To Evaluate the Safety, Tolerability, and Pharmacokinetics of Inavolisib Single Agent in Participants With Solid Tumors and in Combination With Endocrine and Targeted Therapies in Participants With Breast Cancer

Study Overview
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Brief Summary
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This is an open-label, multicenter, Phase I study designed to evaluate the safety, tolerability, and pharmacokinetics of inavolisib administered orally as a single agent in patients with locally advanced or metastatic PIK3CA-mutant solid tumors, including breast cancer, and in combination with standard-of-care endocrine and/or targeted therapies for the treatment of locally advanced or metastatic PIK3CA-mutant breast cancer. Participants will be enrolled in two stages: a dose-escalation stage (Stage I) and an expansion stage (Stage II). Participants will be assigned to one of seven regimens: inavolisib as a single agent (Arm A), inavolisib in combination with palbociclib and letrozole (Arm B), inavolisib in combination with letrozole (Arm C), inavolisib in combination with fulvestrant (Arm D), inavolisib in combination with palbociclib and fulvestrant (Arm E), inavolisib in combination with palbociclib, fulvestrant, and metformin (Arm F), and inavolisib in combination with trastuzumab and pertuzumab (and letrozole or fulvestrant, if applicable (Arm G)).

Official Title
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A Phase I, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0077 as a Single Agent in Patients With Locally Advanced or Metastatic PIK3CA-Mutant Solid Tumors and in Combination With Endocrine and Targeted Therapies in Patients With Locally Advanced or Metastatic PIK3CA-Mutant Breast Cancer

Conditions
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Solid Tumor, Breast Cancer

Intervention / Treatment
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* Drug: Inavolisib
* Drug: Fulvestrant
* Drug: Letrozole
* Drug: Palbociclib
* Drug: Metformin
* Drug: Trastuzumab
* Drug: Pertuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evaluable or measurable disease per RECIST, Version 1.1 (measurable disease only for Arm D) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Life expectancy of greater than or equal to (>=) 12 weeks Adequate hematologic and organ function, including blood counts, liver and kidney function Stage I Arm A (Inavolisib): - Locally advanced, recurrent, or metastatic, PIK3CA mutant, incurable solid tumor malignancy, including breast cancer Stages I and II, Arms B and C: - Postmenopausal female participants with locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer Stage II, Arms D, E, or F: - Female participants with locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer Stage II Arm D: - Prior treatment with CDK4/6 inhibitor Stage II Arm G: Female participants with locally advanced or metastatic PIK3CA-mutant HER2+ breast cancer Left ventricular ejection fraction 50% or greater Stages I and II: - All participants must provide tumor tissue from the primary or metastatic tumor site obtained from a prior or new biopsy or surgical procedure for detection of PIK3CA mutation by central laboratory test. Exclusion Criteria: Metaplastic breast cancer History of leptomeningeal disease Type 1 or 2 diabetes requiring anti-hyperglycemic medication Inability or unwillingness to swallow pills Malabsorption syndrome or other condition that would interfere with enteral absorption Known and untreated, or active central nervous system metastases Uncontrolled pleural effusion or ascites Any active infection that could impact patient safety or serious infection requiring intravenous antibiotics History of other malignancy within 5 years, except for treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer History of or active ventricular dysrhythmias or congestive heart failure requiring medication or symptomatic coronary heart disease Congenital long QT syndrome, prolonged QT interval, or family history of sudden unexplained death or long QT syndrome Stage II Arms B, C, D, and E only: Prior treatment with >1 chemotherapy regimen for metastatic disease Prior treatment with PI3K inhibitor History of significant toxicity related to mTOR inhibitor requiring treatment discontinuation Stage II Arms B and E only: - Prior CDK4/6 inhibitor treatment Stage II Arm G only: Current uncontrolled hypertension or unstable angina History of congestive heart failure, serious cardiac arrhythmia, or recent myocardial infarction Prior ejection fraction decrease on trastuzumab Prior cumulative doxorubicin greater than 360 mg/m2 Symptomatic active lung disease History of significant toxicity related to trastuzumab and/or pertuzumab requiring discontinuation of treatment

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage I Arm A: Inavolisib Single Agent<br>Participants will receive inavolisib in escalating dose levels with starting dose of 6 milligrams (mg). Participants will receive single dose of inavolisib on Day 1 of Cycle 1 followed by once daily from Day 8 of Cycle 1. (Cycle length: 35 days for Cycle 1 and 28 days for all other cycles). Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;|
| Experimental: Stage I Arm B: Inavolisib + Palbociclib + Letrozole<br>Participants will receive inavolisib in escalating dose levels (starting dose 3 mg) on Days 1-28, palbociclib on Days 1-21, and letrozole on Days 1-28 of each 28-day cycle. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;Drug: Letrozole<br>* Participants will receive once daily oral doses of letrozole 2.5 mg on Days 1-28 of each cycle.<br>Drug: Palbociclib<br>* Participants will receive once daily oral doses of palbociclib 125 mg on Days 1-21 of each cycle.<br>|
| Experimental: Stage I Arm C: Inavolisib + Letrozole<br>Participants will receive inavolisib in escalating dose levels along with letrozole on Days 1-28 of each 28-day cycle. The starting dose of inavolisib will not exceed the starting dose in Stage I Arm A. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;Drug: Letrozole<br>* Participants will receive once daily oral doses of letrozole 2.5 mg on Days 1-28 of each cycle.<br>|
| Experimental: Stage II Arm B: Inavolisib + Palbociclib + Letrozole<br>Participants will receive inavolisib on Days 1-28 in combination with palbociclib on Days 1-21 and letrozole on Days 1-28 of each 28-day cycle. Dose of inavolisib will be decided based on the results of Stage I Arm B. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;Drug: Letrozole<br>* Participants will receive once daily oral doses of letrozole 2.5 mg on Days 1-28 of each cycle.<br>Drug: Palbociclib<br>* Participants will receive once daily oral doses of palbociclib 125 mg on Days 1-21 of each cycle.<br>|
| Experimental: Stage II Arm C: Inavolisib + Letrozole<br>Participants will receive inavolisib in combination with letrozole on Days 1-28 of each 28-day cycle. Dose of inavolisib will be decided based on the results of Stage I Arm C. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;Drug: Letrozole<br>* Participants will receive once daily oral doses of letrozole 2.5 mg on Days 1-28 of each cycle.<br>|
| Experimental: Stage II Arm D: Inavolisib + Fulvestrant<br>Participants will receive inavolisib on Days 1-28 in combination with fulvestrant on Day 1 and 15 of Cycle 1 and then on Day 1 from Cycle 2 (cycle length: 28 days). Dose of inavolisib will be decided based on the results of Stage I Arm C. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;Drug: Fulvestrant<br>* Participants will receive fulvestrant 500 mg, administered intramuscularly on Days 1 and 15 of Cycle 1. For subsequent cycles, participants will receive fulvestrant intramuscularly on Day 1 of each cycle.<br>|
| Experimental: Stage II Arm E: Inavolisib + Palbociclib + Fulvestrant<br>Participants will receive inavolisib (Days 1-28) in combination with palbociclib (Days 1-21) and fulvestrant (Days 1 and 15 of Cycle 1; Day 1 for subsequent cycles)(Cycle = 28 days). Dose of inavolisib will be determined from the results of Stage I Arm B. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;Drug: Fulvestrant<br>* Participants will receive fulvestrant 500 mg, administered intramuscularly on Days 1 and 15 of Cycle 1. For subsequent cycles, participants will receive fulvestrant intramuscularly on Day 1 of each cycle.<br>Drug: Palbociclib<br>* Participants will receive once daily oral doses of palbociclib 125 mg on Days 1-21 of each cycle.<br>|
| Experimental: Stage II Arm F: Inavolisib + Palbociclib + Fulvestrant + Metformin<br>Participants will receive inavolisib (Days 1-28) in combination with palbociclib (Days 1-21), fulvestrant (Days 1 and 15 of Cycle 1; Day 1 for subsequent cycles) and metformin (Days 1-28)(Cycle = 28 days). Dose of inavolisib will be determined from the results of Stage I Arm B. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;Drug: Fulvestrant<br>* Participants will receive fulvestrant 500 mg, administered intramuscularly on Days 1 and 15 of Cycle 1. For subsequent cycles, participants will receive fulvestrant intramuscularly on Day 1 of each cycle.<br>Drug: Palbociclib<br>* Participants will receive once daily oral doses of palbociclib 125 mg on Days 1-21 of each cycle.<br>Drug: Metformin<br>* Participants will receive oral metformin once daily, starting on Cycle 1, Day 1, as tolerated.<br>|
| Experimental: Stage II Arm G: Inavolisib + Trastuzumab + Pertuzumab<br>Participants will receive inavolisib in combination with trastuzumab and pertuzumab (Days 1-21). Dose of inavolisib will be determined from the results of Stage I Arm A. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression. | Drug: Inavolisib<br>* Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).<br>* Other names: RO7113755, GDC-0077;Drug: Trastuzumab<br>* Participants will receive trastuzumab, administered by IV infusion on Day 1 of each 21-day cycle, at a loading dose of 8 mg/kg for Cycle 1 and a dose of 6 mg/kg for subsequent cycles, until disease progression or unacceptable toxicity.<br>Drug: Pertuzumab<br>* Participants will receive pertuzumab, administered by IV infusion on Day 1 of each 21-day cycle, at a loading dose of 840 mg for Cycle 1 and a dose of 420 mg for subsequent cycles, until disease progression or unacceptable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Percentage of Participants With Dose Limiting Toxicities |  | Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35) | 
| Recommended Phase II Dose of Inavolisib |  | Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35) | 
| Percentage of Participants With Adverse Events and Serious Adverse Events |  | Day 1 up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration Time-Curve (AUC) from Time Zero to Infinity (AUCinf) of Inavolisib |  | Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to end of study (EOS; up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days) | 
| AUC from Time Zero to Dosing Interval (AUC0-tau) of Inavolisib |  | Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days) | 
| Half-Life of Inavolisib |  | Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days) | 
| Maximum Plasma Concentration (Cmax) of Inavolisib |  | Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days) | 
| Minimum Plasma Concentration (Cmin) of Inavolisib |  | Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days) | 
| Time to Cmax (tmax) of Inavolisib |  | Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days) | 
| Apparent Clearance (CL/F) of Inavolisib |  | Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days) | 
| Accumulation Ratio (AR) of Inavolisib at Steady-State |  | Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days) | 
| AUC of Palbociclib |  | Predose (0-2 hours before inavolisib) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days | 
| Cmax of Palbociclib |  | Predose (0-2 hours before inavolisib) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days | 
| AUC of Letrozole |  | Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days | 
| Cmax of Letrozole |  | Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days | 
| AUC of Fulvestrant |  | Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days | 
| Cmax of Fulvestrant |  | Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days | 
| Percentage of Participants With Objective Response as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (v1.1) |  | Baseline up to occurrence of complete response (CR) or partial response (PR) on 2 consecutive occasions >/=4 weeks apart (up to approximately 6 years) | 
| Duration of Response, as Assessed by RECIST v1.1 |  | From first occurrence of a documented objective response (CR or PR) to disease progression or death from any cause, whichever occurs first (up to approximately 6 years) | 
| Percentage of Participants With Clinical Benefit as Assessed by RECIST v1.1 |  | Baseline up to disease progression or death from any cause, whichever occurs first (up to approximately 6 years) | 
| Progression Free Survival (PFS) as Assessed by RECIST v1.1 |  | Baseline up to disease progression or death from any cause, whichever occurs first (up to approximately 6 years) | 
| Change in Maximum Standard Uptake Value (SUV) of Tumor Regions of Interest (as assessed by [18] F-fluorodeoxyglucose-positron emission tomography) From Baseline to Approximately 2 Weeks of Inavolisib Treatment |  | Baseline, Week 2 | 
| AUC of Pertuzumab |  | Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days | 
| Cmax of Pertuzumab |  | Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days | 
| AUC of Trastuzumab |  | Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days | 
| Cmax of Trastuzumab |  | Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PIK3CA mutant, Breast Cancer