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

Study Overview
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Brief Summary
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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.

Detailed Description
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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. No ongoing antidiabetic treatment.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Alpelisib
* Drug: Metformin
* Drug: Fulvestrant
* Drug: Letrozole
* Drug: Exemestane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form (ICF)Exclusion Criteria: Male or female patients ≥ 18 years of age at the time of signing ICF. Men and pre-menopausal women should have been treated with (LHRH) analogue Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Histologically proven diagnosed of advanced BC not amenable to curative treatment. Documented recurrent ER[+] and/or PgR[+] Measurable or evaluable disease as per RECIST v.1.1 criteria.Patients with no measurable or evaluable disease will be considered by the study medical monitor. Presence of PIK3CAMut 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. Progression on an AI regimen for advanced BC Patients are permitted to have received previous fulvestrant either as (neo)adjuvant regimen or as first-line regimen for metastatic disease. No more than one prior chemotherapy-containing regimen for the treatment of metastatic disease is permitted. Fasting plasma glucose (FPG) and Glycosylated Hemoglobin (HbA1c): Cohort A: FPG ≤100 mg/dL (5.6 mmol/L) and HbA1c < 5,7 Cohort B: FPG 100 mg/dL (5.6 mmol/L) to 140 mg/dL (7.8 mmol/L) (IFG) or HbA1c < 5,7 to 6.4% (CNS) metastasis, controlled local disease without corticoids and/or anti-epileptic medication is required. Adequate organ function Patients willing and able to comply with scheduled visits Resolution of all acute toxic effects of prior anti-cancer therapy Exclusion Criteria: Prior treatment with a PI3K, mTOR or AKT inhibitor Patients with a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients Patients with an established diagnosis of diabetes mellitus [DM] type I or II requiring anti-diabetic drugs. Patients with a high-risk FPG or HbA1c as per inclusion criterion #14 are eligible to enter the cohort B if no anti-diabetic drug were received in the last 14 days prior to the start of study treatment. Inflammatory BC at screening. Subject has a concurrent malignancy or malignancy within 3 years of start of study treatment. Patients with past medical history of acute or chronic pancreatitis within 1 year prior to screening. Patient with impaired gastrointestinal (GI) function Patient with documented pneumonitis/interstitial lung disease Patients with Child-Pugh score B or C liver disease. Patients with renal failure. Patients with unresolved osteonecrosis of the jaw. Subject has a history of Stevens-Johnson Syndrome (SJS), erythema multiforme (EM) or toxic epidermal necrolysis (TEN) or 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 antihypertensive medication. Patients with clinically significant uncontrolled heart disease and/or recent cardiac events Subject has any other concurrent severe and/or uncontrolled medical condition Subject is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of the treatment: Strong inhibitors or inducers of the isoenzyme CYP3A within the last 5 days prior to study entry. Inhibitors of BCRP Subject has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization Subject is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment Participation in a prior investigational study within 30 days prior to the start of study treatment Subject has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1. Subject has a known history of (HIV) infection. Subject has any other concurrent severe and/or uncontrolled medical condition Patient is a breastfeeding or pregnant woman Women of child-bearing potential, unless they are using highly effective methods of contraception during study treatment and for one month after the last dose of any study treatment. Subject is a sexually active male unwilling to use a condom during intercourse while taking study treatment, and up to 6 months after stopping study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: This is a multicenter, open-label, two-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).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CohortA: Normoglycemic patients<br>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 (one tablet of 200mg and two tablets of 50mg 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. 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). | Drug: Alpelisib<br>* 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.<br>* Other names: BYL719;Drug: Metformin<br>* 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<br>Drug: Fulvestrant<br>* 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)<br>Drug: Letrozole<br>* Letrozole 2.5 mg tablets, once daily, orally<br>Drug: Exemestane<br>* Exemestane 25 mg tablets, once daily, orally<br>|
| Experimental: CohortB: Pre-diabetic patients<br>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 (one tablet of 200mg and two tablets of 50mg 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. 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). | Drug: Alpelisib<br>* 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.<br>* Other names: BYL719;Drug: Metformin<br>* 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<br>Drug: Fulvestrant<br>* 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)<br>Drug: Letrozole<br>* Letrozole 2.5 mg tablets, once daily, orally<br>Drug: Exemestane<br>* Exemestane 25 mg tablets, once daily, orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the rate of patients with G3-4 hyperglycemia (HG) by CTCAE v4.03 over the first 2 cycles of treatment with alpelisib (BYL719) | 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 fulvestrant 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy of alpelisib plus fulvestrant and metformin will be exploratory evaluated based on CTCAE V4.03 guidelines. | To evaluate the clinical efficacy of combining alpelisib (300 mg/QD), fulvestrant and metformin in patients with HR[+] HER2 [-], PIK3CAMut advanced BC. Efficacy will be evaluated by number and proportion of patients with objective response, clinical benefit, rate of alpelisib discontinuations and rates of all G3-4 AESIs (HG, cutaneous rash and diarrhea over the first 2 cycles and during treatment) in both cohorts. | Baseline up to 15 months | 
| Type of HG | To define the type HG in patients with G3-4 HG. | Baseline up to 15 months | 
| Evaluate safety and tolerability by incidence of AEs as assessed by the investigator, with severity determined through the use of NCI-CTCAE v.4.03 (in accordance with alpelisib IB). | To evaluate the safety and tolerability of the combination of alpelisib (300 mg/QD) with fulvestrant and metformin in terms of diarrhea and rash | Baseline up to 15 months | 
| Progression free survival [PFS] | 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. 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]). | Baseline up to 15 months | 
| Overall response rate [ORR] | 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). | Baseline up to 15 months | 
| Time to progression [TTP] | 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. If a patient has not had an event, time to progression is censored at the date of last adequate tumor assessment). | Baseline up to 15 months | 
| Clinical benefit rate [CBR] | 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). | Baseline up to 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ER, PI3KMut, HER2, Metastatic, unresectable, breast, hyperglycemia, men