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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.

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.

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.

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.

Alpelisib

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

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)

Letrozole 2.5 mg tablets, once daily, orally

Exemestane 25 mg tablets, once daily, orally

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

Tamoxifen 20 mg tablets, once daily, orally

Alba Meya

Alicia García-Sanz

José Ponce

Cristina Saura

Adela Fernandez Ortega

Elena Galve

Eduardo Martinez

Santiago Gonzalez

Ander Urruticoechea

Mª Isabel Barajas

Elisenda LLabres

Ana López

María Gión

Pablo Tolosa

Beatriz Rojas

Jose Luis Alonso Romero

Juan Fernando Cueva

Manuel Ruiz Borrego

Begoña Bermejo de las Heras

Salavador Blanch

Antonio Llombart

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.

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.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.Measurable or evaluable disease according to RECIST v.1.1 criteria.No prior treatment with fulvestrant or PI3K, AKT or mTOR inhibitors.

No more than one prior line of chemotherapy for metastatic breast cancer (MBC). Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 1. Non-diabetic patients will be assigned to Cohorts A or B and insulin naïve patients with established diagnosis of type 2 diabetes mellitus will be assigned to Cohort C.

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

Study to Evaluate the Effect of Metformin in the Prevention of Hyperglycemia in HR[+]/HER2[-] PIK3CA-mutation Advanced Breast Cancer Patients Treated With Alpelisib Plus Endocrine Therapy. Study Metallica

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).

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).

To evaluate the clinical efficacy -in terms of progression-free survival (PFS), overall response rate (ORR), time to response (TTR), duration of the response (DoR), time to progression (TTP), clinical benefit rate (CBR)- of combining alpelisib plus endocrine therapy, and antidiabetic treatment in patients with HR\[+\]/HER2\[-\], PIK3CAMut ABC in all study cohorts and according to the different endocrine agent received.

Progression free survival \[PFS\] (defined as the time from the date of inclusion to the date of the first documented progression or death due to any cause, in the overall population, in all cohorts, and according to the different endocrine agent received. If a patient has not had an event, PFS will be censored at the date of the last adequate tumor evaluation \[see RECIST 1.1\]).

Overall response rate \[ORR\] (defined as the proportion of patients with best overall response -including complete response \[CR\] or partial response \[PR\]- based on local investigator's assessment (RECIST 1.1), in the overall population, in all cohorts, and according to the different endocrine agent received.

Time to response \[TTR\], defined as the period from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, as determined locally by the investigator through the use of RECIST v.1.1.· in all the cohorts, and according to the different endocrine agent received).

The period from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, as determined locally by the investigator through use of RECIST v.1.1. in all the cohorts, and according to the different endocrine agent received.

Time to progression \[TTP\] (defined as the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to underlying cancer, in the overall population, in all cohorts, and according to the different endocrine agent received. If a patient has not had an event, time to progression is censored at the date of last adequate tumor assessment).

Clinical benefit rate \[CBR\] (defined as the proportion of patients with a best overall response of CR or PR or SD or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment), in the overall population, in all cohorts, and according to the different endocrine agent received.

To assess the rate of any grade and grade 3-4 HG by CTCAE v.4.03 in cohorts A, B, and C for Metallica and its comparation with Solar-1, and Bylieve trials.

To assess the rate of patients with permanent treatment discontinuation at 8 weeks of treatment with alpelisib due to treatment-related AEs in patients with normal fasting glycemia and HbA1c (Cohort A), and in patients with impaired fasting glucose criteria (Cohort B).

To assess the rate of patients with permanent discontinuation due to alpelisib treatment-related AEs in Cohorts A, B, and C for Metallica, and to compare it with SOLAR-1, and Bylieve trials.

To assess the rate of patients with alpelisib permanent discontinuation due to related AEs over the first 8 weeks in the overall population, in all and according to the different endocrine agent received.

To assess the rate of patients with grade 3-4 HG as per CTCAE v.4.03 over the first 8 weeks of treatment with alpelisib plus endocrine therapy and antidiabetic treatment and during the whole study, in all study cohorts, according to the different endocrine agent received.

To assess the rate of patients that requires insulin to control HG during over the first 8 weeks of treatment with alpelisib plus endocrine therapy and antidiabetic treatment and during the whole study, in all study cohorts, according to the different endocrine agent received.

The number and class of antidiabetic agents used during the first 8 weeks and throughout study, in the overall population, in all the cohorts.

To define the type of HG in patients with grade 3-4 HG as per CTCAE v.4.03 and 5.0 in all the study cohorts and according to the different endocrine agent received, and the rate of patients with HG all the cohorts and according to the different endocrine agent received as per CTCAE v.4.03 and as per CTCAE v.5.

To assess the rate of any grade and grade 3-4 diarrhea by CTCAE v.4.03 for Metallica.

To evaluate the safety and tolerability of the combination of alpelisib with endocrine therapy, and antidiabetic treatment in all study cohorts and according to the different endocrine agent received.

To define the rate of patients with grade 3-4 AEs as per CTCAE v.4.03 in all study cohorts and according to the different endocrine agent received.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study to Evaluate the Effect of Metformin in the Prevention of HG in HR[+]/HER2[-] PIK3CA-mut Advanced BC Patients	NCT04300790	Breast Cancer	Alpelisib Metformin Fulvestrant Letrozole Exemestane Vildagliptin Tamoxifen	18 Years -	MedSIR
Study to Evaluate the Effect of Metformin in the Prevention of HG in HR[+]/HER2[-] PIK3CA-mut Advanced BC Patients	NCT04300790	Breast Cancer	Alpelisib Metformin Fulvestrant Letrozole Exemestane Vildagliptin Tamoxifen	18 Years -	MedSIR

Spots Global Cancer Trial Database for pi3kmut

Every month we try and update this database with for pi3kmut cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for pi3kmut

Every month we try and update this database with for pi3kmut cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for pi3kmut cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.