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

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ClinicalTrials.gov Identifier: NCT04300790
Recruitment Status : Recruiting
First Posted : March 9, 2020
Last Update Posted : November 13, 2020
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
MedSIR

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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : January 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hyperglycemia

Arm Intervention/treatment
Experimental: CohortA: Normal fasting glycemia

Alpelisib plus metformin and fulvestrant: During the first cycle, patients will receive fulvestrant 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)


Experimental: CohortB: Fasting glycemia

Alpelisib plus metformin and fulvestrant: During the first cycle, patients will receive fulvestrant 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)





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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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[+] 8.
  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.9.
  8. Presence of PIK3CAMut
  9. Progression on an AI regimen for advanced BC
  10. (CNS) metastasis, controlled local disease without corticoids and/or anti-epileptic medication is required.
  11. At least one prior line of endocrine therapy for advanced disease, or progression on, or within 12 months from completion of a (neo) adjuvant aromatase inhibitor.
  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) and HbA1c < 5,7 to 6.4%

  14. Adequate organ function
  15. Patients willing and able to comply with scheduled visits
  16. Resolution of all acute toxic effects of prior anti-cancer therapy

Exclusion Criteria:

  1. Prior treatment with a PI3K, mTOR or AKT inhibitor
  2. Prior therapy with fulvestrant for advanced BC
  3. Patients with a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients
  4. Patients with an established diagnosis of diabetes mellitus [DM] type I or II requiring anti-diabetic drugs
  5. Prior treatment with metformin.
  6. More than one prior line of chemotherapy for advanced disease.
  7. Inflammatory BC at screening.
  8. Patients receiving systemic corticosteroids within 1 week prior to start treatment with alpelisib (BYL719).
  9. Patients with past medical history of acute or chronic pancreatitis within 1 year prior to screening.
  10. Patient with impaired gastrointestinal (GI) function
  11. Patient with documented pneumonitis/interstitial lung disease
  12. Patients with clinically significant uncontrolled heart disease and/or recent cardiac events
  13. Subject has any other concurrent severe and/or uncontrolled medical condition
  14. 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
  15. Patients with Child-Pugh score B or C liver disease.
  16. Patients with renal failure.
  17. Patients with unresolved osteonecrosis of the jaw
  18. Subject has a history of Stevens-Johnson Syndrome (SJS), erythema multiforme (EM) or toxic epidermal necrolysis (TEN)
  19. Subject has received radiotherapy ≤ 4 weeks or limited field radiation for palliation

    • 2 weeks prior to randomization
  20. 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
  21. Participation in a prior investigational study within 30 days prior to the start of study treatment
  22. Subject has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1.
  23. Subject has a concurrent malignancy or malignancy within 3 years of start of study treatment
  24. Subject has a known history of (HIV) infection.
  25. Subject has any other concurrent severe and/or uncontrolled medical condition
  26. Subject is not able to understand and to comply with study instructions and requirements.
  27. Subject is breastfeeding or pregnant woman
  28. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04300790


Contacts
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Contact: Griselda Martrat 34 610 176 591 griselda.martrast@gmail.com
Contact: Carolina Herrero carol.herrero@medsir.org

Locations
Show Show 19 study locations
Sponsors and Collaborators
MedSIR
Novartis
Investigators
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Principal Investigator: Antonio Llombart MedSIR
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Responsible Party: MedSIR
ClinicalTrials.gov Identifier: NCT04300790    
Other Study ID Numbers: MEDOPP240
First Posted: March 9, 2020    Key Record Dates
Last Update Posted: November 13, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Metformin
Fulvestrant
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists