A Study to Evaluate the Efficacy and Safety of Inavolisib in Combination With Phesgo Versus Placebo in Combination With Phesgo in Participants With PIK3CA-Mutated HER2-Positive Locally Advanced or Metastatic Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of inavolisib in combination with Phesgo (pertuzumab, trastuzumab, and rHuPH20 injection for subcutaneous use) compared with placebo in combination with Phesgo, as maintenance therapy, after induction therapy in participants with previously untreated HER2-positive advanced breast cancer (ABC).

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Inavolisib in Combination With Phesgo Versus Placebo in Combination With Phesgo As Maintenance Therapy After First Line Induction Therapy in Participants With PIK3CA-Mutated HER2-Positive Locally Advanced or Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Inavolisib
* Drug: Phesgo
* Drug: Placebo
* Drug: Taxane-based Chemotherapy
* Drug: Optional Endocrine Therapy of Investigator's Choice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection Confirmation of HER2 biomarker eligibility based on valid results from central testing of tumor tissue documenting HER2-positivity Confirmation of PIK3CA-mutation biomarker eligibility based on valid results from central testing of tumor tissue documenting PIK3CA-mutated tumor status Disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrence of >= 6 months LVEF (left ventricular ejection fraction) of at least 50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) Adequate hematologic and organ function prior to initiation of study treatment Exclusion Criteria: Prior treatment in the 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 Any prior systemic non-hormonal anti-cancer therapy for locally advanced or metastatic HER2-positive breast cancer prior to initiation of induction therapy History or active inflammatory bowel disease Disease progression within 6 months of receiving any HER2-targeted therapy Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes Clinically significant and active liver disease, including severe liver impairment, viral or other hepatitis, current alcohol abuse, or cirrhosis Symptomatic active lung disease, including pneumonitis or interstitial lung disease Any history of leptomeningeal disease or carcinomatous meningitis Serious infection requiring IV antibiotics 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

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Induction Therapy: Phesgo plus Taxane-Based Chemotherapy<br>Participants will be administered the treatments as outlined in the interventions section. | Drug: Phesgo<br>* Phesgo will be administered to participants subcutaneously every 3 weeks (Q3W) on D1 of each 21-day cycle.<br>Drug: Taxane-based Chemotherapy<br>* During the induction therapy phase, the investigator's choice of taxane-based chemotherapy will be administered after Phesgo.<br>* Other names: non-investigational medicinal product (NIMP);|
| Experimental: Maintenance Therapy: Inavolisib plus Phesgo<br>Participants will be administered the treatments as outlined in the interventions section. | Drug: Inavolisib<br>* Participants will receive an inavolisib tablet to be taken orally (PO), once a day (QD), on Days 1-21 of each 21-day cycle, beginning on Day (D) 1 of Cycle (C) 1 of maintenance treatment.<br>Drug: Phesgo<br>* Phesgo will be administered to participants subcutaneously every 3 weeks (Q3W) on D1 of each 21-day cycle.<br>Drug: Optional Endocrine Therapy of Investigator's Choice<br>* Optional endocrine therapy (ET) is allowed at the discretion of the investigator, based on the standard of care. Allowed ETs are tamoxifen, or one of the specified third-generation aromatase inhibitor (AI [anastrozole, letrozole, or exemestane]), or fulvestrant. The investigator will determine and supply the appropriate luteinizing hormone-releasing hormone (LHRH) agonist locally approved for use in breast cancer. The LHRH agonist will be administered according to local prescribing information.<br>* Other names: NIMP;|
| Active Comparator: Maintenance Therapy: Placebo plus Phesgo<br>Participants will be administered the treatments as outlined in the interventions section. | Drug: Phesgo<br>* Phesgo will be administered to participants subcutaneously every 3 weeks (Q3W) on D1 of each 21-day cycle.<br>Drug: Placebo<br>* Inavolisib-matching tablet taken PO QD on Days 1-21 of each 21-day cycle, beginning on D1 C1 of maintenance treatment.<br>Drug: Optional Endocrine Therapy of Investigator's Choice<br>* Optional endocrine therapy (ET) is allowed at the discretion of the investigator, based on the standard of care. Allowed ETs are tamoxifen, or one of the specified third-generation aromatase inhibitor (AI [anastrozole, letrozole, or exemestane]), or fulvestrant. The investigator will determine and supply the appropriate luteinizing hormone-releasing hormone (LHRH) agonist locally approved for use in breast cancer. The LHRH agonist will be administered according to local prescribing information.<br>* Other names: NIMP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-Assessed Progression-Free Survival (PFS) |  | Up to approximately 40 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | Up to approximately 111 months | 
| Investigator-Assessed Objective Response Rate (ORR) |  | Up to approximately 111 months | 
| Investigator-Assessed Duration of Response (DOR) |  | Up to approximately 111 months | 
| Investigator-Assessed Clinical Benefit Rate (CBR) |  | Up to approximately 111 months | 
| Investigator-Assessed PFS2 |  | Up to approximately 111 months | 
| Mean and Mean Changes from Baseline Score in Function and Health-Related Quality of Life (HRQoL) | Assessed through the use of the Functional (Role, Physical) and Global Health Status (GHS)/Quality of Life (QoL) scales of the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) | 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 every 6 months (up to 111 months). Each cycle is 21 days. | 
| Percentage of Participants with Adverse Events |  | Day 1 until 30 days after the final dose of study treatment (up to approximately 111 months). Each cycle is 21 days. | 
| Plasma Concentration of Inavolisib at Specified Timepoints |  | Day 1 of Cycles 1 and 4. Each cycle is 21 days. |