Resumen

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.

Descripción detallada

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).

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

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

Criterios de exclusión

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
Pregnant, lactating, or breastfeeding, or intending to become pregnant during the study or at least 60 days after the final dose of study treatment
Known active, systemic infection at study enrollment, or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 7 days prior to Day 1 of Cycle 1
Investigational drug(s) within 4 weeks before randomization or within 5 half-lives of the investigational drug(s), whichever is longer
Allergy or hypersensitivity to components or excipients of the inavolisib, fulvestrant, or alpelisib formulations
History of severe cutaneous reactions like Stevens-Johnson Syndrome, Erythema Multiforme, Toxic Epidermal Necrolysis, or Drug Reaction with Eosinphilia and Systemic Symptoms
Pregnant, lactating, or breastfeeding, or intending to become pregnant during the substudy or within 2 weeks after the final dose of inavolisib and within 2 years after the final dose of fulvestrant, whichever is longer
Known active, systemic infection at study enrollment, or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 7 days prior to Day -4 of Cycle 1
Investigational drug(s) within 4 weeks prior to Day -4 or within 5 half-lives of the investigational drug(s), whichever is longer
Allergy or hypersensitivity to components or excipients of the inavolisib, fulvestrant formulations
Treatment with mild, moderate, or strong inducers of CYP2B6, CYP3A4, and/or CYP2C19 (including St. John's Wort) within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment on Day -4 until after the final PK sample has been collected on Day 15 of Cycle 1
Treatment with mild, moderate, or strong inhibitors of CYP2B6, CYP3A4, and/or CYP2C19 (including grapefruit juice or supplements) within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment on Day -4 until after the final PK sample has been collected on Day 15 of Cycle 1

Intervenciones

drug

Inavolisib

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.

drug

Fulvestrant

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.

drug

Alpelisib

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.

drug

Bupropion

Participants will be administered bupropion PO on Day -3 and Day 12 of Cycle 1 of the sub-study.

drug

Omeprazole

Participants will be administered omerprazole PO on Day -4 and Day 11 of Cycle 1 of sub-study.

drug

Midazolam

Participants will be administered midazolam PO on Day -4 and Day 11 of Cycle 1 of sub-study.

Ubicaciones

Centro de Investigaciones Médicas y Desarrollo LC S.R.L

Buenos Aires, Argentina

Centro Oncologico Korben

Ciudad Autonoma Buenos Aires, Argentina

Fundacion CORI para la Investigacion y Prevencion del Cancer

La Rioja, Argentina

Instituto de Oncología de Rosario

Rosario, Argentina

Hosp Provincial D. Centenarios

Rosario, Argentina

CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica

San Juan, Argentina

Clinica Viedma S.A.

Viedma, Argentina

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Inavolisib

Fulvestrant

Alpelisib

Bupropion

Omeprazole

Midazolam

Ubicaciones

Centro de Investigaciones Médicas y Desarrollo LC S.R.L

Centro Oncologico Korben

Fundacion CORI para la Investigacion y Prevencion del Cancer

Instituto de Oncología de Rosario

Hosp Provincial D. Centenarios

CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica

Clinica Viedma S.A.

Patrocinadores