A Study of Ipatasertib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Hormone Receptor Positive and HER2 Negative Locally Advanced Unresectable or Metastatic Breast Cancer

PFS was defined as the time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first. Progressive disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of ≥ 5 millimeters (mm).

Time frame: From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months

Population: The study was terminated before initiation of Phase III as per sponsor's decision; hence this outcome measure was not assessed or analyzed, and no data collected.

AUC0-24 of Ipatasertib and its metabolite G-037720 is reported

Time frame: Cycle 1: Day 1 and Day 15

Population: PK-evaluable population included all participants who received study treatment. Overall number analyzed is the number of participants with data available for analysis.

Cmax of ipatasertib and its metabolite G-037720 in plasma is reported.

Time frame: Cycle 1: Day 1 and Day 15

Population: PK-evaluable population included all participants who received study treatment. Overall number analyzed is the number of participants with data available for analysis.

AE=any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Severity of AEs were rated per NCI CTCAE v5 where, Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental Activities of Daily Living (ADL); Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4 Life-threatening consequences; urgent intervention indicated; Grade 5 Death related to AE.

Time frame: Up to 36 Months

Population: Safety evaluable population included all randomized participants who received any amount of study drug (i.e., ipatasertib + palbociclib + fulvestrant).

Plasma concentrations of Ipatasertib and its metabolite G-037720 are reported.

Time frame: Cycle 1, Day 1 and 15: 0.25 hours pre-dose, 0.5, 1, 2, 3, 4 and 6 hours post- dose ; Cycle 2, Day 15: 0.25 hours pre-dose; Cycle 3, Day 15: 0.15 hours pre-dose, 2 hours post-dose (each cycle = 28 days)

Population: Pharmacokinetic (PK)-evaluable population included all participants who received study treatment. Number analyzed is the number of participants with data available for analysis.

Tmax of ipatasertib and its metabolite G-037720 isreported.

Time frame: Cycle 1: Day 1 and Day 15

Population: PK-evaluable population included all participants who received study treatment. Overall number analyzed is the number of participants with data available for analysis.

CBR was defined as the percentage of participants who had a CR or PR, or SD for at least 24 weeks, as determined by the investigator according to RECIST v1.1. CR is defined as disappearance of all target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD is defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of ≥ 5 mm.

Time frame: From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months

Population: The study was terminated before initiation of Phase III as per sponsor's decision; hence this outcome measure was not assessed or analyzed, and no data collected.

DOR was defined as time from first occurrence of a documented objective response to the first occurrence of disease progression as determined by investigator per RECIST v1.1, or death from any cause, whichever occurs first. Objective response was defined using RECIST v1.1 criteria as: CR = disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR = at least a 30% decrease in sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in absence of CR. PD = at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to relative increase of 20%, sum of diameters must also demonstrate an absolute increase of ≥ 5 mm. Stable disease (SD): Neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.

Time frame: From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months

Population: The study was terminated before initiation of Phase III as per sponsor's decision; hence this outcome measure was not assessed or analyzed, and no data collected.

An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product; any new disease or exacerbation of an existing disease; recurrence of an intermittent medical condition; any deterioration in a laboratory value or other clinical test; AEs that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment.

Time frame: Up to approximately 36 months

Population: No data was collected because the study was terminated before the initiation of Phase III per the sponsor's decision.

ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.

Time frame: From randomization in Phase III up to approximately 36 months

Population: The study was terminated before initiation of Phase III as per sponsor's decision; hence this outcome measure was not assessed or analyzed, and no data collected.

OS was defined as the time from randomization to death from any cause.

Time frame: From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months

Population: The study was terminated before initiation of Phase III as per sponsor's decision; hence this outcome measure was not assessed or analyzed, and no data collected.

TTD in severity of pain is defined as the time from randomization to the first documentation of a 2-point or more increase from baseline on the worst pain item from the BPI-SF. A 2-point change is defined as clinically meaningful. The BPI-SF is a widely used patient-reported outcome (PRO) for assessing pain, and the worst pain item, frequently used for evaluating increases in the severity of pain. The BPI-SF asks participants to rate their pain at its worst in the last week on a scale from 0 (No pain) to 10 (pain as bad as one can imagine). Higher score indicates more pain.

Time frame: From randomization in Phase III to the first documentation of a ≥2-point increase in pain scale (up to approximately 36 months)

Population: The study was terminated before initiation of Phase III as per sponsor's decision; hence this outcome measure was not assessed or analyzed, and no data collected.

TTD in PF, RF and GHS/QoL is defined as the time to first documented ≥10-point decrease from baseline in following scales of the EORTC QLQ-C30: PF, RF and GHS/QoL. EORTC QLQ-C30 is a validated 30-item self-report measure assessing 5 aspects of participant functioning (physical, emotional, role, cognitive, & social), eight symptom scales (fatigue, nausea & vomiting, pain, dyspnea, insomnia, appetite loss, constipation, & diarrhea), financial difficulties, & GHS/QoL with a recall period of the previous week. The PF scale has 5 questions about participants' physical functioning and is scored on a 4-point scale (1=Not at All to 4=Very Much). The RF scale is scored on a 4-point scale (1=Not at All to 4=Very Much). The GHS/QoL scale has 7 possible scores of responses (1=Very Poor to 7=Excellent). All sub-scores are linearly transformed to a total score range of 0-100. Higher scores indicate a higher response level (better functioning/QoL).

Time frame: From randomization in Phase III to the first documentation of a ≥10-point decrease in the PF, RF and GHS/QoL of EORTC QLQ-C30 (up to approximately 36 months)

Population: The study was terminated before initiation of Phase III as per sponsor's decision; hence this outcome measure was not assessed or analyzed, and no data collected.

TTD in presence & interference of pain is defined as time from randomization to the first documentation of ≥10-point increase from baseline in EORTC QLQ-C30 pain scale (items 9 & 19). EORTC QLQ-C30 is a validated 30-item self-report measure assessing 5 aspects of participant functioning (physical, emotional, role, cognitive, & social), eight symptom scales (fatigue, nausea & vomiting, pain, dyspnea, insomnia, appetite loss, constipation, & diarrhea), financial difficulties, & global health status/quality of life (GHS/QoL) with a recall period of the previous week. Functioning & symptoms items are scored on a 4-point scale (1=Not at All to 4=Very Much). Pain scale is scored on a 4-point scale (1=Not at All to 4=Very Much) including Item 9: have you had pain? and Item 19: did pain interfere with your daily activity? both range from 1=Not at All to 4=Very Much. All sub-scores are linearly transformed to a total score range of 0-100. Higher scores indicate worse pain symptoms.

Time frame: From randomization in Phase III to the first documentation of a ≥10-point increase (up to approximately 36 months)

Population: The study was terminated before initiation of Phase III as per sponsor's decision; hence this outcome measure was not assessed or analyzed, and no data collected.