Breast Cancer
Conditions
Brief summary
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. Enrollment for the main study is now complete.
Detailed description
The drug-drug interaction (DDI) substudy will evaluate the impact of repeat doses of inavolisib (coadministered with fulvestrant) on single-dose pharmacokinetics of sensitive CYP450 enzyme substrates (midazolam, omeprazole and bupropion) in participants with hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated, locally advanced (LA) or metastatic breast cancer (mBC), who progressed during or after CDK4/6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET). Enrollment for the substudy is now open to recruitment.
Interventions
DRUGInavolisib
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 of main study and sub-study.
DRUGFulvestrant
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 of main study and sub-study.
DRUGAlpelisib
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.
DRUGBupropion
Participants will be administered bupropion PO on Day -3 and Day 12 of Cycle 1 of the sub-study.
DRUGOmeprazole
Participants will be administered omerprazole PO on Day -4 and Day 11 of Cycle 1 of sub-study.
DRUGMidazolam
Participants will be administered midazolam PO on Day -4 and Day 11 of Cycle 1 of sub-study.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Main Study and Sub-study: * 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
for both Main Study and Sub-study: * 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 * 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 * 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 * 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 * Active ongoing osteonecrosis of the jaw
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Sub-study: AUC (0-infinity) for Bupropion | Day -3, -2, -1 of C1D1, C1D12, C1D13, C1D14 and C1D15. A cycle is 28 days. |
| Sub-study: AUC (0-infinity) for Omeprazole | Day -4 and -3 of C1D11 and C1D12. A cycle is 28 days. |
| Sub-study: Cmax for Omeprazole | Day -4 and -3 of C1D11 and C1D12. A cycle is 28 days. |
| Sub-study: Area Under the Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC [0-last]) for Midazolam | Day -4 and -3 of C1D11 and C1D12. A cycle is 28 days. |
| Sub-study: AUC (0-last) for Bupropion | Day -3, -2, -1 of C1D1, C1D12, C1D13, C1D14 and C1D15. A cycle is 28 days. |
| Sub-study: AUC (0-last) for Omeprazole | Day -4 and -3 of C1D11 and C1D12. A cycle is 28 days. |
| Sub-study: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) for Midazolam | Day -4 and -3 of C1D11 and C1D12. A cycle is 28 days. |
| Sub-study: Maximum observed Drug Concentration (Cmax) for Midazolam | Day -4 and -3 of Cycle (C) 1, Day (D) 11 and C1D12. A cycle is 28 days. |
| Sub-study: Cmax for Bupropion | Day -3, -2, -1 of C1D1, C1D12, C1D13, C1D14 and C1D15. A cycle is 28 days. |
| 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
| Measure | Time frame |
|---|---|
| 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. |
| Sub-study: Percentage of Participants with Adverse Events | Day -4 until 30 days after the final dose of study treatment (up to approximately 85 months) |
| 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. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, France, Germany, Italy, Mexico, New Zealand, Poland, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTReference Study ID Number: WO43919 https://forpatients.roche.com/ No attachments to email below
CONTACTFastest response: use the inquiry form. https://www.gene.com/contact-us/submit-medical-inquiry
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed