Breast Cancer, Solid Tumor
Conditions
Keywords
PIK3CA mutant, Breast Cancer
Brief summary
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)).
Interventions
DRUGInavolisib
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).
DRUGFulvestrant
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.
DRUGLetrozole
Participants will receive once daily oral doses of letrozole 2.5 mg on Days 1-28 of each cycle.
DRUGPalbociclib
Participants will receive once daily oral doses of palbociclib 125 mg on Days 1-21 of each cycle.
DRUGMetformin
Participants will receive oral metformin once daily, starting on Cycle 1, Day 1, as tolerated.
DRUGTrastuzumab
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.
DRUGPertuzumab
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.
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Adverse Events and Serious Adverse Events | Day 1 up to 6 years |
| 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) |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| 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) |
| 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) |
| 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) |
| 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 |
Countries
Canada, France, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed