Evaluation of Metformin for Hyperglycemia Prevention in HR+/HER2- PIK3CA-Mutated Advanced Breast Cancer Patients on Alpelisib and Endocrine Therapy
- Trial ID
- 2024-511295-33-00
- Protocol
- MEDOPP240
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the rate of patients with grade 3-4 **hyperglycemia** (HG) as per Common Terminology Criteria for Adverse Events (CTCAE) v.4.03 over the first 8 weeks of treatment with alpelisib plus endocrine therapy and metformin. This evaluation is conducted in patients with normal fasting glycemia and HbA1c (Cohort A), and in patients with impaired fasting glucose criteria (Cohort B). Additionally, for Cohort C, the primary objective is to assess the rate of patients with permanent discontinuation of alpelisib due to related adverse events (AEs) after 8 weeks of treatment with alpelisib plus endocrine therapy and antidiabetic treatment. These objectives are clinically relevant as they aim to determine the safety and tolerability of the treatment regimen, which is crucial for managing HR[+]/HER2[-] PIK3CA-mutated advanced breast cancer patients.
Secondary objectives include: - Evaluating 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), and clinical benefit rate (CBR) of combining alpelisib with endocrine therapy and antidiabetic treatment. - Assessing the rate of any grade and grade 3-4 hyperglycemia by CTCAE v.4.03 in different cohorts and comparing it with SOLAR-1 and Bylieve trials. - Evaluating the rate of patients with permanent treatment discontinuation at 8 weeks due to treatment-related AEs. - Assessing the rate of patients requiring insulin to control hyperglycemia during the study. - Defining the type of hyperglycemia in patients with grade 3-4 hyperglycemia. - Evaluating the safety profile in terms of diarrhea and rash, and the evolution of fasting plasma glucose, SMBG, ketones, C peptide, and continuous monitoring analytical parameters.
Participants
The clinical trial involves a study population comprising both **male** and **female** participants aged 18 years and older, with a focus on individuals diagnosed with advanced breast cancer characterized by HR[+]/HER2[-] and PIK3CA mutations. The trial does not include vulnerable populations. Participants are required to have a histologically confirmed diagnosis of advanced breast cancer, with documented progression following specific endocrine therapies. The study population was selected based on their medical history, including prior treatment regimens and specific laboratory criteria, such as fasting plasma glucose and HbA1c levels. Participants are expected to maintain stable diabetes treatment if applicable and demonstrate adequate bone marrow and organ function. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet and physical activity are not explicitly mentioned, but participants must be able to comply with the study's scheduled visits and procedures. Key inclusion criteria include the presence of PIK3CA mutations and an ECOG Performance Status of 0 or 1, ensuring participants are in a suitable health status to undergo the trial interventions.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **metformin** in preventing hyperglycemia in patients with HR[+]/HER2[-] PIK3CA-mutated advanced breast cancer treated with **alpelisib** plus endocrine therapy. This is a randomized, double-blind, controlled trial with an estimated duration from August 2020 to September 2026. The trial is divided into three cohorts, each with specific objectives and endpoints. The primary objective for Cohorts A and B is to assess the rate of patients with grade 3-4 hyperglycemia over the first 8 weeks of treatment, while Cohort C focuses on the rate of permanent discontinuation of alpelisib due to adverse events.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as prior treatment history and laboratory values. Follow-up visits will occur regularly to monitor treatment effects, adverse events, and compliance with the study protocol. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment. The expected length of participant involvement is approximately 15 weeks, with conditions for early termination including significant adverse events or non-compliance with the study protocol.
Key elements of the research methodology include the use of **exemestane**, **letrozole**, **tamoxifen**, and **fulvestrant** as part of the endocrine therapy regimen, with the primary endpoints focusing on safety and efficacy measures such as progression-free survival and overall response rate. The trial will also evaluate secondary endpoints related to the safety and tolerability of the treatment combination, including the incidence of hyperglycemia and other adverse events. Participants are required to meet specific inclusion criteria, such as having a confirmed diagnosis of advanced breast cancer and adequate organ function, to ensure the validity and reliability of the trial results.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Exemestane**, marketed as Exemestano Kern Pharma 25 mg, is provided in the form of a **coated tablet**. The maximum daily dose is 25 mg, administered orally. This medication is classified as a steroidal aromatase inhibitor and an antineoplastic agent. The treatment period is limited to 15 days.
**Letrozole**, available as Letrozol Kern Pharma 2.5 mg, is a **film-coated tablet**. The maximum daily dose is 2.5 mg, also administered orally. Letrozole functions as an endocrine therapy, specifically as an aromatase inhibitor, and is used in hormonal antagonism. The treatment duration is set for 15 days.
**Alpelisib** is provided in a **film-coated tablet** form, with a maximum daily dose of 300 mg, administered orally. It is categorized under antineoplastic agents, with a treatment period of 15 days. The technical information suggests its use with Fulvestrant, although other endocrine therapies are permissible in the METALLICA study.
**Vildagliptin**, marketed as Vildagliptina Kern Pharma 50 mg, is available in **tablet** form. The maximum daily dose is 100 mg, administered orally. It is classified as a dipeptidyl peptidase 4 (DPP-4) inhibitor, used in diabetes management. The treatment period is 15 days.
**Tamoxifen**, available as tamoxifeno cinfa 20 mg, is provided in **tablet** form. The maximum daily dose is 20 mg, administered orally. It is classified as an antiestrogen, with an ATC code of L02BA01, and the treatment duration is 15 days.
**Fulvestrant**, marketed as Fulvestrant Teva 250 mg, is provided as a **solution for injection** in a pre-filled syringe. The maximum total dose is 500 mg, with a daily dose of 33.33 mg. It is administered as an injection and classified under endocrine therapy and antiestrogens, with an ATC code of L02BA03. The treatment period is 15 days.
**Metformin Hydrochloride**, marketed as Metformina Kern Pharma 1000 mg, is available as a **film-coated tablet**. The maximum daily dose is 2000 mg, administered orally. It is classified as an oral hypoglycemic agent under the biguanides category. The treatment duration is 15 days.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not include any non-experimental treatments such as placebo or comparator treatments. Each medication is administered according to its specific dosing schedule and route, with the aim of evaluating their effects in the context of the study objectives.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on evaluating the rate of patients experiencing grade 3-4 **hyperglycemia** (HG) over the first 8 weeks of treatment with alpelisib plus endocrine therapy and metformin in patients with normal fasting glycemia and HbA1c (Cohort A), and patients with impaired fasting glucose criteria (Cohort B). For Cohort C, the primary endpoint is the rate of patients with permanent discontinuation of alpelisib due to related adverse events (AEs) after 8 weeks of treatment.
Secondary endpoints include several efficacy measures such as progression-free survival (PFS), overall response rate (ORR), time to response (TTR), time to progression (TTP), and clinical benefit rate (CBR). These will be assessed in the overall population, across all cohorts, and according to the different endocrine agents received. PFS is defined as the time from inclusion to the first documented progression or death, while ORR is the proportion of patients with measurable disease achieving a complete or partial response. TTR is the period from treatment initiation to the first objective tumor response, and TTP is the time from treatment start to progression or cancer-related death. CBR is the proportion of patients with a best overall response of complete response, partial response, or stable disease lasting more than 24 weeks.
Safety assessments will also be conducted, focusing on the rate of any grade and grade 3-4 HG, the rate of permanent discontinuation of alpelisib due to AEs, and the requirement for insulin to control HG. Additional safety parameters include the number and class of antidiabetic agents used, the rate of HG as per CTCAE v.4.03 and v.5, and the incidence of diarrhea and cutaneous rash. These safety endpoints will be evaluated over the first 8 weeks and throughout the study, in all cohorts, and according to the different endocrine agents received.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed Informed Consent Form (ICF) prior to participation in any studyrelated 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 boneonly metastases are eligible. Note: 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 paraffinembedded [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.
- Patients are permitted to have received previous fulvestrant either as (neo)adjuvant regimen or as first-line regimen for metastatic disease. Note 01: Patients with secondary resistance (relapse while on adjuvant endocrine therapy but after the first 2 years, or relapse within 12 months of completing adjuvant endocrine therapy, or progression ≥ 6 months after initiating endocrine therapy for metastatic disease, while on endocrine therapy) to fulvestrant will be treated with either fulvestrant, letrozole, exemestane or tamoxifen based on physician’s criteria. Patients with primary endocrine resistance (relapse while on the first 2 years of adjuvant endocrine therapy, or progression within first 6 months of first-line endocrine therapy for metastatic disease, while on endocrine therapy) to fulvestrant would be treated with either letrozole or exemestane based on physician’s criteria. Note 02: Anti-estrogens in current development (i.e. SERMs, SERDs, PROTAC, etc.) are allowed to be used as (neo)adjuvant regimen or as first-line regimen for metastatic disease according to investigator criteria.
- Received no more than 1 prior regimen of chemotherapy in the metastatic setting. Regimen with documented evidence of progression while on (neo)adjuvant chemotherapy or within the first 6 months from completion will be considered as a prior line.
- For Cohort A and B only; Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c): • For Cohort A: FPG < 100 mg/dL (<5,6 mmol/L) and HbA1c < 5,7%; • For Cohort B: FPG 100–140 mg/dL (5,6–7,8 mmol/L) (impaired fasting glucose values) or HbA1c 5,7–6,4%.
- For Cohort C only; • T2DM subjects diagnosed clinically ≥ 90 days prior to screening, • HbA1c < 7,5%. • Stable diabetes treatment for 90 days prior to screening
- If central nervous system (CNS) metastases are present, controlled local disease without corticoids and/or anti-epileptic medication is required.
- Adequate bone marrow and organ function as defined by the following laboratory values: • Hematological: o White blood cell (WBC) count ≥ 3.0 x 109/L; absolute neutrophil count (ANC) > 1.5 x 109/L; platelet count > 100.0 x109/L; and hemoglobin > 9.0 g/dL. o Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ grade 1 according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.03 if judged clinically not significant by the investigator. Potassium within normal limits or corrected with supplements. o International normalized ratio (INR) ≤1.5. • Hepatic: o Bilirubin < 2 times the upper limit of normal (× ULN). Any elevated bilirubin should be asymptomatic at enrollment except for patients with Gilbert’s disease who may be only included if the total bilirubin is ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN. o Aspartate transaminase (AST), and alanine transaminase (ALT) ≤ 3 times × ULN (in the case of liver metastases ≤ 5 × ULN, stable for 2 weeks, without the evidence of biliary obstruction by imaging). • Renal: o Creatinine clearance ≥ 35 mL/min using Cockcroft-Gault formula. • Other: o Fasting serum amylase ≤ 2 × ULN and fasting serum lipase below or equal to ULN. o FPG ≤ 140 mg/dL (7,7 mmol/L) and HbA1c ≤ 6,4% (both criteria must be met for Cohorts A and B only).
- Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- Resolution of all acute toxic effects of prior anti-cancer therapy to grade £ 1 as determined by the NCI-CTCAE v.4.03 (except for alopecia or other toxicities, such as myelosuppression, not considered a safety risk for the patient at investigator's discretion).
Exclusion Criteria
- 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 A and B; Established diagnosis of type 1 or 2 diabetes mellitus (DM) requiring anti-diabetic drugs. Patients with an impaired 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.
- 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.
- Documented pneumonitis/interstitial lung disease (the chest computed tomography [CT] scan performed at baseline for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present.
- Patients with Child-Pugh score B or C liver disease.
- Patients with renal failure.
- Patients with unresolved osteonecrosis of the jaw.
- History of Stevens-Johnson Syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN) 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 anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening.
- Clinically significant uncontrolled heart disease and/or recent cardiac events including any of the following: a. History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 6 months prior to the start of study treatment. b. History of documented congestive heart failure (New York Heart Association functional classification III-IV). c. Left Ventricular Ejection Fraction (LVEF) < 50% at screening as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO). d. Clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g., bifascicular block, Mobitz type II, and third-degree AV block without pacemaker in place). e. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fredericia QT correction formula (QTcF) > 470msec at screening (mean of triplicate ECGs).
- Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate subject participation in the clinical study (e.g., chronic active hepatitis [testing not mandatory unless required by local regulations or requirements], severe hepatic impairment, etc.).
- Treatment with any of the following medications and cannot be discontinued seven days prior to the start of the treatment: o Strong inhibitors or inducers of the isoenzyme cytochrome P450 3A (CYP3A) within the last 5 days prior to study entry. o Inhibitors of breast cancer resistance protein (BCRP).
- Radiotherapy ≤ four weeks or limited field radiation for palliation ≤ two weeks prior to study treatment start, and who has not recovered to grade 1 or better from related side effects of such therapy (except for alopecia).
- Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to study treatment start or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
- Participation in a prior investigational study within 30 days prior to the start of study treatment or within five half-lives of the investigational product, whichever is longer.
- Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE version 4.03 grade ≤1. Exception to this criterion: subjects with any grade of alopecia are allowed to enter the study.
- Known history of Human Immunodeficiency Virus (HIV) infection.
- Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate subject participation in the clinical study (e.g., chronic active hepatitis, severe hepatic impairment).
- Patient is a breastfeeding or pregnant woman as confirmed by a positive serum (hCG) or urine test prior to initiating study treatment.
- Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for at least 1 year after stopping fulvestrant or for at least 1 week after stopping alpelisib. Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. • Male sterilization (at least six months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject. • Combination of the following: • Placement of intrauterine device (IUD) or intrauterine system (IUS) • Use of diaphragm or cervical caps by the patient herself or condom by the male partner combined with use of spermicidal products/vaginal suppository. Note: Use of hormonal methods of contraception (estrogen and progesterone) or hormonal replacement therapy are not allowed in the study. Note: Women are considered postmenopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is, she considered not of childbearing potential.
- Patient is a sexually active male not sterilized (at least 6 months prior to screening) or unwilling to use a condom during intercourse while taking study treatment, and for at least 1 year after stopping fulvestrant or for at least 1 week after stopping alpelisib. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm during study and up to the period specified above. Note: If local regulations to prevent pregnancy deviate from the contraception methods listed above, local regulations apply and will be described in the ICF
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 13 Aug 2020 | 88 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Exemestano Kern Pharma 25 mg comprimidos recubiertos con película EFG | Test | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 25 | 15 | PRD375641 |
Letrozol Kern Pharma 2,5 mg comprimidos recubiertos con película EFG | Test | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 2.5 | 15 | PRD413405 |
ALPELISIB | Test | — | ORAL | 300 | 15 | SUB180707 |
ALPELISIB | Test | — | ORAL | 300 | 15 | SUB180707 |
Vildagliptina Kern Pharma 50 mg comprimidos EFG | Test | COMPRIMIDOS | ORAL | 100 | 15 | PRD7913512 |
tamoxifeno cinfa 20 mg comprimidos EFG | Test | COMPRIMIDOS | ORAL | 20 | 15 | PRD543048 |
Fulvestrant Teva 250 mg solución inyectable en jeringa precargada EFG | Test | SOLUCIÓN INYECTABLE EN JERINGA PRECARGADA | SOLUTION FOR INJECTION | 33.33 | 15 | PRD4527836 |
Metformina Kern Pharma 1000 mg comprimidos recubiertos con película EFG | Test | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 2000 | 15 | PRD8544021 |
ALPELISIB | Test | — | ORAL | 300 | 15 | SUB180707 |