A Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics of inavolisib in combination with palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant in participants with PIK3CA-mutant, hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed during treatment or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for metastatic disease.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Inavolisib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Inavolisib
* Drug: Placebo
* Drug: Palbociclib
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Confirmed diagnosis of HR+/HER2- breast cancer Metastatic or locally advanced disease not amenable to curative therapy Progression of disease during adjuvant endocrine treatment or within 12 months of completing adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen Receiving LHRH agonist therapy for at least 2 weeks prior to Day 1 of Cycle 1 if pre/peri-menopausal Confirmation of biomarker eligibility (detection of specified mutation(s) of PIK3CA via specified test) Consent to provide fresh or archival tumor tissue specimen Measurable disease per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1); evaluable bone-only disease is not eligible; bone-only disease with at least one measurable, soft-tissue component, even if considered disease that is limited to bone but has lytic or mixed lytic/blastic lesions and at least one measurable soft-tissue component per RECIST v1.1 may be eligible Eastern Cooperative Oncology Group Performance Status of 0 or 1 Life expectancy of > 6 months Adequate hematologic and organ function within 14 days prior to initiation of study treatment Exclusion Criteria Metaplastic breast cancer Any history of leptomeningeal disease or carcinomatous meningitis Any prior systemic therapy for metastatic breast cancer Prior treatment with fulvestrant or any selective estrogen-receptor degrader, with the exception of participants that have received fulvestrant or any selective estrogen-receptor degrader as part of neoadjuvant therapy only and with treatment duration of no longer than 6 months Prior treatment with any PI3K, AKT, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K-AKT-mTOR pathway Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes Known and untreated, or active CNS metastases. Patients with a history of treated CNS metastases may be eligible Active inflammatory or infectious conditions in either eye, or any eye conditions expected to require surgery during the study treatment period Symptomatic active lung disease, or requiring daily supplemental oxygen History of inflammatory bowel disease or active bowel inflammation Anti-cancer therapy within 2 weeks before study entry Investigational drug(s) within 4 weeks before randomization Prior radiotherapy to >= 25% of bone marrow, or hematopoietic stem cell or bone marrow transplantation Chronic corticosteroid therapy or immunosuppressants Pregnant, lactating, or breastfeeding, or intending to become pregnant during the study or within 60 days after the final dose of study treatment Major surgical procedure, or significant traumatic injury, within 28 days prior to Day 1 of Cycle 1

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 |
| --- | --- |
| Experimental: Inavolisib + Palbociclib + Fulvestrant<br>Participants will receive inavolisib, palbociclib, and fulvestrant. | Drug: Inavolisib<br>* Participants will receive oral inavolisib on Days 1-28 of each 28-day cycle.<br>* Other names: GDC-0077;Drug: Palbociclib<br>* Participants will receive oral palbociclib on Days 1-21 of each 28-day cycle.<br>Drug: Fulvestrant<br>* Participants will receive intramuscular (IM) fulvestrant approximately every 4 weeks.<br>|
| Placebo Comparator: Placebo + Palbociclib + Fulvestrant<br>Participants will receive placebo, palbociclib, and fulvestrant. | Drug: Placebo<br>* Participants will receive oral placebo on Days 1-28 of each 28-day cycle.<br>Drug: Palbociclib<br>* Participants will receive oral palbociclib on Days 1-21 of each 28-day cycle.<br>Drug: Fulvestrant<br>* Participants will receive intramuscular (IM) fulvestrant approximately every 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) |  | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to 6 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) |  | Up to 6 years | 
| Best Overall Response Rate (BOR) |  | Up to 6 years | 
| Duration of Response (DOR) |  | From the first occurrence of a CR or PR to the first occurrence of disease progression or death from any cause, whichever occurs first (up to 6 years) | 
| Clinical Benefit Rate (CBR) |  | Up to 6 years | 
| Overall Survival (OS) |  | From randomization to death from any cause (up to 6 years) | 
| Time to Deterioration (TTD) in Pain |  | Treatment: Day 1 of Cycles 1-3, then Day 1 of every other cycle until treatment discontinuation. Post-treatment: Every 8 weeks for 2 years, then every 12 weeks thereafter, to end of study (up to 6 years)(Cycle length = 28 days) | 
| TTD in Physical Function |  | Treatment: Day 1 of Cycles 1-3, then Day 1 of every other cycle until treatment discontinuation. Post-treatment: Every 8 weeks for 2 years, then every 12 weeks thereafter, to end of study (up to 6 years)(Cycle length = 28 days) | 
| TTD in Role Function |  | Treatment: Day 1 of Cycles 1-3, then Day 1 of every other cycle until treatment discontinuation. Post-treatment: Every 8 weeks for 2 years, then every 12 weeks thereafter, to end of study (up to 6 years)(Cycle length = 28 days) | 
| TTD in Global Health Status |  | Treatment: Day 1 of Cycles 1-3, then Day 1 of every other cycle until treatment discontinuation. Post-treatment: Every 8 weeks for 2 years, then every 12 weeks thereafter, to end of study (up to 6 years)(Cycle length = 28 days) | 
| Percentage of Participants with Adverse Events |  | From randomization through the end of study (up to 6 years) | 
| Plasma Concentration of Inavolisib |  | At pre-defined intervals from baseline to the end of study (up to 6 years) | 
| Plasma Concentration of Palbociclib |  | At pre-defined intervals from baseline to the end of study (up to 6 years) | 
| Plasma Concentration of Fulvestrant |  | At pre-defined intervals from baseline to the end of study (up to 6 years) |