Study to evaluate the effect of metformin in the prevention of hyperglycemiain HR[+]/HER2[–] PIK3CA-mutated advanced breast cancer patients treatedwith alpelisib plus endocrine therapy. The Metallica study.

Phase 1

Conditions: Study to evaluate the effect of metformin in the prevention of hyperglycemiain HR[+]/HER2[–] PIK3CA-mutated advanced breast cancer patients treatedwith alpelisib plus endocrine therapy. The Metallica study.
Therapeutic area: Diseases [C] - Neoplasms [C04]

Registration Number: CTIS2024-511295-33-00

Lead Sponsor: Medica Scientia Innovation Research S.L.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 88

Inclusion Criteria

Signed Informed Consent Form (ICF) prior to participation in any studyrelated activities., Patients who progressed with documented evidence of progression while on or after an aromatase inhibitors (AI)-based regimen for metastatic disease, or who relapsed with documented evidence of progression while on (neo)adjuvant AI-based regimen or within the first 12 months from completion of (neo)adjuvant AI-based regimen., Patients are permitted to have received previous fulvestrant either as (neo)adjuvant regimen or as first-line regimen for metastatic disease. Note 01: Patients with secondary resistance (relapse while on adjuvant endocrine therapy but after the first 2 years, or relapse within 12 months of completing adjuvant endocrine therapy, or progression = 6 months after initiating endocrine therapy for metastatic disease, while on endocrine therapy) to fulvestrant will be treated with either fulvestrant, letrozole, exemestane or tamoxifen based on physician’s criteria. Patients with primary endocrine resistance (relapse while on the first 2 years of adjuvant endocrine therapy, or progression within first 6 months of first-line endocrine therapy for metastatic disease, while on endocrine therapy) to fulvestrant would be treated with either letrozole or exemestane based on physician’s criteria. Note 02: Anti-estrogens in current development (i.e. SERMs, SERDs, PROTAC, etc.) are allowed to be used as (neo)adjuvant regimen or as first-line regimen for metastatic disease according to investigator criteria., Received no more than 1 prior regimen of chemotherapy in the metastatic setting. Regimen with documented evidence of progression while on (neo)adjuvant chemotherapy or within the first 6 months from completion will be considered as a prior line., For Cohort A and B only; Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c): • For Cohort A: FPG < 100 mg/dL (<5,6 mmol/L) and HbA1c < 5,7%; • For Cohort B: FPG 100–140 mg/dL (5,6–7,8 mmol/L) (impaired fasting glucose values) or HbA1c 5,7–6,4%., For Cohort C only; • T2DM subjects diagnosed clinically = 90 days prior to screening, • HbA1c < 7,5%. • Stable diabetes treatment for 90 days prior to screening, If central nervous system (CNS) metastases are present, controlled local disease without corticoids and/or anti-epileptic medication is required., Adequate bone marrow and organ function as defined by the following laboratory values: • Hematological: o White blood cell (WBC) count = 3.0 x 109/L; absolute neutrophil count (ANC) > 1.5 x 109/L; platelet count > 100.0 x109/L; and hemoglobin > 9.0 g/dL. o Calcium (corrected for serum albumin) and magnesium within normal limits or = grade 1 according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.03 if judged clinically not significant by the investigator. Potassium within normal limits or corrected with supplements. o International normalized ratio (INR) =1.5. • Hepatic: o Bilirubin < 2 times the upper limit of normal (× ULN). Any elevated bilirubin should be asymptomatic at enrollment except for patients with Gilbert’s disease who may be only included if the total bilirubin is = 3 x ULN or direct bilirubin = 1.5 x ULN. o Aspartate transaminase (AST), and alanine transaminase (ALT) = 3 times × ULN (in the case of liver metastases = 5 × ULN, stable for 2 weeks, without the evidence of biliary obstruction by imaging). • Renal: o Creatinine clearance = 35 mL/min using Cockcroft-Gault formula. • Ot

Exclusion Criteria

Prior treatment with a phosphatidylinositol 3-kinase (PI3K), AKT, or mammalian target of the rapamycin (mTOR) inhibitor. Prior treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is allowed., Documented pneumonitis/interstitial lung disease (the chest computed tomography [CT] scan performed at baseline for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present., Patients with Child-Pugh score B or C liver disease., Patients with renal failure., Patients with unresolved osteonecrosis of the jaw., History of Stevens-Johnson Syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)., Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) = 160 mm Hg and/or Diastolic Blood Pressure (DBP) = 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening., Clinically significant uncontrolled heart disease and/or recent cardiac events including any of the following: a. History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 6 months prior to the start of study treatment. b. History of documented congestive heart failure (New York Heart Association functional classification III-IV). c. Left Ventricular Ejection Fraction (LVEF) < 50% at screening as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO). d. Clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g., bifascicular block, Mobitz type II, and third-degree AV block without pacemaker in place). e. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fredericia QT correction formula (QTcF) > 470msec at screening (mean of triplicate ECGs)., Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate subject participation in the clinical study (e.g., chronic active hepatitis [testing not mandatory unless required by local regulations or requirements], severe hepatic impairment, etc.)., Treatment with any of the following medications and cannot be discontinued seven days prior to the start of the treatment: o Strong inhibitors or inducers of the isoenzyme cytochrome P450 3A (CYP3A) within the last 5 days prior to study entry. o Inhibitors of breast cancer resistance protein (BCRP)., Radiotherapy = four weeks or limited field radiation for palliation = two weeks prior to study treatment start, and who has not recovered to grade 1 or better from related side effects of such therapy (except for alopecia)., Known hypersensitivity to alpelisib, fulvestrant, letrozole, exemestane, tamoxifen or to any of their excipients., Patient is currently receiving or has received systemic corticosteroids = 2 weeks prior to study treatment start or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)., Participation in a prior investigational study within 30 days prior to the start of study treatment or within five half-lives of the investigational prod