Study to Evaluate the Effect of Metformin in the Prevention of HG in HR[+]/HER2[-] PIK3CA-mut Advanced BC Patients

NCT04300790 | Completed Phase 2

• 2 other identifiers: MEDOPP2402019-003970-26
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 19

Brief Summary

Men and post- or induced menopausal women with ER\[+\] and/or PgR\[+\], HER2\[- \] advanced BC, with centrally-confirmed PI3KCAMut who progressed to an aromatase inhibitor (AI) regimen.

Conditions

Breast Cancer

Keywords

ER; PI3KMut; HER2; Metastatic; unresectable; breast; hyperglycemia; men

Outcome Measures

Primary Outcomes (2)

• Assess the rate of patients with G3-4 hyperglycemia (HG) by CTCAE v4.03 over the first 2 cycles of treatment with alpelisib (BYL719) (Cohorts A and B)

  The primary objective is to assess the rate of patients with G3-4 (CTCAE v4.03) hyperglycemia (HG) over the first 2 cycles of treatment with alpelisib (BYL719) (300 mg/QD) plus endocrine therapy and metformin, in patients with normal fasting glycemia and HbA1c (cohort A), and in patients with high-risk criteria (cohort B).

  Baseline up tp 15 months

• Assess the rate of patients with permanent discontinuation of alpelisib due to related AEs after 8 weeks of treatment with alpelisib plus endocrine therapy and antidiabetic treatment (Cohort C).

  The primary objective is to assess the rate of patients with permanent discontinuation of alpelisib due to related AEs after 8 weeks of treatment with alpelisib plus endocrine therapy and antidiabetic treatment in patients with insuline naive type 2 diabetic mellitus patients (cohort C).

  Baseline up tp 15 months

Secondary Outcomes (17)

• Clinical efficacy of alpelisib plus endocrine therapy, and antidiabetic treatment will be exploratory evaluated based on CTCAE V4.03 guidelines

  Baseline up to 15 months

• Progression free survival [PFS]

  Baseline up to 15 months

• Overall response rate [ORR]

  Baseline up to 15 months

• Time to response [TTR]

  Baseline up to 15 months

• Duration of the response [DoR]

  Baseline up to 15 months

Study Arms (3)

CohortA: Normoglycemic patients

EXPERIMENTAL

Alpelisib plus metformin and Endocrine Therapy (fulvestrant or Letrozole or Exemestane): During the first cycle, patients will receive Endocrine Therapy and metformin at least one-week prior alpelisib administration (D8). Alpelisib (BYL719) 300 mg PO (two tablets of 150 mg once a day) on a continuous dosing schedule starting on Cycle 1. Metformin 500 mg BID with breakfast and dinner. After 3 days, if no GI intolerance, increase to 1000 mg BID with breakfast and dinner. If not tolerated, reduce to prior tolerated dose. Titrate to 1000mg BID over a period of at least 4 additional days. Endocrine Therapy: Fulvestrant 500 mg (intramuscular injection) on days 1 and 15 of cycle 1 (28 days); then every 4 weeks as per SoC- (day 1 of subsequent 28-days cycles) or Letrozole 2,5 mg, once daily, orally or Exemestane 25 mg once daily, orally.

Drug: Alpelisib; Drug: Metformin; Drug: Fulvestrant; Drug: Letrozole; Drug: Exemestane

CohortB: Pre-diabetic patients

EXPERIMENTAL

Alpelisib plus metformin and Endocrine Therapy (fulvestrant or Letrozole or Exemestane): During the first cycle, patients will receive Endocrine Therapy and metformin at least one-week prior alpelisib administration (D8). Alpelisib (BYL719) 300 mg PO (two tablets of 150 mg once a day) on a continuous dosing schedule starting on Cycle 1. Metformin 500 mg BID with breakfast and dinner. After 3 days, if no GI intolerance, increase to 1000 mg BID with breakfast and dinner. If not tolerated, reduce to prior tolerated dose. Titrate to 1000mg BID over a period of at least 4 additional days. Endocrine Therapy: Fulvestrant 500 mg (intramuscular injection) on days 1 and 15 of cycle 1 (28 days); then every 4 weeks as per SoC- (day 1 of subsequent 28-days cycles) or Letrozole 2,5 mg, once daily, orally or Exemestane 25 mg once daily, orally.

Drug: Alpelisib; Drug: Metformin; Drug: Fulvestrant; Drug: Letrozole; Drug: Exemestane

CohortC: Insulin naïve type 2 diabetic mellitus patients

EXPERIMENTAL

Alpelisib plus metformin plus vildagliptin and Endocrine Therapy (fulvestrant or Letrozole or Exemestane or Tamoxifen): During the first cycle, patients will receive Endocrine Therapy, metformin and vildagliptin at least two-weeks prior alpelisib administration (D15).Alpelisib (BYL719) 300 mg PO (two tablets of 150 mg once a day) on a continuous dosing schedule starting on Cycle 1. Metformin 500 mg BID with breakfast and dinner. After 3 days, if no GI intolerance, increase to 1000 mg BID with breakfast and dinner. If not tolerated, reduce to prior tolerated dose. Titrate to 1000mg BID over a period of at least 4 additional days. Endocrine Therapy: Fulvestrant 500 mg (intramuscular injection) on days 1 and 15 of cycle 1 (28 days); then every 4 weeks as per SoC- (day 1 of subsequent 28-days cycles) or Letrozole 2,5 mg, once daily, orally or Exemestane 25 mg once daily, orally or Tamoxifen 20 mg once daily, orally.

Drug: Alpelisib; Drug: Metformin; Drug: Fulvestrant; Drug: Letrozole; Drug: Exemestane; Drug: Vildagliptin; Drug: Tamoxifen

Interventions

Alpelisib DRUG

Alpelisib (BYL719): starting dose at 300 mg/QD.; 2 tablets once a day, oral administration, continuously during 28-day cycles until disease progression or unacceptable toxicity.

Also known as: BYL719

CohortA: Normoglycemic patients; CohortB: Pre-diabetic patients; CohortC: Insulin naïve type 2 diabetic mellitus patients

Metformin DRUG

500 mg BID with breakfast and dinner. After 3 days, if no (GI) intolerance, increase to 1000 mg BID with breakfast and dinner. If not tolerated, reduce to prior tolerated dose. Titrate to 1000mg BID over a period of at least 4 additional days

CohortA: Normoglycemic patients; CohortB: Pre-diabetic patients; CohortC: Insulin naïve type 2 diabetic mellitus patients

Fulvestrant DRUG

fulvestrant (500 mg IM injections; loading dose 500mg every two weeks for the first month; then every 4 weeks as per standard of care \[SoC\]. Patients should be started on metformin and fulvestrant within 7 to 14 days prior to start on alpelisib (D1C1)

CohortA: Normoglycemic patients; CohortB: Pre-diabetic patients; CohortC: Insulin naïve type 2 diabetic mellitus patients

Letrozole DRUG

Letrozole 2.5 mg tablets, once daily, orally

CohortA: Normoglycemic patients; CohortB: Pre-diabetic patients; CohortC: Insulin naïve type 2 diabetic mellitus patients

Exemestane DRUG

Exemestane 25 mg tablets, once daily, orally

CohortA: Normoglycemic patients; CohortB: Pre-diabetic patients; CohortC: Insulin naïve type 2 diabetic mellitus patients

Vildagliptin DRUG

Vildagliptin 50 mg tablets, twice daily, orally with breakfast and dinner

CohortC: Insulin naïve type 2 diabetic mellitus patients

Tamoxifen DRUG

Tamoxifen 20 mg tablets, once daily, orally

CohortC: Insulin naïve type 2 diabetic mellitus patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Informed Consent Form (ICF)prior to participation in any study- related activities.
• Men, pre-menopausal or post-menopausal women ≥ 18 years of age at the time of signing ICF.
• Men and pre-menopausal women should have been treated with a luteinizing hormone-releasing hormone (LHRH) analogue at least one week prior to study entry. Post-menopausal women are defined as per the following criteria:
• Age 3 60 years, or
• Age \< 60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and/or follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females; or documented bilateral oophorectomy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Histologically proven diagnosis of advanced breast cancer (ABC, loco regionally recurrent not amenable to curative therapy or metastatic disease).
• Confirmed diagnosis of estrogen receptor (ER)\[+\] and/or progesterone receptor (PR)\[+\] (with ≥1% positive stained cells according to National Comprehensive Cancer Network \[NCCN\] and American Society of Clinical Oncology \[ASCO\] guidelines) and human epidermal growth factor receptor 2 (HER2)-negative (0 or 1+ by immunohistochemistry \[IHC\] or 2+ and negative by in situ hybridization \[ISH\] test) breast cancer in the advanced setting.
• Measurable or evaluable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1 criteria. Patients with bone- only metastases are eligible.
• Patients with no measurable or evaluable disease will be considered by the study medical monitor.
• Presence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated (PIK3CAMut) determined on the most recent tumor tissue specimen (frozen or formalin-fixed paraffin- embedded \[FFPE\]) or plasma circulating tumor DNA (ctDNA).
• Note: Prior tests of PIK3CAMut preceding the ICF signature will be considered valid if the results are documented and captured in the medical record during the pre-screening period. If the PIK3CA status is unknown, tumor tissue can be provided during pre-screening phase to assess the presence of PIK3CAMut. In case when tumor tissue specimen cannot be obtained, presence of PIK3CAMut can be carried out on plasma in the pre-screening period prior to initiate the study treatment.
• No more than 2 prior lines of endocrine therapy for ABC. Regimen with documented evidence of progression while on (neo)adjuvant endocrine therapy or within the first 12 months from completion of (neo)adjuvant endocrine therapy will be considered as a prior line.
• 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.
• PPatients are permitted to have received previous fulvestrant either as (neo)adjuvant regimen or as first-line regimen for metastatic disease.

You may not qualify if:

• 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.
• Known hypersensitivity to alpelisib, fulvestrant, letrozole, exemestane, tamoxifen or to any of their excipients.
• Patients treated with insulin.
• Cohort C;
• Type 1 diabetes patients.
• Renal impairment defined as eGFR \< 25 mL/min/1.73 m2 as per CKD-EPI.
• History of proliferative retinopathy or maculopathy requiring acute treatment.
• History of pancreatitis (acute or chronic).
• Severe neuropathy, in particular autonomic neuropathy, i.e. gastroparesis, as judged by the investigator.
• History of ketoacidosis or hyperosmolar state episodes.
• History of intolerance to antidiabetic drugs except metformin.
• Inflammatory breast cancer at screening.
• Concurrent malignancy or malignancy within first 3 years of start of study treatment, except for adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.
• Past medical history of acute or chronic pancreatitis within one year prior to screening.
• Impaired gastrointestinal (GI) function or GI disease that may affect the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) based on investigator's discretion.

Sponsors & Collaborators

• MedSIR: lead
• Novartis: collaborator

Study Sites (19)

Hospital General Universitario de Alicante

Alicante, Spain

Location

Hospital Universitari Vall D'Hebron

Barcelona, Spain

Location

Institut Català d' Oncologia L'Hospitalet (ICO)

Barcelona, Spain

Location

Hospital Universitario de Basurto

Bilbao, Spain

Location

Hospital Provincial de Castellón

Castellon, Spain

Location

Hospital San Pedro de Alcántara

Cáceres, Spain

Location

Onkologikoa

Donostia / San Sebastian, Spain

Location

Hospital Universitario Clínico San Cecilio de Granada

Granada, Spain

Location

Hospital Universitario Insular de Gran Canaria

Las Palmas de Gran Canaria, Spain

Location

Hospital Universitario de Leon

León, Spain

Location

Hospital Beata María Ana

Madrid, Spain

Location

Hospital Ruber Internacional

Madrid, Spain

Location

Hospital Universitario Doce de Octubre

Madrid, Spain

Location

Hospital Universitario Sanchinarro

Madrid, Spain

Location

Hospital Clínico Universitario Virgen de la Arrixaca

Murcia, Spain

Location

Complejo Hospitalario Universitario de Santiago (CHUS)

Santiago de Compostela, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, Spain

Location

Instituto Valenciano de Oncología (IVO)

Valencia, Spain

Location

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis; Hyperglycemia; Multiple Endocrine Neoplasia Type 1

Interventions

Alpelisib; Metformin; Fulvestrant; Letrozole; exemestane; Vildagliptin; Tamoxifen

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Multiple Endocrine Neoplasia; Endocrine Gland Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Nitriles; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrrolidines; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Antonio Llombart

  MedSIR

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multicenter, open-label, three-cohort, Simon's two stage design, phase II clinical trial. Cohort A: Normal fasting glycemia \< 100 mg/dL and HbA1c \< 5,7: 48 patients (20 stage 1 + 28 stage 2). Patients in cohort A will receive. Cohort B: fasting glycemia 100 mg/dL (5.6 mmol/L) to 140mg/dL (7.8 mmol/L). 20 patients (7 stage 1 + 13 stage 2). Cohort C: T2DM diagnosed clinically ≥ 90 days prior to screening, HbA1c \< 7,5 %, insulin naïve (5 during stage I + 15 during stage II).

Study Record Dates

• First Submitted: February 11, 2020
• First Posted: March 9, 2020
• Study Start: October 23, 2020
• Primary Completion: June 15, 2022
• Study Completion: March 16, 2025
• Last Updated: July 29, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (19)