A Study of Atezolizumab in Combination With Nab-Paclitaxel Compared With Placebo With Nab-Paclitaxel for Participants With Previously Untreated Metastatic Triple-Negative Breast Cancer (IMpassion130)

Study Overview
=================
Brief Summary
-----------------
This multicenter, randomized, double-blind study evaluated the efficacy, safety, and pharmacokinetics of atezolizumab (MPDL3280A) administered with nab-paclitaxel compared with placebo in combination with nab-paclitaxel in participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not received prior systemic therapy for metastatic breast cancer (mBC). The safety of single-agent nab-paclitaxel has been determined in previous studies of participants with mBC and the safety data to date suggest that atezolizumab can be safely combined with standard chemotherapy agents.

Official Title
-----------------
A Phase III, Multicenter, Randomized, Placebo-Controlled Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Nab-Paclitaxel Compared With Placebo With Nab-Paclitaxel for Patients With Previously Untreated Metastatic Triple-Negative Breast Cancer

Conditions
-----------------
Triple Negative Breast Cancer

Intervention / Treatment
-----------------
* Drug: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody
* Drug: Nab-Paclitaxel
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Metastatic or locally advanced, histologically documented TNBC characterized by absence of human epidermal growth factor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) expression No prior chemotherapy or targeted systemic therapy for inoperable locally advanced or metastatic TNBC Eligible for taxane monotherapy (i.e., absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control) A representative formalin-fixed, paraffin-embedded tumor specimen in paraffin blocks, or at least 20 unstained slides with an associated pathology report documenting ER, PR, and HER2 negativity. Participants with fewer than 20 unstained slides available at baseline, and not fewer than 12 unstained slides will be eligible upon discussion with Medical Monitor Eastern Cooperative Oncology Group performance status of 0 or 1 Measurable disease as defined by RECIST v1.1 Adequate hematologic and end-organ function Exclusion Criteria: Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases Leptomeningeal disease Pregnancy or lactation History of autoimmune disease Prior allogeneic stem cell or solid organ transplantation Positive test for human immunodeficiency virus Active hepatitis B or hepatitis C Receipt of a live, attenuated vaccine within 4 weeks prior to randomization, during treatment, or within 5 months following the last dose of atezolizumab/placebo

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab Plus Nab-Paclitaxel<br>Participants assigned to atezolizumab plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity. | Drug: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody<br>* Atezolizumab at a fixed dose of 840 milligrams via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity.<br>* Other names: Tecentriq, MPDL3280A;Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel at a starting dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle. Nab-Paclitaxel was administered for a target of at least 6 cycles, with no maximum in the absence of disease progression or unacceptable toxicity.<br>* Other names: Abraxane®;|
| Placebo Comparator: Placebo Plus Nab-Paclitaxel<br>Participants assigned to placebo plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity. | Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel at a starting dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle. Nab-Paclitaxel was administered for a target of at least 6 cycles, with no maximum in the absence of disease progression or unacceptable toxicity.<br>* Other names: Abraxane®;Drug: Placebo<br>* Placebo administered via IV infusion on Days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) in All Randomized Participants | PFS was defined as the time from randomization to the occurrence of disease progression, as determined by investigators from tumor assessments per RECIST v1.1, or death from any cause, whichever occurred first. | Baseline up to approximately 34 months | 
| PFS According to RECIST v1.1 in Participants With Detectable Programmed Death-Ligand 1 (PD-L1) | PFS was defined as the time from randomization to the occurrence of disease progression, as determined by investigators from tumor assessments per RECIST v1.1, or death from any cause, whichever occurred first. | Baseline up to approximately 34 months | 
| Overall Survival (OS) in All Randomized Participants | OS was defined as the time from the date of randomization to the date of death from any cause. | Baseline until death due to any cause (up to approximately 58 months) | 
| OS in Participants With Detectable PD-L1 | OS was defined as the time from the date of randomization to the date of death from any cause. | Baseline until death due to any cause (up to approximately 58 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST v1.1 in All Randomized Participants | An objective response was defined for participants with measurable disease at baseline as either a partial response (PR) or a complete response (CR) using RECIST v1.1. | Baseline up to approximately 34 months | 
| Percentage of Participants With an Objective Response of CR or PR According to RECIST v1.1 in Participants With Detectable PD-L1 | An objective response was defined for participants with measurable disease at baseline as either a partial response (PR) or a complete response (CR) using RECIST v1.1. | Baseline up to approximately 34 months | 
| Duration of Response (DOR) According to RECIST v1.1 in All Randomized Participants | DOR was defined for participants who had an objective response as the time from the first occurrence of a documented unconfirmed response (CR or PR) to the date of disease progression per RECIST v1.1 or death from any cause, whichever occurred first. | Baseline up to approximately 34 months | 
| DOR Acccording to RECIST v1.1 in Participants With Detectable PD-L1 | DOR was defined for participants who had an objective response as the time from the first occurrence of a documented unconfirmed response (CR or PR) to the date of disease progression per RECIST v1.1 or death from any cause, whichever occurred first. | Baseline up to approximately 34 months | 
| Time to Deterioration (TTD) in Global Health Status/Health Related Quality of Life According to European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) v3.0 in All Randomized Participants | Deterioration in GHS/HRQoL (Items 29, 30 of the EORTC QLQ C30) was defined by the following two criteria: 1. The time from randomization to the first time the participant's GHS/HRQoL scale score showed a >=10-point decrease from the baseline scale score. A 10-point change was defined as the minimally important difference (MID). 2. The score decrease of >= 10-points from baseline was held for at least two consecutive cycles, or an initial score decrease of >= 10-points was followed by death or treatment discontinuation within 3 weeks from the last assessment. | Baseline up to approximately 58 months | 
| TTD in Global Health Status/Health Related Quality of Life According to EORTC QLQ-C30 v3.0 in Participants With Detectable PD-L1 | Deterioration in GHS/HRQoL (Items 29, 30 of the EORTC QLQ C30) was defined by the following two criteria: 1. The time from randomization to the first time the participants's GHS/HRQoL scale score showed a >=10-point decrease from the baseline scale score. A 10-point change was defined as the minimally important difference (MID). 2. The score decrease of >= 10-points from baseline was held for at least two consecutive cycles, or an initial score decrease of >= 10-points was followed by death or treatment discontinuation within 3 weeks from the last assessment. | Baseline up to approximately 58 months | 
| Percentage of Participants With at Least One Adverse Event | Percentage of participants with at least one adverse event. | Baseline up to to the data cutoff date: 31 August 2021 (up to approximately 74 months) | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab | Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab | Baseline up to approximately 53 months | 
| Maximum Serum Concentration (Cmax) for Atezolizumab | Maximum serum concentration for atezolizumab. | Cycle 1 Day 1 (Cycle = 28 days) | 
| Minimum Serum Concentration (Cmin) for Atezolizumab | Minimum serum concentration for atezolizumab. | Day 27 of Cycle 1, 2, 3, and 7 (Cycle = 28 days) | 
| Plasma Concentrations of Total Paclitaxel | Plasma Concentrations of Total Paclitaxel | Pre-dose (Hour 0) on Cycle 1 Day 1, pre-dose (Hour 0), 5-10 minutes before end of nab-paclitaxel infusion, 1 hour after end of nab-paclitaxel infusion (infusion duration = 30 minutes) on Cycle 3 Day 1 (Cycle = 28 days) |