A Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Compared With Alpelisib Plus Fulvestrant in Participants With HR-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Post CDK4/6i and Endocrine Combination Therapy

Study Overview
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Brief Summary
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This is a Phase III, multicenter, randomized, open-label, global study designed to evaluate the efficacy and safety of inavolisib plus fulvestrant compared with alpelisib plus fulvestrant in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative, PIK3CA-mutated, locally advanced (LA) or metastatic breast cancer (mBC), who progressed during or after cyclin dependent kinase 4/6i (CDK4/6i)-based therapy.

Official Title
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A Phase III, Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Versus Alpelisib Plus Fulvestrant in Patients With Hormone Receptor-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Who Progressed During or After CDK4/6 Inhibitor and Endocrine Combination Therapy

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Inavolisib
* Drug: Fulvestrant
* Drug: Alpelisib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: If pre/perimenopausal women and men treatment with luteinizing hormone-releasing hormone (LHRH) agonist therapy beginning at least 2 weeks prior to Day 1 of Cycle 1 Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to surgical or radiation therapy with curative intent Documented HR +/ HER2- tumor according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines Confirmation of biomarker eligibility: detection of specified mutation(s) of PIK3CA via specified test Disease progression after or during treatment with a combination of CDK4/6i and endocrine therapy: <= 2 prior lines of systemic therapy in mBC setting; CDK4/6i based therapy does not need to be the last one received prior study entry; one line of chemotherapy in mBC setting allowed Measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Participants for whom endocrine-based therapy is recommended and treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or local treatment guidelines Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Life expectancy of > 6 months Adequate hematologic and organ function prior to initiation of study treatment Exclusion Criteria: Metaplastic breast cancer Prior treatment in locally advanced or metastatic setting with any PI3K, AKT, or mTOR inhibitor or any agent whose mechanism of action is to inhibit the PI3K/-AKT/-mTOR pathway Participant who relapsed with documented evidence of progression > 12 months from completion of adjuvant CDK4/6i based therapy with no treatment for metastatic disease Pregnant, lactating, or breastfeeding, or intending to become pregnant during the study or at least 60 days after the final dose of study treatment Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes Inability or unwillingness to swallow pills Malabsorption syndrome or other condition that would interfere with enteral absorption Any history of leptomeningeal disease or carcinomatous meningitis Known and untreated, or active central nervous system (CNS) metastases. Participants with a history of treated CNS metastases are eligible if they meet specific certain criteria Known active, systemic infection at study enrollment, or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 7 days prior to Day 1 of Cycle 1 Any concurrent ocular or intraocular condition that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition Active inflammatory or infectious conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye Requirement for daily supplemental oxygen Symptomatic active lung disease, including pneumonitis History of or active inflammatory bowel disease Any active bowel inflammation Clinically significant and active liver disease, including severe liver impairment, viral or other hepatitis, current alcohol abuse, or cirrhosis Participants with known human immunodeficiency virus infection that meet specific criteria Investigational drug(s) within 4 weeks before randomization or within 5 half-lives of the investigational drug(s), whichever is longer History of other malignancy within 5 years prior to screening, except for cancers with very low risk of recurrence Chronic therapy of >= 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease Allergy or hypersensitivity to components or excipients of the inavolisib, fulvestrant, or alpelisib formulations History of severe cutaneous reactions like Stevens-Johnson Syndrome, Erythema Multiforme, Toxic Epidermal Necrolysis, or Drug Reaction with Eosinphilia and Systemic Symptoms Active ongoing osteonecrosis of the jaw

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inavolisib + Fulvestrant<br>Participants will be administered the treatments as outlined in the interventions section. | Drug: Inavolisib<br>* Participants will be administered a 9 milligram (mg) inavolisib tablet orally once a day (PO QD) on Days 1-28 of each 28-day cycle.<br>Drug: Fulvestrant<br>* Participants will be administered 500 mg of fulvestrant on Days 1 and 15 of Cycle 1 and then on Day 1 of each subsequent 28-day cycle.<br>|
| Active Comparator: Alpelisib + Fulvestrant<br>Participants will be administered the treatments as outlined in the interventions section. | Drug: Fulvestrant<br>* Participants will be administered 500 mg of fulvestrant on Days 1 and 15 of Cycle 1 and then on Day 1 of each subsequent 28-day cycle.<br>Drug: Alpelisib<br>* Alpelisib will be administered to participants at the approved dose in combination with fulvestrant: 300 mg taken PO QD and on days 1-28 of each 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blinded Independent Central Review (BICR)-Assessed Progression Free Survival (PFS) |  | From randomization until disease progression or death due to any cause (up to approximately 64 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | From randomization until death due to any cause (up to approximately 85 months) | 
| BICR-Assessed Overall Response Rate (ORR) |  | Up to approximately 64 months | 
| BICR-Assessed Best Overall Response (BOR) |  | Up to approximately 64 months | 
| BICR-Assessed Clinical Benefit Rate (CBR) |  | Up to approximately 64 months | 
| BICR-Assessed Duration of Response (DOR) |  | From CR or PR until disease progression or death due to any cause (up to approximately 64 months) | 
| Time to Confirmed Deterioration (TTCD) in Pain |  | Day 1 of Cycles 1 and 2 and beyond, 30-day safety follow up visit, post-treatment tumor assessment follow-up with PRO collection and survival follow up visit (up to approximately 85 months). Each cycle is 28 days. | 
| TTCD in Physical Functioning |  | Day 1 of Cycles 1 and 2 and beyond, 30-day safety follow up visit, post-treatment tumor assessment follow-up with PRO collection and survival follow up visit (up to approximately 85 months). Each cycle is 28 days. | 
| TTCD in Role Functioning |  | Day 1 of Cycles 1 and 2 and beyond, 30-day safety follow up visit, post-treatment tumor assessment follow-up with PRO collection and survival follow up visit (up to approximately 85 months). Each cycle is 28 days. | 
| TTCD in Global Health Status/Quality of Life (QOL) |  | Day 1 of Cycles 1 and 2 and beyond, 30-day safety follow up visit, post-treatment tumor assessment follow-up with PRO collection and survival follow up visit (up to approximately 85 months). Each cycle is 28 days. | 
| Percentage of Participants with Adverse Events |  | Day 1 until 30 days after the final dose of study treatment (up to approximately 85 months) | 
| Plasma Concentration of Inavolisib at Specified Timepoints |  | Day 1 and 15 of Cycle 1, and Day 1 of Cycles 2 and 3. Each cycle is 28 days. |