A Study of Ipatasertib in Combination With Paclitaxel as a Treatment for Participants With PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor-Positive, HER2-Negative Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Double-Blind, Placebo-Controlled, Randomized Phase III Study of Ipatasertib in Combination With Paclitaxel as a Treatment for Patients With PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor-Positive, HER2-Negative Breast Cancer

Conditions
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Breast Cancer

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: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipatasertib + Paclitaxel<br> | Drug: Ipatasertib<br>* 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.<br>Drug: Paclitaxel<br>* 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.<br>|
| Experimental: Placebo + Paclitaxel<br> | Drug: Paclitaxel<br>* 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.<br>Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Progression-Free Survival (PFS) as determined by the Investigator using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 (v1.1) | From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 53 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Proportion of participants with an objective response (ORR), defined as partial response or complete response on 2 consecutive occasions ≥4 weeks apart) as determined by the Investigator using RECIST v.1.1 | From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 53 months | 
| Duration of Response (DOR) | Time from the first occurrence of a documented objective response to the time of the first documented disease progression or death from any cause. | Time from the first occurrence of a documented objective response to the time of the first documented disease progression or death from any cause, whichever occurs earlier, up to approximately 53 months | 
| Clinical Benefit Rate (CBR) | Proportion of participants with a clinical benefit (CB), defined as an objective response (CR or PR), or stable disease for at least 24 weeks, as determined by the Investigator through the use of RECIST v1.1. | From randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 53 months | 
| Overall Survival (OS) | Time from randomization to death from any cause. | From randomization up to death from any cause, up to approximately 53 months | 
| Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score | GHS/HRQoL scores, assessed using selected questions from European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). | From Day 1 of Cycle 1 up to approximately 53 months | 
| Time to Deterioration in Pain | Time to deterioration in pain is defined as the first minimally important increase of >10 points from the baseline pain scale score of selected questions of the EORTC QLQ-C30 and will only be assessed in the cohort with HR+/HER2- breast cancer participants. | From Day 1 of Cycle 1 up to approximately 53 months | 
| Incidence and Severity of Adverse Events (AEs) | Percentage of participants with an adverse event (AE), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0, including analysis of pre-specified AEs. | From randomization up to approximately 53 months | 
| Changes in Vital Signs | Change from baseline in selected vital signs. | From randomization up to approximately 53 months | 
| Changes in Targeted Laboratory Results | Change from baseline in selected laboratory test results. | From randomization up to approximately 53 months | 
| Plasma Concentration of Ipatasertib and Its Metabolite (G-037720) |  | Day 1 and Day 15 of Cycle 1, and on Day 15 of Cycle 3 |