This is a study consisting of four cohorts in this setting. In Cohort 1, the safety and efficacy of ipatasertib (ipat) in combination with atezolizumab (atezo) and paclitaxel (pac) or nab-paclitaxel will be evaluated for participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not previously received chemotherapy. In Cohort 2, ipatasertib and atezolizumab (with no chemotherapy), will be administered to participants with locally advanced or metastatic TNBC. In Cohort 3, the safety and efficacy of neoadjuvant ipatasertib, atezolizumab, doxorubicin and cyclophosphamide (AC) (Ipat + Atezo + AC) followed by Ipat + Atezo + Pac will be evaluated in participants with locally advanced Type 2-4 (T2-4) TNBC. In Cohort 4, the safety and efficacy of Ipat + Atezo + Pac will be evaluated in participants with PD-L1 (Programmed Death-Ligand-1) positive locally advanced or metastatic TNBC that is not amenable to resection and who have not previously received chemotherapy in the advanced setting.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
139
Ipatasertib will be administered at a dose of 400 milligrams (mg) orally daily on Days 1-21 of each 28 day cycle for all arms except for arms F1/F2 where it will be administered at a dose of 300 milligrams (mg) orally daily for the first two cycles and 400 mg for the remaining three cycles.
Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m\^2) as IV infusion on Days 1, 8, and 15 of each 28 day cycle for all arms, with the exceptions of Arms F1, F2, G1 and G2, where it will be also administered on Day 22 as well, of each 28 day cycle.
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28 day cycle for all arms, although in Arms C1/C2, it will be administered on Day 15 of Cycle 1 followed by Days 1 and 15 in subsequent cycles.
Nab-paclitaxel will be administered by IV infusion at a dose of 100 mg/m\^2 on Days 1, 8, and 15 of each 28 day cycle.
AC (Doxorubicin and Cyclophosphamide) will be administered by IV infusion at 60 mg/m\^2 and 600 mg/m\^2 respectively on Days 1 and 15 of Cycles 1 and 2 for Arms F1, F2, G1 and G2.
Pacific Shores Medical Group
Long Beach, California, United States
St Vincents Hospital; Cardiopulmonary transplant Ambulatory Care Dept
Darlinghurst, New South Wales, Australia
Austin Hospital
Heidelberg, Victoria, Australia
Peter MacCallum Cancer Center
North Melbourne, Victoria, Australia
Institut de Cancerologie de l Ouest
Angers, France
Institut Bergonie
Bordeaux, France
Centre Georges Francois Leclerc
Dijon, France
Institut Curie
Paris, France
Gustave Roussy
Villejuif, France
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain
...and 8 more locations
Cohort 1 and Cohort 4: Percentage of Participants With Objective Response (OR) as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors (RECIST), Version (v) 1.1
Objective Response Rate: percentage participants with confirmed complete response (CR) or partial response (PR) on 2 consecutive occasions \>or= 4 weeks apart, as determined by investigator according to RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Percentages have been rounded off. No participants were enrolled in cohort 4, hence no data reported.
Time frame: From screening up to approximately 43.6 months
Cohort 3: Pathological Complete Response (pCR) Rate
pCR rate was defined as the percentage of participants who had no residual invasive disease in the breast and no residual disease in the lymph nodes (ypT0/Tis ypN0 in the current American Joint Committee on Cancer (AJCC )staging system) based on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant therapy.
Time frame: 2-6 weeks following last dose of study treatment (up to 69 weeks)
Cohort 1, Cohort 2, Cohort 3 and Cohort 4: Number of Participants With Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any new disease or worsening of an existing disease are also considered as AEs. AEs were reported based on the National Cancer Institute Common Terminology Criteria for AEs, version 4.0 (NCI-CTCAE, v4.0). No participants were enrolled in cohort 3 Arm G and 4, and hence no data was reported.
Time frame: Up until 90 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to 4 years 1 month)
Cohort 1 and Cohort 4: Duration of Response (DOR), as Determined by the Investigator According to RECIST v1.1
DOR was defined as the time from the first occurrence of a documented confirmed CR or PR to the first date of recorded disease progression (PD), as determined by the investigator according to RECIST v1.1 or death from any cause. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduced 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 diameter of target lesions, taking as reference the smallest sum on study (nadir) including baseline; the appearance of one or more new lesions. No participants were enrolled in cohort 4, and hence no data was reported. Participants who did not progress or died at time of analysis were censored at last disease assessment date.
Time frame: From the date of first documented confirmed response (CR or PR) to disease progression or death due to any cause (up to approximately 43.6 months)
Cohort 1 and Cohort 4: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1
PFS: time from enrollment to date of 1st recorded occurrence of PD, as determined by investigator according to RECIST v1.1 or death from any cause, whichever occurs first. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (nadir) including baseline; appearance of one or more new lesions. Data for participants who did not experience PD or death was censored at last date of evaluable tumor assessment. No participants were enrolled in cohort 4, and hence no data was reported.
Time frame: From enrollment up to disease progression or death due to any cause whichever occurs first (up to approximately 43.6 months)
Cohort 1 and Cohort 4: Overall Survival (OS)
OS was defined as the time from enrollment to death from any cause.
Time frame: From enrollment up to death due to any cause (up to approximately 43.6 months).
Cohort 1 and Cohort 4: Plasma Concentration of Ipatasertib
Since, Cohort 4 did not enroll any participants, data is only reported for Cohort 1.
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Time frame: Day 15 Cycle 1: pre-dose and 1, 2, 4 and 6 hours post-dose, Day 15 Cycle2: predose and 1, 2, 4 and 6 hours post-dose and Day 15 Cycle 3 - post dose up to - 3 hours (each cycle is of 28 days)
Cohort 1 and Cohort 4: Plasma Concentration of Ipatasertib Metabolite M1 (G-037720)
Since, Cohort 4 did not enroll any participants, data is only reported for Cohort 1.
Time frame: Day 15 Cycle 1 - pre-dose and 1 hour, 2 hours, 4 hours and 6 hours post-dose, Day 15 Cycle2: predose and 1 hour, 2 hours, 4 hours and 6 hours post-dose and Day 15 Cycle 3 - post dose up to - 3 hours (each cycle is of 28 days)
Cohort 1 and Cohort 4: Number of Participants With Anti-Drug Antibodies (ADAs) for Atezolizumab During Study Treatment
Participants were considered to be ADA positive if they were ADA negative or were missing data at Baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA positive at Baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than the titer of the Baseline sample (treatment-enhanced ADA response). Participants were considered to be ADA negative if they were ADA negative or had missing data at Baseline and all postbaseline samples were negative, or if they were ADA positive at Baseline but did not have any postbaseline samples with a titer that was at least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected). Since, Cohort 4 did not enroll any participants, data is only reported for Cohort 1.
Time frame: From baseline up to 30 days from the last dose of atezolizumab (to approximately 4 years 1.1 month)
Cohort 1 and Cohort 4: Plasma Concentration of Atezolizumab
Since, Cohort 4 did not enroll any participants, data is only reported for Cohort 1.
Time frame: Cycle 1 Day 1 and 15: predose and 30 mins post dose; Cycle 2: Day 1 and 15 predose, Cycle 3, 4, 8, 12, and 16 Day 1: predose; treatment discontinuation visit
Cohort 1 and Cohort 4: Clinical Benefit Rate (CBR) as Assessed by Investigator Based on RECIST v1.1
CBR was defined as percentage of participants with stable disease (SD) for at least 24 weeks or with confirmed CR or PR as determined by the investigator according to RECIST v1.1. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have 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. Since, Cohort 4 did not enroll any participants, data is only reported for Cohort 1.
Time frame: From screening up to confirmed SD or CR or PR (up to approximately 43.6 months)