A Phase III, Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Versus Alpelisib Plus Fulvestrant in Patients With Hormone Receptor-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Who Progressed During or After CDK4/6 Inhibitor and Endocrine Combination Therapy
Overview
- Phase
- Phase 3
- Intervention
- Bupropion
- Conditions
- Breast Cancer
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 420
- Locations
- 239
- Primary Endpoint
- Sub-study: AUC (0-infinity) for Omeprazole
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
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.
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).
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Sub-study: Inavolisib + Fulvestrant + CYP substrates
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Bupropion
Sub-study: Inavolisib + Fulvestrant + CYP substrates
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Omeprazole
Sub-study: Inavolisib + Fulvestrant + CYP substrates
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Midazolam
Inavolisib + Fulvestrant
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Inavolisib
Inavolisib + Fulvestrant
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Fulvestrant
Alpelisib + Fulvestrant
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Fulvestrant
Alpelisib + Fulvestrant
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Alpelisib
Sub-study: Inavolisib + Fulvestrant + CYP substrates
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Inavolisib
Sub-study: Inavolisib + Fulvestrant + CYP substrates
Participants will be administered the treatments as outlined in the interventions section.
Intervention: Fulvestrant
Outcomes
Primary Outcomes
Sub-study: AUC (0-infinity) for Omeprazole
Time Frame: Day -4 and -3 of C1D11 and C1D12. A cycle is 28 days.
Blinded Independent Central Review (BICR)-Assessed Progression Free Survival (PFS)
Time Frame: From randomization until disease progression or death due to any cause (up to approximately 64 months)
Sub-study: Maximum observed Drug Concentration (Cmax) for Midazolam
Time Frame: Day -4 and -3 of Cycle (C) 1, Day (D) 11 and C1D12. A cycle is 28 days.
Sub-study: Cmax for Bupropion
Time Frame: Day -3, -2, -1 of C1D1, C1D12, C1D13, C1D14 and C1D15. A cycle is 28 days.
Sub-study: Cmax for Omeprazole
Time Frame: 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
Time Frame: Day -4 and -3 of C1D11 and C1D12. A cycle is 28 days.
Sub-study: AUC (0-last) for Bupropion
Time Frame: Day -3, -2, -1 of C1D1, C1D12, C1D13, C1D14 and C1D15. A cycle is 28 days.
Sub-study: AUC (0-last) for Omeprazole
Time Frame: 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
Time Frame: Day -4 and -3 of C1D11 and C1D12. A cycle is 28 days.
Sub-study: AUC (0-infinity) for Bupropion
Time Frame: Day -3, -2, -1 of C1D1, C1D12, C1D13, C1D14 and C1D15. A cycle is 28 days.
Secondary Outcomes
- BICR-Assessed Best Overall Response (BOR)(Up to approximately 64 months)
- BICR-Assessed Clinical Benefit Rate (CBR)(Up to approximately 64 months)
- Overall survival (OS)(From randomization until death due to any cause (up to approximately 85 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))
- BICR-Assessed Overall Response Rate (ORR)(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.)
- 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))