Breast Neoplasms
Conditions
Brief summary
This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with inoperable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have progressed during or following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be performed in two stages. During Stage 1, participants will be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet combination. Those who experience disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.
Interventions
Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.
DRUGBevacizumab
Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.
DRUGEntinostat
Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.
DRUGExemestane
Exemestane will be given as 25 mg orally QD in each 21-day cycle.
DRUGFulvestrant
Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.
DRUGIpatasertib
Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
DRUGTamoxifen
Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.
DRUGAbemaciclib
Abemaciclib will be given as 150mg twice daily during each 28-day cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Both Stages: * Measurable disease per RECIST v1.1 * Adequate hematologic and end organ function * Disease progression during or after first- or second-line hormonal therapy with CDK4/6 inhibitor Inclusion Criteria for Stage 1: * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Metastatic or inoperable, locally advanced, histologically or cytologically confirmed invasive HR-positive HER2-negative breast cancer * Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study entry * Recurrence or progression following most recent systemic breast cancer therapy * Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease * Postmenopausal according to protocol-defined criteria * Life expectancy \>3 months * Available tumor specimen for determination of PD-L1 status Inclusion Criteria for Stage 2: * ECOG performance status of 0-2 * Ability to initiate treatment within 3 months after disease progression or unacceptable toxicity on a Stage 1 regimen
Exclusion criteria
for Both Stages: * Significant or uncontrolled comorbid disease as specified in the protocol * Uncontrolled tumor-related pain * Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes mellitus, or certain dermatologic conditions * Positive human immunodeficiency virus test * Active hepatitis B or C * Active tuberculosis * Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study treatment * Prior allogeneic stem cell or solid organ transplantation * History of malignancy other than breast cancer within 2 years prior to screening except those with negligible risk of metastasis/death * History of or known hypersensitivity to study drug or excipients * For patients entering Stage 2, recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Percentage of Participants With Objective Response | Up to 50.4 months | Objective response rate (ORR) was defined as the percentage of participants with an objective response of complete response (CR) or partial response (PR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) that have a reduction in short axis to \< 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. Percentages have been rounded off to the nearest whole number. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Clinical Benefit Rate (CBR) | Up to 51.9 months | CBR was defined as the percentage of participants with stable disease (SD) ≥ 24 weeks or with confirmed CR or PR, as determined by the investigator according to RECIST v1.1. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Percentages have been rounded off to the nearest whole number. |
| Stage 1: Overall Survival (OS) | From randomization to death (up to 62.2 months) | OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier method was used to estimate the median for OS. |
| Stage 1: Percentage of Participants Event-free for OS at Month 18 | At Month 18 | OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS at Month 18. Percentages have been rounded off to the nearest whole number. |
| Stage 1: Duration of Response (DOR) | From first occurrence of a documented OR to the first date of recorded PD or death (up to 50.4 months) | DOR was defined as the time from the first occurrence of a documented objective response (CR or PR) to the first date of recorded PD or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in study including baseline in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Participants who did not have documented PD or death, DOR was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for DOR. |
| Stages 1 and 2: Number of Participants With Adverse Events (AEs) | From baseline until 30 days (for AEs) or 135 days (for SAEs & AESIs) after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurred first (Stage 1: up to 52 months; Stage 2: up to 21.7 months) | An AE was any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE = serious adverse events; AESIs = adverse events of special interest. |
| Stage 1: Plasma Concentration of Entinostat | Predose on Day 1 of Cycles 1 and 2; 2-4 hours postdose on Day 1 Cycle 1 (Cycle length = 21 days) | — |
| Stage 1: Progression-free Survival (PFS) | From randomization to the first occurrence of PD or death (up to 51.9 months) | PFS was defined as the time from randomization to the date of the first recorded occurrence of PD or death from any cause (whichever occurred first) in Stage 1, as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in the study including baseline in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Participants who did not have documented PD or death, PFS was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for PFS. |
| Stage 1: Plasma Concentration of Ipatasertib | Predose and Postdose at 1 Hour, 2 Hour, 4 Hour, and 6 Hour on Day 15 Cycle 1; Post dose at 1-3 Hour on Day 15 Cycle 3 (Cycle length = 28 days) | — |
| Stage 1: Plasma Concentration of Fulvestrant | Predose on Day 1 of Cycle 2 and Cycle 3 (Cycle length = 28 days) | — |
| Stage 2: Plasma Concentration of Fulvestrant | Predose on Day 1 of Cycles 2 and 3 (Cycle length = 21 days) | Nominal time restarted to 0 at Stage 2. PK data for Stage was analyzed and reported for the subgroups \[crossover arms (Stage 1 to Stage 2)\] only. |
| Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 of Cycles 1, 2, 3, 4, 8 and 12; 30 minutes (mins) postdose on Day 1 Cycle 1; postdose on Day 120 and Treatment Discontinuation Visit (Cycle length = 21 days) | Nominal time restarted to 0 at Stage 2; RO5541267 = atezolizumab. PK data for Stage was analyzed and reported for the subgroups \[crossover arms (Stage 1 to Stage 2)\] only. |
| Stage 2: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Post-baseline (up to approximately 134 days) | Participants who received atezolizumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 t.u. greater than the titer of the baseline sample (treatment unaffected). Participants with a positive post-baseline sample has been reported here. |
| Stage 1: Plasma Concentration of Abemaciclib | Predose on Day 1 of Cycles 1, 2 and 3, and on Day 15 Cycle 1; 4-8 hours postdose on Day 1 Cycle 1 (Cycle length = 28 days) | — |
Countries
Israel, South Korea, United States
Participant flow
Recruitment details
A total of 144 participants with inoperable locally advanced or metastatic hormone receptor-positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer took part in the study at 26 investigative sites across the United States of America and South Korea from 22 December 2017 to 26 September 2024. The study is considered Completed because all the pre-planned study activities and analyses have been performed.
Pre-assignment details
The study consisted of two stages: Stage 1: participants were randomized to either the control arm (fulvestrant) or the experimental arms. Stage 2: participants from Stage 1 who experienced unacceptable toxicity, disease progression (PD), or loss of clinical benefit received treatment in Stage 2. Stage 1 participants who did not enter Stage 2 and Stage 2 participants who completed treatment entered the long-term survival follow-up.
Participants by arm
| Arm | Count |
|---|---|
| Fulvestrant Control Participants received fulvestrant, 500 mg, as an IM injection on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter until unacceptable toxicity or PD (1 cycle = 28 days). After Stage 1, participants who did not enter Stage 2 entered the long-term survival follow-up. | 25 |
| Stage 1: Fulvestrant + Atezolizumab Participants received fulvestrant, 500 mg, as an IM injection on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter along with atezolizumab 840 mg as an IV infusion on Days 1 and 15 of each cycle until unacceptable toxicity or loss of clinical benefit (1 cycle = 28 days). After Stage 1, participants who did not enter Stage 2 entered the long-term survival follow-up. | 31 |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib Participants received fulvestrant, 500 mg, as an IM injection on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter along with atezolizumab, 840 mg, as an IV infusion on Days 1 and 15 of each cycle and ipatasertib, 400 mg, PO, QD, on Days 1 to 21 of each 28-day cycle until unacceptable toxicity or loss of clinical benefit (1 cycle = 28 days). After Stage 1, participants who did not enter Stage 2 entered the long-term survival follow-up. | 27 |
| Stage 1: Atezolizumab + Ipatasertib Participants received atezolizumab, 840 mg as an IV infusion on Days 1 and 15 of each cycle along with ipatasertib, 400 mg, PO, QD, on Days 1 to 21 of each 28-day cycle until unacceptable toxicity or loss of clinical benefit (1 cycle = 28 days). After Stage 1, participants who did not enter Stage 2 entered the long-term survival follow-up. | 6 |
| Stage 1: Atezolizumab + Entinostat Participants received atezolizumab, 1200 mg, as an IV infusion on Day 1 of each cycle along with entinostat, 5 mg, PO, once a week on Days 1, 8, and 15 of each cycle until unacceptable toxicity or loss of clinical benefit (1 cycle = 21 days). After Stage 1, participants who did not enter Stage 2 entered the long-term survival follow-up. | 15 |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib Participants received fulvestrant, 500 mg, as IM injection on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter along with atezolizumab, 840 mg, as an IV infusion on Days 1 and 15 of each cycle and abemaciclib, 150 mg, PO, BID until unacceptable toxicity or loss of clinical benefit (1 cycle = 28 days). After Stage 1, participants who did not enter Stage 2 entered the long-term survival follow-up. | 40 |
| Stage 2: Atezolizumab + Bevacizumab + Fulvestrant Participants received fulvestrant, 500 mg, as IM injection on Days 1 and 15 of Cycle 1 and on Day 1 of each cycle thereafter along with atezolizumab, 840 mg, as an IV infusion on Days 1 and 15 of each cycle and bevacizumab, 10 milligrams per kilogram (mg /kg), as an IV infusion on Days 1 and 15 of each cycle until unacceptable toxicity or loss of clinical benefit (1 cycle = 28 days). Participants who completed Stage 2 treatment entered the long-term survival follow-up. | 13 |
| Stage 2: Atezolizumab + Bevacizumab + Exemestane Participants received atezolizumab, 1200 mg, as an IV infusion on Day 1 of each cycle along with bevacizumab, 15 mg/kg, as an IV infusion on Day 1 of each cycle and exemestane, 25 mg, PO, QD during each cycle until unacceptable toxicity, or loss of clinical benefit (1 cycle = 21 days). Participants who completed Stage 2 treatment entered the long-term survival follow-up. | 4 |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen Participants received atezolizumab, 1200 mg, as an IV infusion on Day 1 of each cycle along with bevacizumab, 15 mg/kg, as an IV infusion on Day 1 of each cycle and tamoxifen, 20 mg, PO, QD during each cycle until unacceptable toxicity or loss of clinical benefit (1 cycle = 21 days). Participants who completed Stage 2 treatment entered the long-term survival follow-up. | 3 |
| Total | 164 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Long-term Survival Follow-up | Death | 10 | 14 | 15 | 3 | 6 | 18 | 11 | 1 | 3 |
| Long-term Survival Follow-up | Lost to Follow-up | 0 | 1 | 1 | 0 | 2 | 1 | 0 | 0 | 0 |
| Long-term Survival Follow-up | Study Ended by Sponsor | 4 | 9 | 3 | 0 | 0 | 13 | 0 | 2 | 0 |
| Long-term Survival Follow-up | Withdrawal by Subject | 1 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 1 | Death | 2 | 1 | 0 | 0 | 0 | 3 | 0 | 0 | 0 |
| Stage 1 | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Reason Not Specified | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Stage 1 | Study Ended by Sponsor | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Stage 1 | Withdrawal by Subject | 5 | 1 | 2 | 0 | 0 | 2 | 0 | 0 | 0 |
| Stage 2 | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Stage 2 | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Stage 1: Fulvestrant + Atezolizumab | Total | Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Atezolizumab + Bevacizumab + Exemestane | Stage 2: Atezolizumab + Bevacizumab + Fulvestrant | Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 1: Atezolizumab + Entinostat | Stage 1: Atezolizumab + Ipatasertib | Fulvestrant Control | Stage 1: Fulvestrant + Atezolizumab + Ipatasertib |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical Stage 1 <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Stage 1 >=65 years | 8 Participants | 33 Participants | 0 Participants | 0 Participants | 0 Participants | 12 Participants | 3 Participants | 1 Participants | 4 Participants | 5 Participants |
| Age, Categorical Stage 1 Between 18 and 65 years | 23 Participants | 111 Participants | 0 Participants | 0 Participants | 0 Participants | 28 Participants | 12 Participants | 5 Participants | 21 Participants | 22 Participants |
| Age, Categorical Stage 2 <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Stage 2 >=65 years | 0 Participants | 6 Participants | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Stage 2 Between 18 and 65 years | 0 Participants | 14 Participants | 1 Participants | 3 Participants | 10 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Stage 1 Hispanic or Latino | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Stage 1 Not Hispanic or Latino | 28 Participants | 136 Participants | 0 Participants | 0 Participants | 0 Participants | 40 Participants | 14 Participants | 6 Participants | 23 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Stage 1 Unknown or Not Reported | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Stage 2 Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Stage 2 Not Hispanic or Latino | 0 Participants | 19 Participants | 3 Participants | 3 Participants | 13 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Stage 2 Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 1 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 1 Asian | 10 Participants | 49 Participants | 0 Participants | 0 Participants | 0 Participants | 15 Participants | 5 Participants | 0 Participants | 8 Participants | 11 Participants |
| Race (NIH/OMB) Stage 1 Black or African American | 3 Participants | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Stage 1 More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 1 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 1 Unknown or Not Reported | 2 Participants | 9 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Stage 1 White | 16 Participants | 79 Participants | 0 Participants | 0 Participants | 0 Participants | 24 Participants | 9 Participants | 6 Participants | 12 Participants | 12 Participants |
| Race (NIH/OMB) Stage 2 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 2 Asian | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 2 Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 2 More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 2 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 2 Unknown or Not Reported | 0 Participants | 3 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Stage 2 White | 0 Participants | 15 Participants | 3 Participants | 0 Participants | 12 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Stage 1 Female | 31 Participants | 144 Participants | 0 Participants | 0 Participants | 0 Participants | 40 Participants | 15 Participants | 6 Participants | 25 Participants | 27 Participants |
| Sex: Female, Male Stage 1 Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Stage 2 Female | 0 Participants | 20 Participants | 3 Participants | 4 Participants | 13 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Stage 2 Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 25 | 16 / 31 | 15 / 27 | 3 / 6 | 6 / 15 | 23 / 40 | 11 / 13 | 2 / 4 | 3 / 3 |
| other Total, other adverse events | 18 / 20 | 28 / 30 | 25 / 26 | 6 / 6 | 15 / 15 | 38 / 39 | 12 / 13 | 3 / 4 | 3 / 3 |
| serious Total, serious adverse events | 2 / 20 | 3 / 30 | 12 / 26 | 3 / 6 | 4 / 15 | 14 / 39 | 1 / 13 | 1 / 4 | 0 / 3 |
Outcome results
Primary
Stage 1: Percentage of Participants With Objective Response
Objective response rate (ORR) was defined as the percentage of participants with an objective response of complete response (CR) or partial response (PR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) that have a reduction in short axis to \< 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. Percentages have been rounded off to the nearest whole number.
Time frame: Up to 50.4 months
Population: Efficacy-evaluable population included all participants who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant Control | Stage 1: Percentage of Participants With Objective Response | 10.0 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Percentage of Participants With Objective Response | 10.0 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 1: Percentage of Participants With Objective Response | 26.9 percentage of participants |
| Stage 1: Atezolizumab + Ipatasertib | Stage 1: Percentage of Participants With Objective Response | 16.7 percentage of participants |
| Stage 1: Atezolizumab + Entinostat | Stage 1: Percentage of Participants With Objective Response | 6.7 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 1: Percentage of Participants With Objective Response | 26.3 percentage of participants |
95% CI: [-21.14, 21.14]
95% CI: [-9.03, 42.88]
95% CI: [-36.76, 50.09]
95% CI: [-27.39, 20.73]
95% CI: [-6.71, 39.34]
Secondary
Stage 1: Clinical Benefit Rate (CBR)
CBR was defined as the percentage of participants with stable disease (SD) ≥ 24 weeks or with confirmed CR or PR, as determined by the investigator according to RECIST v1.1. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Percentages have been rounded off to the nearest whole number.
Time frame: Up to 51.9 months
Population: Efficacy-evaluable population included all participants who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant Control | Stage 1: Clinical Benefit Rate (CBR) | 15.0 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Clinical Benefit Rate (CBR) | 26.7 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 1: Clinical Benefit Rate (CBR) | 42.3 percentage of participants |
| Stage 1: Atezolizumab + Ipatasertib | Stage 1: Clinical Benefit Rate (CBR) | 16.7 percentage of participants |
| Stage 1: Atezolizumab + Entinostat | Stage 1: Clinical Benefit Rate (CBR) | 6.7 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 1: Clinical Benefit Rate (CBR) | 42.1 percentage of participants |
Secondary
Stage 1: Duration of Response (DOR)
DOR was defined as the time from the first occurrence of a documented objective response (CR or PR) to the first date of recorded PD or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in study including baseline in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Participants who did not have documented PD or death, DOR was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for DOR.
Time frame: From first occurrence of a documented OR to the first date of recorded PD or death (up to 50.4 months)
Population: Efficacy-evaluable population included all participants who received at least one dose of each drug for their assigned treatment regimen. Overall number analyzed included participants with an objective response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant Control | Stage 1: Duration of Response (DOR) | 13.03 months |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Duration of Response (DOR) | 5.88 months |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 1: Duration of Response (DOR) | 11.07 months |
| Stage 1: Atezolizumab + Ipatasertib | Stage 1: Duration of Response (DOR) | 4.40 months |
| Stage 1: Atezolizumab + Entinostat | Stage 1: Duration of Response (DOR) | 2.46 months |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 1: Duration of Response (DOR) | 13.36 months |
95% CI: [0.15, 7.9]
95% CI: [0.15, 4.2]
95% CI: [0.15, 3.84]
Secondary
Stage 1: Overall Survival (OS)
OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier method was used to estimate the median for OS.
Time frame: From randomization to death (up to 62.2 months)
Population: Efficacy-evaluable population included all participants who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant Control | Stage 1: Overall Survival (OS) | 26.02 months |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Overall Survival (OS) | 26.48 months |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 1: Overall Survival (OS) | 26.91 months |
| Stage 1: Atezolizumab + Ipatasertib | Stage 1: Overall Survival (OS) | 10.91 months |
| Stage 1: Atezolizumab + Entinostat | Stage 1: Overall Survival (OS) | 23.10 months |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 1: Overall Survival (OS) | 26.71 months |
95% CI: [0.36, 1.65]
95% CI: [0.34, 1.58]
95% CI: [0.55, 9.34]
95% CI: [0.28, 2.01]
95% CI: [0.35, 1.46]
Secondary
Stage 1: Percentage of Participants Event-free for OS at Month 18
OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS at Month 18. Percentages have been rounded off to the nearest whole number.
Time frame: At Month 18
Population: Efficacy-evaluable population included all participants who received at least one dose of each drug for their assigned treatment regimen. Overall number analyzed included all participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant Control | Stage 1: Percentage of Participants Event-free for OS at Month 18 | 63.91 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Percentage of Participants Event-free for OS at Month 18 | 63.16 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 1: Percentage of Participants Event-free for OS at Month 18 | 81.61 percentage of participants |
| Stage 1: Atezolizumab + Ipatasertib | Stage 1: Percentage of Participants Event-free for OS at Month 18 | NA percentage of participants |
| Stage 1: Atezolizumab + Entinostat | Stage 1: Percentage of Participants Event-free for OS at Month 18 | 75.76 percentage of participants |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 1: Percentage of Participants Event-free for OS at Month 18 | 74.40 percentage of participants |
95% CI: [-30.98, 29.48]
95% CI: [-10.84, 46.23]
95% CI: [-26.63, 50.33]
95% CI: [-16.96, 37.95]
Secondary
Stage 1: Plasma Concentration of Abemaciclib
Time frame: Predose on Day 1 of Cycles 1, 2 and 3, and on Day 15 Cycle 1; 4-8 hours postdose on Day 1 Cycle 1 (Cycle length = 28 days)
Population: PK population included all participants who received at least one dose of atezolizumab and drugs given in combination with atezolizumab during Stage 1. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fulvestrant Control | Stage 1: Plasma Concentration of Abemaciclib | Predose on Cycle 1 Day 1 | 0.00417 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 50.3 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Abemaciclib | 4-8 Hour Postdose on Cycle 1 Day 1 | 0.0581 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 170 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Abemaciclib | Predose on Cycle 1 Day 15 | 0.319 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 57.4 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Abemaciclib | Predose on Cycle 2 Day 1 | 0.108 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 573.7 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Abemaciclib | Predose on Cycle 3 Day 1 | 0.144 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 177.7 |
Secondary
Stage 1: Plasma Concentration of Entinostat
Time frame: Predose on Day 1 of Cycles 1 and 2; 2-4 hours postdose on Day 1 Cycle 1 (Cycle length = 21 days)
Population: Pharmacokinetic (PK) population included all participants who received at least one dose of atezolizumab and drugs given in combination with atezolizumab during Stage 1. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fulvestrant Control | Stage 1: Plasma Concentration of Entinostat | Predose on Cycle 1 Day 1 | NA nanograms per milliliter (ng/mL) | — |
| Fulvestrant Control | Stage 1: Plasma Concentration of Entinostat | 2-4 Hrs Postdose on Cycle 1 Day 1 | 22.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 91 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Entinostat | Predose on Cycle 2 Day 1 | 2.12 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 60.3 |
Secondary
Stage 1: Plasma Concentration of Fulvestrant
Time frame: Predose on Day 1 of Cycle 2 and Cycle 3 (Cycle length = 28 days)
Population: PK population included all participants who received at least one dose of atezolizumab and drugs given in combination with atezolizumab during Stage 1. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fulvestrant Control | Stage 1: Plasma Concentration of Fulvestrant | Predose on Cycle 2 Day 1 | 0.0127 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Plasma Concentration of Fulvestrant | Predose on Cycle 2 Day 1 | 0.0136 µg/mL | Geometric Coefficient of Variation 60.2 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Plasma Concentration of Fulvestrant | Predose on Cycle 3 Day 1 | 0.0107 µg/mL | Geometric Coefficient of Variation 40.3 |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 1: Plasma Concentration of Fulvestrant | Predose on Cycle 2 Day 1 | 0.0161 µg/mL | Geometric Coefficient of Variation 74.3 |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 1: Plasma Concentration of Fulvestrant | Predose on Cycle 3 Day 1 | 0.0121 µg/mL | Geometric Coefficient of Variation 38 |
Secondary
Stage 1: Plasma Concentration of Ipatasertib
Time frame: Predose and Postdose at 1 Hour, 2 Hour, 4 Hour, and 6 Hour on Day 15 Cycle 1; Post dose at 1-3 Hour on Day 15 Cycle 3 (Cycle length = 28 days)
Population: PK population included all participants who received at least one dose of atezolizumab and drugs given in combination with atezolizumab during Stage 1. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fulvestrant Control | Stage 1: Plasma Concentration of Ipatasertib | 1 Hour Postdose on Cycle 1 Day 15 | 0.154 µg/mL | Geometric Coefficient of Variation 185 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Ipatasertib | Predose on Cycle 1 Day 15 | 0.0353 µg/mL | Geometric Coefficient of Variation 248.9 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Ipatasertib | 2 Hour Postdose on Cycle 1 Day 15 | 0.447 µg/mL | Geometric Coefficient of Variation 53.7 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Ipatasertib | 4 Hour Postdose on Cycle 1 Day 15 | 0.273 µg/mL | Geometric Coefficient of Variation 45.9 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Ipatasertib | 6 Hour Postdose on Cycle 1 Day 15 | 0.203 µg/mL | Geometric Coefficient of Variation 45.4 |
| Fulvestrant Control | Stage 1: Plasma Concentration of Ipatasertib | 1-3 Hour Postdose on Cycle 3 Day 15 | 0.576 µg/mL | Geometric Coefficient of Variation 25.9 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Plasma Concentration of Ipatasertib | 6 Hour Postdose on Cycle 1 Day 15 | 0.227 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Plasma Concentration of Ipatasertib | 4 Hour Postdose on Cycle 1 Day 15 | 0.303 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Plasma Concentration of Ipatasertib | Predose on Cycle 1 Day 15 | 0.0105 µg/mL | Geometric Coefficient of Variation 10113.9 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Plasma Concentration of Ipatasertib | 1 Hour Postdose on Cycle 1 Day 15 | 0.203 µg/mL | Geometric Coefficient of Variation 38.5 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Plasma Concentration of Ipatasertib | 1-3 Hour Postdose on Cycle 3 Day 15 | 0.0664 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Plasma Concentration of Ipatasertib | 2 Hour Postdose on Cycle 1 Day 15 | 0.398 µg/mL | — |
Secondary
Stage 1: Progression-free Survival (PFS)
PFS was defined as the time from randomization to the date of the first recorded occurrence of PD or death from any cause (whichever occurred first) in Stage 1, as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in the study including baseline in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Participants who did not have documented PD or death, PFS was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for PFS.
Time frame: From randomization to the first occurrence of PD or death (up to 51.9 months)
Population: Efficacy-evaluable population included all participants who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant Control | Stage 1: Progression-free Survival (PFS) | 1.95 months |
| Stage 1: Fulvestrant + Atezolizumab | Stage 1: Progression-free Survival (PFS) | 3.15 months |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 1: Progression-free Survival (PFS) | 5.86 months |
| Stage 1: Atezolizumab + Ipatasertib | Stage 1: Progression-free Survival (PFS) | 2.28 months |
| Stage 1: Atezolizumab + Entinostat | Stage 1: Progression-free Survival (PFS) | 1.82 months |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 1: Progression-free Survival (PFS) | 6.28 months |
95% CI: [0.5, 1.66]
95% CI: [0.35, 1.2]
95% CI: [0.45, 3.48]
95% CI: [0.74, 3.23]
95% CI: [0.28, 0.88]
Secondary
Stage 2: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
Participants who received atezolizumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 t.u. greater than the titer of the baseline sample (treatment unaffected). Participants with a positive post-baseline sample has been reported here.
Time frame: Post-baseline (up to approximately 134 days)
Population: Pharmacodynamic (PD) population included all participants in the atezolizumab plus entinostat arm with at least one ADA assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fulvestrant Control | Stage 2: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | 0 Participants |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | 0 Participants |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 2: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | 0 Participants |
Secondary
Stage 2: Plasma Concentration of Fulvestrant
Nominal time restarted to 0 at Stage 2. PK data for Stage was analyzed and reported for the subgroups \[crossover arms (Stage 1 to Stage 2)\] only.
Time frame: Predose on Day 1 of Cycles 2 and 3 (Cycle length = 21 days)
Population: PK population included all participants who received at least one dose of atezolizumab and drugs given in combination with atezolizumab during Stage 1. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fulvestrant Control | Stage 2: Plasma Concentration of Fulvestrant | Predose on Day 1 Cycle 2 (Stage 2) | 0.0207 µg/mL | Geometric Coefficient of Variation 14.1 |
| Fulvestrant Control | Stage 2: Plasma Concentration of Fulvestrant | Predose on Day 1 Cycle 3 (Stage 2) | 0.0121 µg/mL | Geometric Coefficient of Variation 39.3 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Plasma Concentration of Fulvestrant | Predose on Day 1 Cycle 2 (Stage 2) | 0.00938 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Plasma Concentration of Fulvestrant | Predose on Day 1 Cycle 3 (Stage 2) | 0.0175 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 2: Plasma Concentration of Fulvestrant | Predose on Day 1 Cycle 2 (Stage 2) | 0.0142 µg/mL | Geometric Coefficient of Variation 41.2 |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 2: Plasma Concentration of Fulvestrant | Predose on Day 1 Cycle 3 (Stage 2) | 0.0132 µg/mL | Geometric Coefficient of Variation 10.3 |
Secondary
Stage 2: Serum Concentration of Atezolizumab
Nominal time restarted to 0 at Stage 2; RO5541267 = atezolizumab. PK data for Stage was analyzed and reported for the subgroups \[crossover arms (Stage 1 to Stage 2)\] only.
Time frame: Predose on Day 1 of Cycles 1, 2, 3, 4, 8 and 12; 30 minutes (mins) postdose on Day 1 Cycle 1; postdose on Day 120 and Treatment Discontinuation Visit (Cycle length = 21 days)
Population: PK population included all participants who received at least one dose of atezolizumab and drugs given in combination with atezolizumab during Stage 1. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fulvestrant Control | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | 217 µg/mL | — |
| Fulvestrant Control | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 202 µg/mL | — |
| Fulvestrant Control | Stage 2: Serum Concentration of Atezolizumab | 30 mins postdose on Day 1 Cycle 1 (Stage 2) | 617 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Serum Concentration of Atezolizumab | Postdose on Day 120 (Stage 2) | 27.4 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | 128 µg/mL | Geometric Coefficient of Variation 49.2 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 251 µg/mL | Geometric Coefficient of Variation 35.8 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Serum Concentration of Atezolizumab | 30 mins postdose on Day 1 Cycle 1 (Stage 2) | 388 µg/mL | Geometric Coefficient of Variation 22.3 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Serum Concentration of Atezolizumab | Treatment Discontinuation Visit (Stage 2) | 250 µg/mL | Geometric Coefficient of Variation 18.9 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 4 (Stage 2) | 302 µg/mL | Geometric Coefficient of Variation 20.8 |
| Stage 1: Fulvestrant + Atezolizumab | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 3 (Stage 2) | 318 µg/mL | Geometric Coefficient of Variation 8.8 |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | 30 mins postdose on Day 1 Cycle 1 (Stage 2) | 907 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 434 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Treatment Discontinuation Visit (Stage 2) | 450 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | 443 µg/mL | — |
| Stage 1: Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | 160 µg/mL | Geometric Coefficient of Variation 209.6 |
| Stage 1: Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Treatment Discontinuation Visit (Stage 2) | 130 µg/mL | — |
| Stage 1: Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 3 (Stage 2) | 208 µg/mL | Geometric Coefficient of Variation 93.2 |
| Stage 1: Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Postdose on Day 120 (Stage 2) | 30.0 µg/mL | — |
| Stage 1: Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 4 (Stage 2) | 115 µg/mL | — |
| Stage 1: Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 211 µg/mL | Geometric Coefficient of Variation 143.9 |
| Stage 1: Atezolizumab + Ipatasertib | Stage 2: Serum Concentration of Atezolizumab | 30 mins postdose on Day 1 Cycle 1 (Stage 2) | 725 µg/mL | Geometric Coefficient of Variation 52.9 |
| Stage 1: Atezolizumab + Entinostat | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 3 (Stage 2) | 333 µg/mL | — |
| Stage 1: Atezolizumab + Entinostat | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | 277 µg/mL | — |
| Stage 1: Atezolizumab + Entinostat | Stage 2: Serum Concentration of Atezolizumab | 30 mins postdose on Day 1 Cycle 1 (Stage 2) | 1030 µg/mL | — |
| Stage 1: Atezolizumab + Entinostat | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 373 µg/mL | — |
| Stage 1: Atezolizumab + Entinostat | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 4 (Stage 2) | 341 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 3 (Stage 2) | 284 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 2: Serum Concentration of Atezolizumab | 30 mins postdose on Day 1 Cycle 1 (Stage 2) | 679 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | 167 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 253 µg/mL | — |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 4 (Stage 2) | 310 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Fulvestrant | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 141 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Fulvestrant | Stage 2: Serum Concentration of Atezolizumab | 30 mins postdose on Day 1 Cycle 1 (Stage 2) | 498 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Fulvestrant | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | NA µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Fulvestrant | Stage 2: Serum Concentration of Atezolizumab | Postdose on Day 120 (Stage 2) | 22.6 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Exemestane | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 4 (Stage 2) | 238 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Exemestane | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | NA µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Exemestane | Stage 2: Serum Concentration of Atezolizumab | Treatment Discontinuation Visit (Stage 2) | 201 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Exemestane | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 3 (Stage 2) | 220 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Exemestane | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 136 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | Postdose on Day 120 (Stage 2) | 7.38 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | 30 mins postdose on Day 1 Cycle 1 (Stage 2) | 491 µg/mL | Geometric Coefficient of Variation 16.3 |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 3 (Stage 2) | 274 µg/mL | Geometric Coefficient of Variation 47.4 |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | Treatment Discontinuation Visit (Stage 2) | 169 µg/mL | Geometric Coefficient of Variation 145.8 |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 1 (Stage 2) | 16.3 µg/mL | Geometric Coefficient of Variation 63062.7 |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 2 (Stage 2) | 227 µg/mL | Geometric Coefficient of Variation 65.2 |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 4 (Stage 2) | 309 µg/mL | Geometric Coefficient of Variation 35.2 |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 8 (Stage 2) | 131 µg/mL | — |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stage 2: Serum Concentration of Atezolizumab | Predose on Day 1 Cycle 12 (Stage 2) | 182 µg/mL | — |
Secondary
Stages 1 and 2: Number of Participants With Adverse Events (AEs)
An AE was any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE = serious adverse events; AESIs = adverse events of special interest.
Time frame: From baseline until 30 days (for AEs) or 135 days (for SAEs & AESIs) after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurred first (Stage 1: up to 52 months; Stage 2: up to 21.7 months)
Population: SE population included all participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fulvestrant Control | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 18 Participants |
| Stage 1: Fulvestrant + Atezolizumab | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 28 Participants |
| Stage 1: Fulvestrant + Atezolizumab + Ipatasertib | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 26 Participants |
| Stage 1: Atezolizumab + Ipatasertib | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 6 Participants |
| Stage 1: Atezolizumab + Entinostat | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 15 Participants |
| Stage 1: Fulvestrant + Atezolizumab + Abemaciclib | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 39 Participants |
| Stage 2: Atezolizumab + Bevacizumab + Fulvestrant | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 12 Participants |
| Stage 2: Atezolizumab + Bevacizumab + Exemestane | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 3 Participants |
| Stage 2: Atezolizumab + Bevacizumab + Tamoxifen | Stages 1 and 2: Number of Participants With Adverse Events (AEs) | 3 Participants |