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

• ClinicalTrials.gov Identifier: NCT04300790
• Recruitment Status: Active, not recruiting
• First Posted: March 9, 2020
• Last Update Posted: August 26, 2022
• Sponsor: MedSIR
• Collaborator: Novartis
• Information provided by (Responsible Party): MedSIR

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Alpelisib; Drug: Metformin; Drug: Fulvestrant; Drug: Letrozole; Drug: Exemestane	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment

Intervention 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)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 23, 2020
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: July 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: CohortA: Normoglycemic patients; 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; 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.; Other Name: BYL719; Drug: 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; Drug: Fulvestrant; 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); Drug: Letrozole; Letrozole 2.5 mg tablets, once daily, orally; Drug: Exemestane; Exemestane 25 mg tablets, once daily, orally
Experimental: CohortB: Pre-diabetic patients; 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; 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.; Other Name: BYL719; Drug: 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; Drug: Fulvestrant; 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); Drug: Letrozole; Letrozole 2.5 mg tablets, once daily, orally; Drug: Exemestane; Exemestane 25 mg tablets, once daily, orally

Outcome Measures

Primary Outcome Measures :

1. Assess the rate of patients with G3-4 hyperglycemia (HG) by CTCAE v4.03 over the first 2 cycles of treatment with alpelisib (BYL719) [ Time Frame: Baseline up tp 15 months ]
   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).

Secondary Outcome Measures :

1. Clinical efficacy of alpelisib plus fulvestrant and metformin will be exploratory evaluated based on CTCAE V4.03 guidelines. [ Time Frame: Baseline up to 15 months ]
   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.
2. Type of HG [ Time Frame: Baseline up to 15 months ]
   To define the type HG in patients with G3-4 HG.
3. 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). [ Time Frame: Baseline up to 15 months ]
   To evaluate the safety and tolerability of the combination of alpelisib (300 mg/QD) with fulvestrant and metformin in terms of diarrhea and rash
4. Progression free survival [PFS] [ Time Frame: Baseline up to 15 months ]
   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]).
5. Overall response rate [ORR] [ Time Frame: Baseline up to 15 months ]
   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).
6. Time to progression [TTP] [ Time Frame: Baseline up to 15 months ]
   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).
7. Clinical benefit rate [CBR] [ Time Frame: Baseline up to 15 months ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Signed Informed Consent Form (ICF)Exclusion Criteria:
2. Male or female patients ≥ 18 years of age at the time of signing ICF.
3. Men and pre-menopausal women should have been treated with (LHRH) analogue
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
5. Histologically proven diagnosed of advanced BC not amenable to curative treatment.
6. Documented recurrent ER[+] and/or PgR[+]
7. 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.
8. Presence of PIK3CAMut
9. 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.
10. Progression on an AI regimen for advanced BC
11. Patients are permitted to have received previous fulvestrant either as (neo)adjuvant regimen or as first-line regimen for metastatic disease.
12. No more than one prior chemotherapy-containing regimen for the treatment of metastatic disease is permitted.

13. 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%

14. (CNS) metastasis, controlled local disease without corticoids and/or anti-epileptic medication is required.
15. Adequate organ function
16. Patients willing and able to comply with scheduled visits
17. Resolution of all acute toxic effects of prior anti-cancer therapy

Exclusion Criteria:

1. Prior treatment with a PI3K, mTOR or AKT inhibitor
2. Patients with a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients
3. 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.
4. Inflammatory BC at screening.
5. Subject has a concurrent malignancy or malignancy within 3 years of start of study treatment.
6. Patients with past medical history of acute or chronic pancreatitis within 1 year prior to screening.
7. Patient with impaired gastrointestinal (GI) function
8. Patient with documented pneumonitis/interstitial lung disease
9. Patients with Child-Pugh score B or C liver disease.
10. Patients with renal failure.
11. Patients with unresolved osteonecrosis of the jaw.
12. 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).
13. 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.
14. Patients with clinically significant uncontrolled heart disease and/or recent cardiac events
15. Subject has any other concurrent severe and/or uncontrolled medical condition

16. 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
17. Subject has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization
18. 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
19. Participation in a prior investigational study within 30 days prior to the start of study treatment
20. Subject has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1.
21. Subject has a known history of (HIV) infection.
22. Subject has any other concurrent severe and/or uncontrolled medical condition
23. Patient is a breastfeeding or pregnant woman
24. 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.
25. 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.

Contacts and Locations

Locations

Spain

Hospital General Universitario de Alicante

Alicante, Spain

Hospital Universitari Vall D'Hebron

Barcelona, Spain

Institut Català d' Oncologia L'Hospitalet (ICO)

Barcelona, Spain

Hospital Universitario de Basurto

Bilbao, Spain

Hospital Provincial de Castellón

Castellón De La Plana, Spain

Hospital San Pedro de Alcántara

Cáceres, Spain

Onkologikoa

Donostia, Spain

Hospital Universitario Clínico San Cecilio de Granada

Granada, Spain

Hospital Universitario Insular de Gran Canaria

Las Palmas De Gran Canaria, Spain

Hospital Universitario de Leon

León, Spain

Hospital Ruber Internacional

Madrid, Spain

Hospital Universitario Doce de Octubre

Madrid, Spain

Hospital Universitario Sanchinarro

Madrid, Spain

Hospital Clínico Universitario Virgen de la Arrixaca

Murcia, Spain

Complejo Hospitalario Universitario de Santiago (CHUS)

Santiago De Compostela, Spain

Hospital Universitario Virgen del Rocio

Sevilla, Spain

Hospital Clinico Universitario de Valencia

Valencia, Spain

Instituto Valenciano de Oncología (IVO)

Valencia, Spain

Sponsors and Collaborators

MedSIR

Novartis

Investigators

• Principal Investigator: Antonio Llombart; MedSIR

More Information

• Responsible Party: MedSIR
• ClinicalTrials.gov Identifier: NCT04300790
• Other Study ID Numbers: MEDOPP240; 2019-003970-26 ( EudraCT Number )
• First Posted: March 9, 2020
• Last Update Posted: August 26, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by MedSIR:

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

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Metformin; Letrozole; Fulvestrant; Exemestane; Hypoglycemic Agents; Physiological Effects of Drugs; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Estrogen Receptor Antagonists