Breast Cancer
Conditions
Brief summary
This study will evaluate the efficacy of ipatasertib + paclitaxel versus placebo + paclitaxel in participants with histologically confirmed, locally advanced or metastatic triple-negative breast cancer (TNBC) and in participants with locally advanced or metastatic hormone receptor positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2-) breast adenocarcinoma who are not suitable for endocrine therapy.
Interventions
DRUGIpatasertib
Ipatasertib, 400 milligrams (mg), administered orally once a day (QD) on Days 1-21 of each 28-day cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
DRUGPaclitaxel
Paclitaxel, 80 mg/square meter (m\^2), administered intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
DRUGPlacebo
Matching placebo, administered orally QD on Days 1-21 of each 28-day cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women or men aged =\>18 years with histologically documented triple-negative breast cancer (TNBC) or HR+/HER2- adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Adequate hematologic and organ function within 14 days prior to treatment initiation * Histologically documented TNBC or HR+/HER2- adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent * Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 * Eligible for taxane monotherapy, as per local investigator assessment (e.g., absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control which may require combination chemotherapy) * HR+/HER2- breast cancer that is not considered appropriate for endocrine-based therapy and meets one of the following: patient has recurrent disease \<=5 years of being on adjuvant endocrine therapy or if patient with de novo metastatic disease have progressed within 6 months of being on first line endocrine therapy. * Consent to submit a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or freshly cut unstained, serial tumor slides from the most recently collected tumor tissue for central molecular analysis * Confirmation of biomarker eligibility using an appropriately validated molecular assay at a diagnostic laboratory, Clinically Laboratory Improvement Amendments (CLIA) or equivalently accredited i.e., valid results from either central testing or local testing of tumor tissue or blood demonstrating PIK3CA/AKT1/PTEN-altered status * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and agreement to refrain from donating sperm
Exclusion criteria
* Treatment with approved or investigational cancer therapy within 14 days prior to treatment initiation * Any previous chemotherapy for inoperable locally advanced or metastatic TNBC or HR+/HER2- adenocarcinoma of the breast (patients receiving neo/adjuvant chemotherapy eligible provided they have at least a 12 month disease-free interval) * History of or known presence of brain or spinal cord metastases * Malignancies other than breast cancer within 5 years prior to treatment initiation (except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer) * Prior treatment with an Akt inhibitor (prior PI3K or mTOR inhibitors are allowed) * History of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills * Active infection requiring systemic anti-microbial treatment (including antibiotics, anti-fungals, and anti-viral agents) * Known human immunodeficiency virus (HIV) infection * Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis, current drug or alcohol abuse, or cirrhosis * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of treatment (or anticipated need during study) * Pregnant or breastfeeding, or intending to become pregnant during the study * Clinically significant cardiac dysfunction (including NYHA Class II/III/IV heart failure, left ventricular ejection fraction \[LVEF\] \<50%, active ventricular arrhythmia requiring medication, history of myocardial infarction within 6 months of treatment initiation, clinically significant electrocardiogram \[ECG\] abnormalities). * Need for chronic corticosteroid therapy of \>=10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease * Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 peripheral neuropathy * Uncontrolled clinical symptoms including pleural effusion, pericardial effusion, or ascites, tumor-related pain, hypercalcemia (or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy) * History of Type I or Type II diabetes mellitus requiring insulin * Grade \>=2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia * History of or active inflammatory bowel disease or active bowel inflammation * Clinically significant lung disease (including pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, active infection/ history of opportunistic infections) * Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of treatment * Grade \>=2 peripheral neuropathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A: Progression-Free Survival (PFS) | From randomization up to 27 months | PFS was defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator through the use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1), or death from any cause, whichever occurred first, assessed up to 27 months for this outcome measure. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). The appearance of one or more new lesions was also considered progression. |
| Cohort B: PFS | From randomization up to 24.4 months | PFS was defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first, assessed up to 24.4 months for this outcome measure. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Abbreviation used in statistical analysis: PI3K=phosphoinositide 3-kinase and mTOR=mammalian target of rapamycin inhibitor. |
| Cohort C: PFS | From enrollment up to 31 months | PFS for Cohort C was defined as the time from enrollment to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first, assessed up to 31 months for this outcome measure. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort C: DOR | From enrollment up to 31 months | DOR was defined as the time from the first occurrence of a documented OR (CR or PR) to PD, as determined locally by the investigator through the use of RECIST v1.1, or death from any cause, whichever occurred first, assessed up to 31 months for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| Cohort A and B: Clinical Benefit Rate (CBR) | From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B | CBR was defined as percentage of participants with an objective response (CR or PR), or stable disease (SD) for at least 24 weeks, as determined by the investigator through the use of RECIST v.1.1. assessed up to From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentages are rounded off to the nearest decimal point. |
| Cohort C: CBR | From enrollment up to 31 months | CBR was defined as percentage of participants with an objective response (CR or PR), or SD for at least 24 weeks, as determined by the investigator through the use of RECIST v.1.1 assessed up to 31 months for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentages are rounded off to the nearest decimal point. |
| Overall Survival (OS) | From randomization/ enrollment (Cohort C) up to death from any cause, up to 45 months for Cohort A, up to 46 months for Cohort B and up to 31 months for Cohort C | OS was defined as the time from randomization to death from any cause. |
| Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 (cycle length=28 days) | European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) is a cancer-specific instrument with 30 questions covering symptoms, functioning, and health-related quality of life (HRQoL). The participant's assessment of overall HRQoL is assessed by using the last 2 questions (29 and 30) of the instrument, with each of these items based on a 7-point scale (1=very poor to 7=excellent), which are then combined into the GHS/QoL multi-item scale. The scores obtained for each question were averaged into a raw score for the scale, and this raw score for the scale was then subsequently linearly transformed to a scale score of 0 to 100, with a high score indicating better GHS/QoL. Negative change from Baseline values in the GHS/QoL change from baseline analysis indicated deterioration in HRQoL and positive values indicated improvement. |
| Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 (cycle length=28 days) | EORTC QLQ-C30 is a cancer-specific instrument with 30 questions covering symptoms, functioning, and health-related quality of life (HRQoL). The participant's assessment of overall HRQoL is assessed by using the last 2 questions (29 and 30) of the instrument, with each of these items based on a 7-point scale (1=very poor to 7=excellent), which are then combined into the GHS/QoL multi-item scale. The scores obtained for each question were averaged into a raw score for the scale, and this raw score for the scale was then subsequently linearly transformed to a scale score of 0 to 100, with a high score indicating better GHS/QoL. Negative change from Baseline values in the GHS/QoL change from baseline analysis indicated deterioration in HRQoL and positive values indicated improvement. |
| Cohort B: Time to Deterioration (TTD) in Pain | Baseline up to 24.4 months | Time to deterioration in GHS/HRQoL was defined as the time from randomization to first observed ≥ 11-point increase from Baseline in pain scale score (Question 9 and 19) in EORTC QLQ-C30 linearly transformed GHS/HRQoL scale score, assessed up 24.4 months for this outcome measure. TTD was planned to be assessed only in cohort with HR+/HER2 - breast cancer participants (Cohort B). Questions 9 and 19 that assessed pain, used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). The scores were linearly transformed on a scale of 0 to 100, with higher scores indicating increased severity in symptoms. |
| Number of Participants With Adverse Events (AEs) | Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. |
| Cohort A and B: Objective Response Rate (ORR) | From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B | ORR was defined as percentage of participants with partial response (PR) or complete response (CR) on 2 consecutive occasions ≥4 weeks apart as determined by the investigator using RECIST v.1.1, assessed up to 27 months for Cohort A and up to 24.4 months for Cohort B, for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. Percentages are rounded off to the nearest decimal point. |
| Cohorts A and B:Plasma Concentration of Ipatasertib | Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days) | — |
| Cohort C: Plasma Concentration of Ipatasertib | Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days) | — |
| Cohorts A and B: Plasma Concentration of G-037720 | Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days ) | G-037720 was a metabolite of ipatasertib. |
| Cohort C: Plasma Concentration of G-037720 | Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days ) | G-037720 was a metabolite of ipatasertib. |
| Cohort C: 1-year Event-free PFS Rate | From enrollment until the occurrence of disease progression or death from any cause, whichever occurred earlier, up to 1 year | PFS was defined as the time from enrollment to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first. Event-free PFS rate was defined as percentage of participants who did not experience any event and survived at 1 year after enrollment. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Percentages are rounded off to the nearest decimal point. As prespecified in the protocol, this outcome measure was applicable only to Cohort C. |
| Cohort C: 1-year Event-free OS Rate | From enrollment up to death from any cause, up to 1 year | OS was defined as the time from enrollment to death from any cause. Event-free OS rate was defined as percentage of participants who did not experience any event and survived at 1 year after enrollment. As prespecified in the protocol, this outcome measure was applicable only to Cohort C. Percentages were rounded off to the nearest decimal. |
| Cohort C: Serum Concentration of Atezolizumab | Day 1 of Cycle 1: 30 minutes post dose, predose on Day 15 of Cycle 1 and predose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length=28 days) | As prespecified in the protocol, this outcome measure was applicable only to Cohort C. |
| Cohort C: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Up to 45.5 months | The numbers of ADA-positive participants after drug administration were summarized for participants exposed to atezolizumab. As prespecified in the protocol, this outcome measure was applicable only to Cohort C. |
| Number of Participants With at Least One Adverse Events of Special Interest (AESI) | Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the NCI CTCAE, Version 4.0. AESI include cases of potential drug-induced liver injury that include an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law. Suspected transmission of an infectious agent by the study drug, Grade \>= 3 fasting hyperglycemia, hepatotoxicity, diarrhea, rash, ALT/AST elevations. Grade \>= 2 colitis/enterocolitis. |
| Cohort C: ORR | From enrollment up to 31 months | ORR was defined as percentage of participants with PR or CR on 2 consecutive occasions ≥4 weeks apart as determined by the investigator using RECIST v.1.1, assessed up to 31 months for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. Percentages are rounded off to the nearest decimal point. |
| Cohort A and B: Duration of Response (DOR) | From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B | DOR was defined as the time from the first occurrence of a documented OR (CR or PR) to PD, as determined locally by the investigator through the use of RECIST v1.1, or death from any cause, whichever occurred first assessed up to 27 months for Cohort A and up to 24.4 months for Cohort B, for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, Costa Rica, Czechia, France, Germany, Greece, Hungary, India, Italy, Japan, Mexico, North Macedonia, Peru, Poland, Russia, Singapore, Slovenia, South Africa, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants with protocol specified triple-negative breast cancer (TNBC) or HR+/HER- took part in the study in the following countries: Argentina, Australia, Belgium, Brazil, Canada, Chile, Costa Rica, Czech Republic, France, Greece, Germany, Hungary, Italy, India, Japan, Macedonia, Mexico, Poland, Peru, Republic of Korea, Russian Federation, Slovenia, Spain, Singapore, South Africa, Taiwan, Turkey, Ukraine, United Kingdom, and United States from 6 January 2018 to 4 January 2023.
Pre-assignment details
Participants with TNBC or hormone receptor positive(HR+)/human epidermal growth factor receptor 2 negative(HER2-) breast adenocarcinoma with phosphatidylinositol-4,5-bisphosphate3-kinase,catalytic subunit, alpha(PIK3CA)/serine-threonine kinase(AKT1)/phosphatase & tensin homolog (PTEN)-altered tumor were randomized to ipatasertib 400 mg+paclitaxel or placebo+paclitaxel (Cohorts A,B) & those with TNBC without PIK3CA/ AKT1/PTEN-altered tumor received ipatasertib+atezolizumab+paclitaxel (Cohort C).
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Placebo + Paclitaxel Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m\^2, IV, on Days 1, 8, and 15 of each 28-day cycle and placebo, orally QD, on Days 1 to 21 of each 28-day cycle up to 58.9 months. | 87 |
| Cohort A: Ipatasertib + Paclitaxel Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m\^2, IV, on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle up to 58.9 months. | 168 |
| Cohort B: Placebo + Paclitaxel Participants with histologically confirmed HR+ /HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m\^2, IV, on Days 1, 8, and 15 of each 28-day cycle and placebo, orally QD, on Days 1 to 21 of each 28-day cycle up to 59.9 months. | 76 |
| Cohort B: Ipatasertib + Paclitaxel Participants with histologically confirmed HR+/HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m\^2, IV, on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle up to 59.9 months. | 146 |
| Cohort C: Ipatasertib + Atezolizumab + Paclitaxel Participants with histologically confirmed locally advanced unresectable or metastatic TNBC without PIK3CA/AKT1/PTEN-altered tumors and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m\^2, IV, on Days 1, 8, and 15 of each 28-day cycle, ipatasertib at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle, and atezolizumab 840 mg, IV, on Days 1 and 15 of each 28-day cycle up to 45.5 months. | 102 |
| Total | 579 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 1 | 0 |
| Overall Study | Death | 40 | 89 | 43 | 76 | 50 |
| Overall Study | Lost to Follow-up | 5 | 5 | 4 | 7 | 4 |
| Overall Study | Physician Decision | 16 | 34 | 14 | 34 | 13 |
| Overall Study | Progressive Disease | 0 | 2 | 1 | 2 | 0 |
| Overall Study | Protocol Deviation | 0 | 1 | 1 | 1 | 0 |
| Overall Study | Reason not Specified | 12 | 21 | 9 | 9 | 29 |
| Overall Study | Symptomatic Deterioration | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 13 | 15 | 4 | 15 | 6 |
Baseline characteristics
| Characteristic | Cohort A: Placebo + Paclitaxel | Cohort A: Ipatasertib + Paclitaxel | Cohort B: Placebo + Paclitaxel | Cohort B: Ipatasertib + Paclitaxel | Cohort C: Ipatasertib + Atezolizumab + Paclitaxel | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 54.2 years STANDARD_DEVIATION 12.6 | 54.6 years STANDARD_DEVIATION 12.8 | 54.5 years STANDARD_DEVIATION 11.3 | 57.2 years STANDARD_DEVIATION 11.1 | 54.6 years STANDARD_DEVIATION 11.7 | 55.2 years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants | 59 Participants | 13 Participants | 29 Participants | 36 Participants | 166 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 101 Participants | 62 Participants | 115 Participants | 58 Participants | 393 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 8 Participants | 1 Participants | 2 Participants | 8 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 13 Participants | 15 Participants | 3 Participants | 4 Participants | 5 Participants | 40 Participants |
| Race (NIH/OMB) Asian | 17 Participants | 37 Participants | 22 Participants | 38 Participants | 12 Participants | 126 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 3 Participants | 2 Participants | 9 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 4 Participants | 2 Participants | 0 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 1 Participants | 9 Participants | 15 Participants | 38 Participants |
| Race (NIH/OMB) White | 51 Participants | 99 Participants | 45 Participants | 93 Participants | 55 Participants | 343 Participants |
| Sex: Female, Male Female | 87 Participants | 167 Participants | 76 Participants | 144 Participants | 102 Participants | 576 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 3 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 41 / 87 | 91 / 168 | 44 / 76 | 78 / 146 | 50 / 102 |
| other Total, other adverse events | 82 / 87 | 161 / 166 | 72 / 75 | 141 / 145 | 101 / 102 |
| serious Total, serious adverse events | 20 / 87 | 34 / 166 | 11 / 75 | 30 / 145 | 29 / 102 |
Outcome results
Primary
Cohort A: Progression-Free Survival (PFS)
PFS was defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator through the use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1), or death from any cause, whichever occurred first, assessed up to 27 months for this outcome measure. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). The appearance of one or more new lesions was also considered progression.
Time frame: From randomization up to 27 months
Population: ITT Population included all randomized participants in Cohorts A regardless of whether the participants received the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort A: Progression-Free Survival (PFS) | 6.1 months |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A: Progression-Free Survival (PFS) | 7.4 months |
p-value: 0.923795% CI: [0.71, 1.45]Log Rank
Primary
Cohort B: PFS
PFS was defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first, assessed up to 24.4 months for this outcome measure. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Abbreviation used in statistical analysis: PI3K=phosphoinositide 3-kinase and mTOR=mammalian target of rapamycin inhibitor.
Time frame: From randomization up to 24.4 months
Population: ITT Population included all randomized participants in Cohort B regardless of whether the participants received the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort B: PFS | 9.3 months |
| Cohort A: Ipatasertib + Paclitaxel | Cohort B: PFS | 9.3 months |
p-value: 0.996595% CI: [0.71, 1.4]Log Rank
Primary
Cohort C: PFS
PFS for Cohort C was defined as the time from enrollment to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first, assessed up to 31 months for this outcome measure. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: From enrollment up to 31 months
Population: ITT population included of all enrolled participants in Cohort C.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: PFS | 7.1 months |
Secondary
Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) is a cancer-specific instrument with 30 questions covering symptoms, functioning, and health-related quality of life (HRQoL). The participant's assessment of overall HRQoL is assessed by using the last 2 questions (29 and 30) of the instrument, with each of these items based on a 7-point scale (1=very poor to 7=excellent), which are then combined into the GHS/QoL multi-item scale. The scores obtained for each question were averaged into a raw score for the scale, and this raw score for the scale was then subsequently linearly transformed to a scale score of 0 to 100, with a high score indicating better GHS/QoL. Negative change from Baseline values in the GHS/QoL change from baseline analysis indicated deterioration in HRQoL and positive values indicated improvement.
Time frame: Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 (cycle length=28 days)
Population: Patient-reported outcome (PRO)-evaluable Population included all randomized (Cohorts A and B) participants who had a baseline and at least 1 postbaseline PRO assessment.Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 2 | 0.95 score on scale | Standard Deviation 20.59 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 19 | -4.17 score on scale | Standard Deviation 8.33 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 14 | -2.38 score on scale | Standard Deviation 10.45 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 5 | -2.08 score on scale | Standard Deviation 16.46 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 15 | -9.72 score on scale | Standard Deviation 11.08 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 18 | -8.33 score on scale | Standard Deviation 9.62 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 16 | -6.67 score on scale | Standard Deviation 13.69 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 3 | -0.93 score on scale | Standard Deviation 20.53 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 17 | -8.33 score on scale | Standard Deviation 9.62 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 23 | -16.67 score on scale | — |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 6 | -6.94 score on scale | Standard Deviation 15.97 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 7 | -5.48 score on scale | Standard Deviation 12.45 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 22 | -16.67 score on scale | — |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 8 | -6.90 score on scale | Standard Deviation 13.56 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 24 | -16.67 score on scale | — |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 9 | 0.00 score on scale | Standard Deviation 10.29 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 4 | -4.44 score on scale | Standard Deviation 19.42 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 21 | -16.67 score on scale | — |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 10 | -2.38 score on scale | Standard Deviation 9.91 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 11 | -3.43 score on scale | Standard Deviation 15.88 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 20 | -8.33 score on scale | Standard Deviation 11.79 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 12 | 0.76 score on scale | Standard Deviation 11.46 |
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 13 | -5.21 score on scale | Standard Deviation 10.85 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 20 | -5.56 score on scale | Standard Deviation 9.62 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 23 | -25.00 score on scale | — |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 8 | 0.33 score on scale | Standard Deviation 22.11 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 14 | -3.57 score on scale | Standard Deviation 19.26 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 11 | -4.46 score on scale | Standard Deviation 21.09 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 18 | -15.48 score on scale | Standard Deviation 16.96 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 21 | -16.67 score on scale | Standard Deviation 0 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 15 | -5.77 score on scale | Standard Deviation 12.9 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 5 | -2.87 score on scale | Standard Deviation 18.61 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 24 | -41.67 score on scale | — |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 9 | -3.49 score on scale | Standard Deviation 25.28 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 16 | -8.33 score on scale | Standard Deviation 14.91 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 19 | -20.00 score on scale | Standard Deviation 7.45 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 17 | -6.82 score on scale | Standard Deviation 13.34 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 13 | -8.33 score on scale | Standard Deviation 23.57 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 12 | -8.33 score on scale | Standard Deviation 19.94 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 10 | -4.52 score on scale | Standard Deviation 21.61 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 6 | -2.06 score on scale | Standard Deviation 21.04 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 3 | 0.35 score on scale | Standard Deviation 21.73 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 22 | -16.67 score on scale | — |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 4 | -2.42 score on scale | Standard Deviation 21.95 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 7 | -3.28 score on scale | Standard Deviation 20.93 |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 2 | -0.26 score on scale | Standard Deviation 24.58 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 13 | -2.43 score on scale | Standard Deviation 21.63 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 2 | 4.79 score on scale | Standard Deviation 15.83 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 3 | 1.19 score on scale | Standard Deviation 19.62 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 4 | -0.79 score on scale | Standard Deviation 21.1 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 5 | -1.19 score on scale | Standard Deviation 20 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 6 | 1.42 score on scale | Standard Deviation 19.18 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 7 | 0.34 score on scale | Standard Deviation 20.34 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 8 | 0.35 score on scale | Standard Deviation 16.84 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 9 | 1.10 score on scale | Standard Deviation 18.8 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 10 | 1.28 score on scale | Standard Deviation 19.64 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 11 | 2.38 score on scale | Standard Deviation 22.83 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 12 | 0.00 score on scale | Standard Deviation 22.46 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 14 | -0.76 score on scale | Standard Deviation 21.81 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 15 | -2.22 score on scale | Standard Deviation 18.49 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 16 | -4.17 score on scale | Standard Deviation 19.27 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 17 | -7.64 score on scale | Standard Deviation 15.27 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 18 | -9.26 score on scale | Standard Deviation 19.74 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 19 | -11.67 score on scale | Standard Deviation 16.24 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 20 | -16.67 score on scale | Standard Deviation 11.79 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 21 | -13.89 score on scale | Standard Deviation 20.97 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 22 | -11.11 score on scale | Standard Deviation 9.62 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 23 | -16.67 score on scale | Standard Deviation 16.67 |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 24 | -16.67 score on scale | Standard Deviation 0 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 12 | -4.02 score on scale | Standard Deviation 16.32 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 24 | -16.67 score on scale | Standard Deviation 11.79 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 19 | -7.64 score on scale | Standard Deviation 23.96 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 11 | -5.13 score on scale | Standard Deviation 19.3 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 10 | -6.43 score on scale | Standard Deviation 18.83 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 23 | -15.00 score on scale | Standard Deviation 18.07 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 20 | -10.00 score on scale | Standard Deviation 12.3 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 9 | -7.37 score on scale | Standard Deviation 20.05 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 8 | -5.99 score on scale | Standard Deviation 18.55 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 3 | -2.13 score on scale | Standard Deviation 17.99 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 21 | -10.71 score on scale | Standard Deviation 13.36 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 7 | -4.17 score on scale | Standard Deviation 19.47 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 6 | -3.88 score on scale | Standard Deviation 20.67 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 2 | -3.61 score on scale | Standard Deviation 21.45 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 22 | -14.29 score on scale | Standard Deviation 15 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 16 | -2.33 score on scale | Standard Deviation 16.05 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 5 | -3.01 score on scale | Standard Deviation 18.7 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 17 | -5.95 score on scale | Standard Deviation 13.73 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 15 | -0.62 score on scale | Standard Deviation 20.14 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 14 | -3.29 score on scale | Standard Deviation 15.68 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 4 | -1.99 score on scale | Standard Deviation 20.75 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 18 | -6.55 score on scale | Standard Deviation 16.07 |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 13 | -4.65 score on scale | Standard Deviation 18.57 |
Secondary
Cohort A and B: Clinical Benefit Rate (CBR)
CBR was defined as percentage of participants with an objective response (CR or PR), or stable disease (SD) for at least 24 weeks, as determined by the investigator through the use of RECIST v.1.1. assessed up to From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentages are rounded off to the nearest decimal point.
Time frame: From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B
Population: ITT Population included all randomized participants in Cohorts A and B regardless of whether the participants received the assigned treatment. Overall number analyzed is the number of participants with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Clinical Benefit Rate (CBR) | 45.3 percentage of participants |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Clinical Benefit Rate (CBR) | 46.7 percentage of participants |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Clinical Benefit Rate (CBR) | 65.3 percentage of participants |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Clinical Benefit Rate (CBR) | 68.8 percentage of participants |
Secondary
Cohort A and B: Duration of Response (DOR)
DOR was defined as the time from the first occurrence of a documented OR (CR or PR) to PD, as determined locally by the investigator through the use of RECIST v1.1, or death from any cause, whichever occurred first assessed up to 27 months for Cohort A and up to 24.4 months for Cohort B, for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B
Population: ITT Population included all randomized participants in Cohorts A and B regardless of whether the participants received the assigned treatment. Overall number analyzed is the number of participants with objective response i.e., responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Duration of Response (DOR) | 16.6 months |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Duration of Response (DOR) | 9.4 months |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Duration of Response (DOR) | 9.2 months |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Duration of Response (DOR) | 9.2 months |
Secondary
Cohort A and B: Objective Response Rate (ORR)
ORR was defined as percentage of participants with partial response (PR) or complete response (CR) on 2 consecutive occasions ≥4 weeks apart as determined by the investigator using RECIST v.1.1, assessed up to 27 months for Cohort A and up to 24.4 months for Cohort B, for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. Percentages are rounded off to the nearest decimal point.
Time frame: From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B
Population: ITT Population included all randomized participants in Cohorts A and B regardless of whether the participants received the assigned treatment. Overall number analyzed is the number of participants with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort A and B: Objective Response Rate (ORR) | 34.9 percentage of participants |
| Cohort A: Ipatasertib + Paclitaxel | Cohort A and B: Objective Response Rate (ORR) | 38.9 percentage of participants |
| Cohort B: Placebo + Paclitaxel | Cohort A and B: Objective Response Rate (ORR) | 46.7 percentage of participants |
| Cohort B: Ipatasertib + Paclitaxel | Cohort A and B: Objective Response Rate (ORR) | 46.5 percentage of participants |
Secondary
Cohort B: Time to Deterioration (TTD) in Pain
Time to deterioration in GHS/HRQoL was defined as the time from randomization to first observed ≥ 11-point increase from Baseline in pain scale score (Question 9 and 19) in EORTC QLQ-C30 linearly transformed GHS/HRQoL scale score, assessed up 24.4 months for this outcome measure. TTD was planned to be assessed only in cohort with HR+/HER2 - breast cancer participants (Cohort B). Questions 9 and 19 that assessed pain, used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). The scores were linearly transformed on a scale of 0 to 100, with higher scores indicating increased severity in symptoms.
Time frame: Baseline up to 24.4 months
Population: ITT Population for Cohort B included as all randomized participants regardless of whether the participants received the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort B: Time to Deterioration (TTD) in Pain | NA months |
| Cohort A: Ipatasertib + Paclitaxel | Cohort B: Time to Deterioration (TTD) in Pain | NA months |
p-value: 0.216295% CI: [0.83, 2.22]Log Rank
Secondary
Cohort C: 1-year Event-free OS Rate
OS was defined as the time from enrollment to death from any cause. Event-free OS rate was defined as percentage of participants who did not experience any event and survived at 1 year after enrollment. As prespecified in the protocol, this outcome measure was applicable only to Cohort C. Percentages were rounded off to the nearest decimal.
Time frame: From enrollment up to death from any cause, up to 1 year
Population: ITT Population for Cohort C included all enrolled participants in Cohort C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: 1-year Event-free OS Rate | 79.38 percentage of participants |
Secondary
Cohort C: 1-year Event-free PFS Rate
PFS was defined as the time from enrollment to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first. Event-free PFS rate was defined as percentage of participants who did not experience any event and survived at 1 year after enrollment. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Percentages are rounded off to the nearest decimal point. As prespecified in the protocol, this outcome measure was applicable only to Cohort C.
Time frame: From enrollment until the occurrence of disease progression or death from any cause, whichever occurred earlier, up to 1 year
Population: ITT Population for Cohort C included all enrolled participants in Cohort C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: 1-year Event-free PFS Rate | 31.17 percentage of participants |
Secondary
Cohort C: CBR
CBR was defined as percentage of participants with an objective response (CR or PR), or SD for at least 24 weeks, as determined by the investigator through the use of RECIST v.1.1 assessed up to 31 months for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentages are rounded off to the nearest decimal point.
Time frame: From enrollment up to 31 months
Population: ITT population consisted of all enrolled participants in Cohort C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: CBR | 54.9 percentage of participants |
Secondary
Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30
EORTC QLQ-C30 is a cancer-specific instrument with 30 questions covering symptoms, functioning, and health-related quality of life (HRQoL). The participant's assessment of overall HRQoL is assessed by using the last 2 questions (29 and 30) of the instrument, with each of these items based on a 7-point scale (1=very poor to 7=excellent), which are then combined into the GHS/QoL multi-item scale. The scores obtained for each question were averaged into a raw score for the scale, and this raw score for the scale was then subsequently linearly transformed to a scale score of 0 to 100, with a high score indicating better GHS/QoL. Negative change from Baseline values in the GHS/QoL change from baseline analysis indicated deterioration in HRQoL and positive values indicated improvement.
Time frame: Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 (cycle length=28 days)
Population: PRO-evaluable Population for Cohort C included all enrolled participants who had a baseline and at least 1 postbaseline PRO assessment.Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 2 | -0.42 score on scale | Standard Deviation 18.02 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 3 | 0.18 score on scale | Standard Deviation 18.32 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 4 | -4.37 score on scale | Standard Deviation 22.83 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 5 | -6.41 score on scale | Standard Deviation 20.19 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 6 | -7.10 score on scale | Standard Deviation 21.24 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 7 | -5.09 score on scale | Standard Deviation 18.2 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 8 | -4.83 score on scale | Standard Deviation 21.24 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 9 | -7.66 score on scale | Standard Deviation 23.68 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 10 | -7.07 score on scale | Standard Deviation 18.76 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 11 | -6.00 score on scale | Standard Deviation 19.02 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 12 | -2.90 score on scale | Standard Deviation 18.57 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 13 | -1.45 score on scale | Standard Deviation 19.08 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 14 | -7.89 score on scale | Standard Deviation 21.24 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 15 | -5.09 score on scale | Standard Deviation 26.37 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 16 | -11.98 score on scale | Standard Deviation 27.55 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 17 | -10.90 score on scale | Standard Deviation 32.16 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 18 | -3.85 score on scale | Standard Deviation 20.3 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 19 | -3.21 score on scale | Standard Deviation 25.35 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 20 | -3.21 score on scale | Standard Deviation 24.89 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 21 | -2.56 score on scale | Standard Deviation 24.86 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 22 | -12.18 score on scale | Standard Deviation 32.92 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 23 | 3.03 score on scale | Standard Deviation 24.23 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 24 | 3.79 score on scale | Standard Deviation 24.54 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 25 | -4.63 score on scale | Standard Deviation 21.29 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 26 | -0.83 score on scale | Standard Deviation 19.82 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 27 | 2.08 score on scale | Standard Deviation 26.63 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 28 | 1.39 score on scale | Standard Deviation 23.81 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 29 | -1.19 score on scale | Standard Deviation 28.64 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 30 | 3.33 score on scale | Standard Deviation 24.01 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 31 | 22.22 score on scale | Standard Deviation 12.73 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 32 | 10.42 score on scale | Standard Deviation 23.94 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 33 | 16.67 score on scale | Standard Deviation 22.05 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 34 | 16.67 score on scale | Standard Deviation 30.05 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 35 | 13.89 score on scale | Standard Deviation 17.35 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 36 | 20.83 score on scale | Standard Deviation 29.46 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 37 | 16.67 score on scale | Standard Deviation 23.57 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 38 | 16.67 score on scale | Standard Deviation 23.57 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 39 | 25.00 score on scale | Standard Deviation 35.36 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 40 | 33.33 score on scale | — |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 41 | 50.00 score on scale | — |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 42 | 41.67 score on scale | — |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 43 | 41.67 score on scale | — |
| Cohort A: Placebo + Paclitaxel | Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 | Day 1 Cycle 44 | 50.00 score on scale | — |
Secondary
Cohort C: DOR
DOR was defined as the time from the first occurrence of a documented OR (CR or PR) to PD, as determined locally by the investigator through the use of RECIST v1.1, or death from any cause, whichever occurred first, assessed up to 31 months for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: From enrollment up to 31 months
Population: ITT population consisted of all enrolled participants in Cohort C. Overall number analyzed is the number of participants with objective response i.e., responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: DOR | 8.7 months |
Secondary
Cohort C: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
The numbers of ADA-positive participants after drug administration were summarized for participants exposed to atezolizumab. As prespecified in the protocol, this outcome measure was applicable only to Cohort C.
Time frame: Up to 45.5 months
Population: For Cohort C, Safety Evaluable Population included all participants who received any amount of study treatment in cohort C. Overall number analyzed is the number of participants with an ADA assay result from at least one post-baseline sample.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | 18 Participants |
Secondary
Cohort C: ORR
ORR was defined as percentage of participants with PR or CR on 2 consecutive occasions ≥4 weeks apart as determined by the investigator using RECIST v.1.1, assessed up to 31 months for this outcome measure. CR was defined as the disappearance of all target lesions or 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 sum of diameters of target lesions, taking as reference the baseline sum of diameters. Percentages are rounded off to the nearest decimal point.
Time frame: From enrollment up to 31 months
Population: ITT population consisted of all enrolled participants in Cohort C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: ORR | 52.9 percentage of participants |
Secondary
Cohort C: Plasma Concentration of G-037720
G-037720 was a metabolite of ipatasertib.
Time frame: Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days )
Population: PK Evaluable Population included all participants who had at least one evaluable plasma sample. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: Plasma Concentration of G-037720 | Cycle 1 Day 1 | 67.3 ng/mL | Geometric Coefficient of Variation 222.3 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Plasma Concentration of G-037720 | Cycle 1 Day 15 | 96.8 ng/mL | Geometric Coefficient of Variation 140.7 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Plasma Concentration of G-037720 | Cycle 3 Day 15 | 96.5 ng/mL | Geometric Coefficient of Variation 167.9 |
Secondary
Cohort C: Plasma Concentration of Ipatasertib
Time frame: Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days)
Population: PK Evaluable Population included all participants who had at least one evaluable plasma sample. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: Plasma Concentration of Ipatasertib | Cycle 1 Day 1 | 175 ng/mL | Geometric Coefficient of Variation 183 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Plasma Concentration of Ipatasertib | Cycle 1 Day 15 | 233 ng/mL | Geometric Coefficient of Variation 161.6 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Plasma Concentration of Ipatasertib | Cycle 3 Day 15 | 207 ng/mL | Geometric Coefficient of Variation 197.6 |
Secondary
Cohort C: Serum Concentration of Atezolizumab
As prespecified in the protocol, this outcome measure was applicable only to Cohort C.
Time frame: Day 1 of Cycle 1: 30 minutes post dose, predose on Day 15 of Cycle 1 and predose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length=28 days)
Population: For Cohort C, PK Evaluable Population included all participants who had at least one evaluable plasma sample in Cohort C. 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 |
|---|---|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohort C: Serum Concentration of Atezolizumab | Day 1 Cycle 1 | 309 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 31.7 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Serum Concentration of Atezolizumab | Day 15 Cycle 1 | 91.5 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 23.9 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Serum Concentration of Atezolizumab | Day 1 Cycle 2 | 130 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 54.1 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Serum Concentration of Atezolizumab | Day 1 Cycle 3 | 200 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 41.1 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Serum Concentration of Atezolizumab | Day 1 Cycle 4 | 231 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 52.3 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Serum Concentration of Atezolizumab | Day 1 Cycle 8 | 327 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 27.6 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Serum Concentration of Atezolizumab | Day 1 Cycle 12 | 371 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 30.5 |
| Cohort A: Placebo + Paclitaxel | Cohort C: Serum Concentration of Atezolizumab | Day 1 Cycle 16 | 402 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 42.4 |
Secondary
Cohorts A and B: Plasma Concentration of G-037720
G-037720 was a metabolite of ipatasertib.
Time frame: Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days )
Population: PK Evaluable Population included all participants who had at least one evaluable plasma sample. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohorts A and B: Plasma Concentration of G-037720 | Cycle 1 Day 1 | 45.6 ng/mL | Geometric Coefficient of Variation 777 |
| Cohort A: Placebo + Paclitaxel | Cohorts A and B: Plasma Concentration of G-037720 | Cycle 1 Day 15 | 83.9 ng/mL | Geometric Coefficient of Variation 183 |
| Cohort A: Placebo + Paclitaxel | Cohorts A and B: Plasma Concentration of G-037720 | Cycle 3 Day 15 | 90.8 ng/mL | Geometric Coefficient of Variation 180 |
| Cohort A: Ipatasertib + Paclitaxel | Cohorts A and B: Plasma Concentration of G-037720 | Cycle 1 Day 1 | 68.2 ng/mL | Geometric Coefficient of Variation 405 |
| Cohort A: Ipatasertib + Paclitaxel | Cohorts A and B: Plasma Concentration of G-037720 | Cycle 1 Day 15 | 95.1 ng/mL | Geometric Coefficient of Variation 211 |
| Cohort A: Ipatasertib + Paclitaxel | Cohorts A and B: Plasma Concentration of G-037720 | Cycle 3 Day 15 | 109 ng/mL | Geometric Coefficient of Variation 169 |
Secondary
Cohorts A and B:Plasma Concentration of Ipatasertib
Time frame: Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days)
Population: PK Evaluable Population included all participants who had at least one evaluable plasma sample. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Placebo + Paclitaxel | Cohorts A and B:Plasma Concentration of Ipatasertib | Cycle 1 Day 1 | 176 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 232 |
| Cohort A: Placebo + Paclitaxel | Cohorts A and B:Plasma Concentration of Ipatasertib | Cycle 1 Day 15 | 191 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 184 |
| Cohort A: Placebo + Paclitaxel | Cohorts A and B:Plasma Concentration of Ipatasertib | Cycle 3 Day 15 | 165 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 169 |
| Cohort A: Ipatasertib + Paclitaxel | Cohorts A and B:Plasma Concentration of Ipatasertib | Cycle 1 Day 1 | 165 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 326 |
| Cohort A: Ipatasertib + Paclitaxel | Cohorts A and B:Plasma Concentration of Ipatasertib | Cycle 1 Day 15 | 211 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 216 |
| Cohort A: Ipatasertib + Paclitaxel | Cohorts A and B:Plasma Concentration of Ipatasertib | Cycle 3 Day 15 | 234 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 149 |
Secondary
Number of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.
Time frame: Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C
Population: Safety Evaluable Population included all participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Number of Participants With Adverse Events (AEs) | 84 Participants |
| Cohort A: Ipatasertib + Paclitaxel | Number of Participants With Adverse Events (AEs) | 162 Participants |
| Cohort B: Placebo + Paclitaxel | Number of Participants With Adverse Events (AEs) | 74 Participants |
| Cohort B: Ipatasertib + Paclitaxel | Number of Participants With Adverse Events (AEs) | 144 Participants |
| Cohort C: Ipatasertib + Atezolizumab + Paclitaxel | Number of Participants With Adverse Events (AEs) | 102 Participants |
Secondary
Number of Participants With at Least One Adverse Events of Special Interest (AESI)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the NCI CTCAE, Version 4.0. AESI include cases of potential drug-induced liver injury that include an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law. Suspected transmission of an infectious agent by the study drug, Grade \>= 3 fasting hyperglycemia, hepatotoxicity, diarrhea, rash, ALT/AST elevations. Grade \>= 2 colitis/enterocolitis.
Time frame: Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C
Population: Safety Evaluable Population included all participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Number of Participants With at Least One Adverse Events of Special Interest (AESI) | 79 Participants |
| Cohort A: Ipatasertib + Paclitaxel | Number of Participants With at Least One Adverse Events of Special Interest (AESI) | 157 Participants |
| Cohort B: Placebo + Paclitaxel | Number of Participants With at Least One Adverse Events of Special Interest (AESI) | 73 Participants |
| Cohort B: Ipatasertib + Paclitaxel | Number of Participants With at Least One Adverse Events of Special Interest (AESI) | 141 Participants |
| Cohort C: Ipatasertib + Atezolizumab + Paclitaxel | Number of Participants With at Least One Adverse Events of Special Interest (AESI) | 101 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death from any cause.
Time frame: From randomization/ enrollment (Cohort C) up to death from any cause, up to 45 months for Cohort A, up to 46 months for Cohort B and up to 31 months for Cohort C
Population: ITT Population included all randomized participants in Cohorts A and B regardless of whether the participants received the assigned treatment. For Cohort C, the ITT population consisted of all enrolled participants in Cohort C.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Placebo + Paclitaxel | Overall Survival (OS) | 24.9 months |
| Cohort A: Ipatasertib + Paclitaxel | Overall Survival (OS) | 24.2 months |
| Cohort B: Placebo + Paclitaxel | Overall Survival (OS) | 28.4 months |
| Cohort B: Ipatasertib + Paclitaxel | Overall Survival (OS) | 29.0 months |
| Cohort C: Ipatasertib + Atezolizumab + Paclitaxel | Overall Survival (OS) | 22.8 months |
95% CI: [0.73, 1.58]
95% CI: [0.65, 1.37]