical Benefit Rate (CBR) | 38.3 Percentage of participants |
Secondary
Core Phase: Duration of Response (DOR)
DOR is the time from the date of first documented response (confirmed CR or PR based on local investigator's assessment according to RECIST v1.1) to the date of first documented progression or death due to underlying cancer. Subjects continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. DOR was estimated using the Kaplan-Meier method.
Time frame: From date of first documented response to first documented progression or death, up to 33.3 months
Population: Subjects who have been assigned and received at least one dose of the study treatment. They must have a confirmed PI3KCA mutation from a Novartis designated laboratory. Additionally, subjects must have a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI | Core Phase: Duration of Response (DOR) | 13.8 Months |
| Cohort B: Pre-treated With CDK 4/6i + Fulvestrant | Core Phase: Duration of Response (DOR) | 6.5 Months |
| Cohort C: Pre-treated With Systemic Chemotherapy or ET | Core Phase: Duration of Response (DOR) | 16.5 Months |
Secondary
Core Phase: Overall Response Rate (ORR)
ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1 in each cohort. CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm and all lymph nodes assigned as non-target lesions must be non-pathological in size (\<10 mm short axis) PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to 46 months
Population: Subjects who have been assigned and received at least one dose of the study treatment. They must have a confirmed PI3KCA mutation from a Novartis designated laboratory.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI | Core Phase: Overall Response Rate (ORR) | 19.3 Percentage of participants |
| Cohort B: Pre-treated With CDK 4/6i + Fulvestrant | Core Phase: Overall Response Rate (ORR) | 17.5 Percentage of participants |
| Cohort C: Pre-treated With Systemic Chemotherapy or ET | Core Phase: Overall Response Rate (ORR) | 25.2 Percentage of participants |
Secondary
Core Phase: Overall Survival (OS)
OS is defined as the time of start of treatment to date of death or lost to follow-up. If a subject was not known to have died, then the OS data was censored at the date of the last known alive status for the patient.
Time frame: From date of first dose and up to approximately 55 months
Population: Subjects who have been assigned and received at least one dose of the study treatment. They must have a confirmed PI3KCA mutation from a Novartis designated laboratory.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI | Core Phase: Overall Survival (OS) | 27.3 Months |
| Cohort B: Pre-treated With CDK 4/6i + Fulvestrant | Core Phase: Overall Survival (OS) | 29.0 Months |
| Cohort C: Pre-treated With Systemic Chemotherapy or ET | Core Phase: Overall Survival (OS) | 20.7 Months |
Secondary
Core Phase: Progression Free Survival on Next Line Treatment (PFS2)
PFS2 is defined as time from the date of first dose of study medication to the date of first documented progression on next-line therapy or death from any cause. The first documented progression on next-line treatment is based on investigator assessment of progressive disease. PFS2 was estimated using the Kaplan-Meier method.
Time frame: From date of first dose to date of first documented progression on next-line therapy or death, up to approximately 55 months
Population: Subjects who have been assigned and received at least one dose of the study treatment. They must have a confirmed PI3KCA mutation from a Novartis designated laboratory.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI | Core Phase: Progression Free Survival on Next Line Treatment (PFS2) | 15.2 Months |
| Cohort B: Pre-treated With CDK 4/6i + Fulvestrant | Core Phase: Progression Free Survival on Next Line Treatment (PFS2) | 13.0 Months |
| Cohort C: Pre-treated With Systemic Chemotherapy or ET | Core Phase: Progression Free Survival on Next Line Treatment (PFS2) | 13.5 Months |
Secondary
Core Phase: Progression Free Survival (PFS)
PFS is defined as the time from the date of first dose of study medication to the date of the first documented progression or death due to any cause occurring in the study. PFS was assessed based on local investigator's assessment according to RECIST v1.1. PFS was censored if no PFS event was observed before the cut-off date. The censoring date was the date of last adequate tumor assessment before the cut-off date. If a PFS event was observed after two or more missing or non-adequate tumor assessments, then PFS was censored at the last adequate tumor assessment. PFS was estimated using the Kaplan-Meier method.
Time frame: From date of first dose to date of first documented progression or death, up to 46 months
Population: Subjects who have been assigned and received at least one dose of the study treatment. They must have a confirmed PI3KCA mutation from a Novartis designated laboratory.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI | Core Phase: Progression Free Survival (PFS) | 8.0 Months |
| Cohort B: Pre-treated With CDK 4/6i + Fulvestrant | Core Phase: Progression Free Survival (PFS) | 5.6 Months |
| Cohort C: Pre-treated With Systemic Chemotherapy or ET | Core Phase: Progression Free Survival (PFS) | 5.6 Months |
Secondary
Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase
Clinical Benefit Rate, as assessed by the Investigator during the Extension Phase, was defined as the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR), or an overall lesion response of Stable Disease (SD) or non-complete response/non-progressive disease that lasted at least 24 weeks, based on the local investigator's assessment according to Response Evaluation Criteria in Solid Tumors version 1.1.
Time frame: Day 1 of each extension cycle up to Cycle 29 (each cycle lasting 28 days); median duration of exposure to study treatment (alpelisib or fulvestrant) = 41 months
Population: All subjects in Extension Phase who received at least 1 dose of study treatment. All patients consisted of 1 patient from Cohort A and 10 patients from Cohort C pulled together.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 1 Day 1 | 8 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 2 Day 1 | 7 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 3 Day 1 | 7 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 4 Day 1 | 6 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 5 Day 1 | 8 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 6 Day 1 | 7 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 7 Day 1 | 7 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 8 Day 1 | 6 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 9 Day 1 | 7 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 10 Day 1 | 5 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 11 Day 1 | 4 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 12 Day 1 | 7 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 13 Day 1 | 4 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 14 Day 1 | 5 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 15 Day 1 | 4 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 16 Day 1 | 3 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 17 Day 1 | 3 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 18 Day 1 | 3 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 19 Day 1 | 3 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 20 Day 1 | 3 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 21 Day 1 | 3 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 22 Day 1 | 3 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 23 Day 1 | 3 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 24 Day 1 | 2 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 25 Day 1 | 2 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 26 Day 1 | 2 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 27 Day 1 | 2 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 28 Day 1 | 2 Participants |
| Cohort A: Pre-treated With CDK 4/6i + AI | Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase | Extension Cycle 29 Day 1 | 1 Participants |