A Study Assessing the Safety and Efficacy of Adding Ipatasertib to Paclitaxel Treatment in Participants With Breast Cancer That Has Spread Beyond the Initial Site, and the Cancer Does Not Have Certain Hormonal Receptors

Study Overview
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Brief Summary
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This multicenter, randomized, double-blind study will estimate the efficacy, safety and tolerability of ipatasertib combined with paclitaxel compared with placebo combined with paclitaxel in participants with inoperable locally advanced or metastatic triple-negative breast cancer (mTNBC), as measured by progression-free survival (PFS) in all participants and in participants with phosphatase and tensin homolog (PTEN)-low tumors.

Official Title
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A Randomized, Phase II, Multi-Center, Placebo-Controlled Study of Ipatasertib (GDC-0068), an Inhibitor of Akt, in Combination With Paclitaxel as Front-Line Treatment for Patients With Metastatic Triple-Negative Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Ipatasertib
* Drug: Paclitaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented triple-negative adenocarcinoma of the breast that is inoperable locally advanced or metastatic and is not amenable to resection with curative intent Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen, required prior to randomization Measurable disease, according to the RECIST v1.1 Adequate hematologic and organ function within 14 days before the first study treatment For female participants of childbearing potential, agreement (by both participant and partner) to use an effective form of contraception for the duration of the study and for 6 months after last dose of study treatment Exclusion Criteria: Any previous therapy, including chemotherapy or hormonal or targeted therapy, for inoperable locally advanced or metastatic triple-negative adenocarcinoma of the breast. Participants may have received prior neoadjuvant or adjuvant chemotherapy and/or radiation treatment for locally advanced triple negative adenocarcinoma, provided all treatments were completed greater than or equal to (>/=) 6 months prior to Cycle 1 Day 1. Locally recurrent disease must not be amenable to resection with curative intent Any radiation treatment to metastatic site within 28 days of Cycle 1, Day 1 Known Human Epidermal Growth Factor Receptor 2 (HER2) positive, erythrocyte receptor (ER) positive, or progesterone receptor (PR) positive breast cancer Previous therapy with Akt, PI3K, and/or mTOR inhibitors Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study Known presence of the brain or spinal cord metastasis, as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening or prior radiographic assessments

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipatasertib + Paclitaxel<br>Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. | Drug: Ipatasertib<br>* Participants received ipatasertib orally 400 milligrams (mg) daily on Days 1-21 of each 28-day cycle.<br>* Other names: GDC-0068;Drug: Paclitaxel<br>* Participants received paclitaxel 80 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, and 15 of each cycle.<br>|
| Placebo Comparator: Placebo + Paclitaxel<br>Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. | Drug: Paclitaxel<br>* Participants received paclitaxel 80 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, and 15 of each cycle.<br>Drug: Placebo<br>* Participants received oral placebo matched to ipatasertib, daily on Days 1-21 of each 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first. | Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016) | 
| PFS in Participants With Phosphatase and Tensin Homolog (PTEN)-Low Tumors | PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first. | Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS in Participants With Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha (PIK3CA)/ Protein Kinase B (AKT1)/ PTEN-altered Tumors | PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first. | Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016) | 
| Overall Survival (OS) | OS was defined as the time from the date of randomization to the date of death from any cause. | Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019) | 
| OS in Participants With PTEN-Low Tumors | OS was defined as the time from the date of randomization to the date of death from any cause. | Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019) | 
| OS in Participants With PIK3CA/AKT1/PTEN-altered Tumors | OS was defined as the time from the date of randomization to the date of death from any cause. | Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019) | 
| Objective Response Rate (ORR) | Confirmed tumor ORR in participants with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of participants who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Participants for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| ORR in Participants With PTEN-Low Tumors | Confirmed tumor ORR in participants with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of participants who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Participants for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| ORR in Participants With PIK3CA/AKT1/PTEN-altered Tumors | Confirmed tumor ORR in subjects with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of subjects who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Subjects for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| Duration of Response | Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| Duration of Response in Participants With PTEN-Low Tumors | Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| Duration of Response in Participants With PIK3CA/AKT1/PTEN-altered Tumors | Duration of objective response in participants with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| Time to Disease Progression | Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| Time to Disease Progression in Participants With PTEN-Low Tumors | Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| Time to Disease Progression in Participants With PIK3CA/AKT1/PTEN-altered Tumors | Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1. | Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) | 
| Safety: Percentage of Participants With Adverse Events | An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Baseline up to 30 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurs first (up to 3 years, 3 months) | 
| Pharmacokinetic Endpoint: Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) of Ipatasertib | PK parameters were not calculated due to sparse PK sampling. | Cycle 1 Day 1, Cycle 1 Day 8 | 
| Pharmacokinetic Endpoint: Apparent Clearance Following Oral Dosing (CL/F) of Ipatasertib | PK parameters were not calculated due to sparse PK sampling. | Cycle 1 Day 1, Cycle 1 Day 8 | 
| Patient Reported Outcome (PRO) Measure: Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) Score | EORTC QLQ-C30 included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1=Not at all to 4=Very much; 2 questions used 7-point scale [1=very poor to 7=Excellent]). Scores averaged, transformed to 0-100 scale; a higher score=better level of functioning. For symptom scale scores, higher level=severe level of symptoms. A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139-44). PRO measures were analyzed from baseline up to cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of participants remained on treatment beyond cycle 5). | Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1 | 
| PRO Measure: Percentage of Participants With Improved, Worsened, or Remained Stable for Bothersome Side Effects of Treatment Measured by the Scales of the EORTC QLQ-C30 | Subjects reporting >/= 10-point increase compared to baseline (Cycle 1 Day 1) were considered improved, those reporting <10-point difference were considered remained stable, and those reporting >/=10-point decrease were considered worsened. A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139-44). Patient reported outcome measures were analyzed from baseline up to and including cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of participants remained on treatment beyond cycle 5). | Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1 |