AzTrials
AzTrials

Advanced Breast CancerPhase 3ALPHABETNCT05063786

Trastuzumab + Alpelisib +/- Fulvestrant vs Trastuzumab + CT in PIK3CA-mutated HER2+ Advanced BC (ALPHABET)

A Phase 3 study testing Trastuzumab, Alpelisib and Fulvestrant in people with Advanced Breast Cancer, run by Spanish Breast Cancer Research Group at 106 sites in 6 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Randomized phase III trial of trastuzumab + Alpelisib +/- fulvestrant versus trastuzumab + chemotherapy in patients with PIK3CA mutated previously treated HER2+ Advanced Breast cancer. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Breast Cancer
What is being tested?
Trastuzumab, Alpelisib and Fulvestrant
Could I receive a placebo?
No, everyone receives an active treatment
How many people
27 participants
Where
106 sitesin 6 countries
Study dates
14 Sep 2021to 23 Dec 2025
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients are eligible to be enrolled for randomization in the study only if they meet all of the following criteria:
  • Written informed consent prior to any specific study procedures, showing patient willingness to comply with all study procedures.
  • Histologically or cytologically documented locally recurrent inoperable or metastatic breast cancer with HER2+ status based on local laboratory determination, preferably on the most recent available FFPE tumor sample, and according to American Society of ClinicalOncology (ASCO)/College of American Pathologists (CAP) international guidelines valid at the time of the assay. In case of discordance in HER2+ status in different biopsies, we will consider the result from the most recent biopsy one will be used.
  • Documented HR status based on local laboratory, preferably on the most recent available FFPE tumor sample, and according to ASCO/CAP international guidelines valid at the time of the assay. In case of discordance in HR status in different biopsies, the result from the most recent biopsy will be used. HR+ will be defined as ≥1% positive cells by immunohistochemistry for Estrogen Receptor (ER) and/or Progesterone Receptor (PgR). HR- will be defined as <1% positive cells by immunohistochemistry for both ER and PgR. Considering that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive, for the purpose of this study, patients with ER and PgR expression between 1 and 10% (considered to be HR low by the most recent ASCO/CAP guidelines) will be eligible for inclusion in the HR- cohort.
  • Patients with a PIK3CA tumor mutation at central laboratory determination, preferably on the most recent available FFPE tumor sample.
  • At least 1 but no more than 5 prior lines of anti-HER2 based therapy for metastatic breast cancer (MBC). Maintenance therapy will not count as an additional line of therapy.
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  • At least 1 prior line of trastuzumab in the metastatic setting, or in the (neo)adjuvant setting (provided the patient relapsed while on therapy or within 6 months after completing adjuvant trastuzumab).
  • Female or male patient is at least 18 years of age.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
  • Patients can be either males or premenopausal/perimenopausal or postmenopausal females. In the HR+ cohort, males and females who are not post-menopausal must have been on a gonadotropin-releasing hormone (GnRH) agonist (e.g. goserelin or leuprorelin) for at least 28 days prior to starting study treatment.
  • Premenopausal status is defined as either:
  • Last menstrual period occurred within the last 12 months, or
  • If on tamoxifen: last menstrual period occurred within the past 14 days, plasma estradiol is ≥ 10 pg/mL and follicle-stimulating hormone (FSH) ≤ 40 IU/l or in the premenopausal range, according to local laboratory definition, or
  • In case of therapy induced amenorrhea: plasma estradiol is ≥ 10 pg/mL and FSH ≤ 40 IU/l or in the premenopausal range, according to local laboratory definition.
  • Postmenopausal status is defined as either:
  • Natural (spontaneous) amenorrhea lasting more than 12 months and either age from49 to 59 years and/or history of vasomotor symptoms (e.g., hot flush) in the absence of other medical justification, or Levels of plasma estradiol ≤ 20 pg/mL and follicle-stimulating hormone (FSH) ≥ 40 IU/l or in the postmenopausal range, according to local laboratory definition, or Surgical bilateral oophorectomy.
  • Perimenopausal status is defined as neither premenopausal nor postmenopausal.
  • Measurable disease or at least one evaluable bone lesion, lytic or mixed (lytic+blastic), which has not been previously irradiated and is assessable by computer tomography (CT)/magnetic resonance imaging (MRI) in the absence of measurable disease according to RECIST 1.1 criteria.
  • Life expectancy ≥ 12 weeks.
  • Adequate organ and marrow function defined as follows:
  • Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5x109/L).
  • Platelets ≥ 100,000/mm3 (100x109/L).
  • Hemoglobin ≥ 9g/dL (90g/L).
  • Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ grade 1 according to NCI-CTCAE version 5.0 if judged clinically not significant by the investigator.
  • Creatinine <1.5 x upper limit of normal (ULN) or creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula (if creatinine is ≥1.5 ULN).
  • Total bilirubin < 2 x ULN (any elevated bilirubin should be asymptomatic at enrollment) except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN.
  • Potassium within normal limits, or corrected with supplements.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN.
  • If patient has liver metastasis, AST and ALT ≤ 5.0 x ULN (elevated AST or AST values must be stable for 2 weeks, without evidence of biliary obstruction by imaging).
  • Fasting serum amylase ≤ 2.0 x ULN.
  • Fasting serum lipase ≤ ULN.
  • Fasting plasma glucose (FPG) < 140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) < 6.5%.
  • Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI-CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).
  • Adequate cardiac function as defined by left ventricular ejection fraction (LVEF) of ≥ 50% measured by echocardiography or multi-gated acquisition (MUGA) scans.

Who cannot join

  • Patients will be excluded from the study if they meet any of the following criteria:
  • Have received more than 5 previous lines of anti-HER2 based therapy for MBC, or prior fulvestrant.
  • Symptomatic visceral disease or any disease burden that makes the patient ineligible for experimental therapy per the investigator's best judgment.
  • Symptomatic central nervous system (CNS) metastases. However, patients with CNS metastases who have been adequately treated, are asymptomatic and do not require corticosteroid or anti-epileptic medication are eligible.
  • Presence of leptomeningeal carcinomatosis.
  • Other invasive malignancy (different from the current breast cancer) at the time of enrollment or previous diagnosis of a completely removed malignancy within 3 years prior to randomization except for adequately treated (including complete surgical removal) of International Federation of Gynecology and Obstetrics (FIGO) stage I grade 1 endometrial cancer, basal or squamous cell carcinoma of the skin, thyroid cancer limited to thyroid gland, in situ carcinoma of the cervix, and grade 1-2 early stage bladder cancer defined as T1 or less, without nodal involvement (N0).
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  • Patients with an established diagnosis of diabetes mellitus type I or not controlled type II (FPG ≥ 140 mg/dL [7.7 mmol/L] or HbA1c ≥ 6.5%), or history of gestational diabetes (as per American College of Obstetricians and Gynecologists (ACOG) guidelines) or documented steroid-induced diabetes mellitus.
  • Prior treatment with any mTOR, AKT or PI3K inhibitor.
  • Patients treated within the last 7 days prior to treatment initiation with:
  • Drugs that are strong inducers of CYP3A4.
  • Drugs that are inhibitors of Breast Cancer Resistance Protein (BCRP).
  • Patients who received before randomization:
  • Any investigational agent within 4 weeks.
  • Chemotherapy within a period of time that is shorter than the cycle duration used for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicin or < 1 week for weekly chemotherapy).
  • Biologic therapy (e.g., antibodies, other than trastuzumab which is permitted): within 4 weeks prior to starting study treatment.
  • Endocrine therapy: tamoxifen or aromatase inhibitor (AI) within 2 weeks prior to starting study treatment.
  • Corticosteroids within 2 weeks prior to starting study treatment. Note: the following uses of corticosteroids are permitted at any time: 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).
  • Radiotherapy within 2 weeks prior to starting study treatment (all acute toxic effects must be resolved to NCI-CTCAE version 5.0 grade <1, except toxicities not considered a safety risk for the patient at investigator´s discretion). Patients who received prior radiotherapy to >25% of bone marrow are not eligible regardless of when it was administered.
  • Major surgery or other anti-cancer therapy not previously specified within 4 weeks prior to starting study treatment, (all acute toxic effects, including peripheral neurotoxicity must be resolved to NCI-CTCAE version 5.0 grade ≤ 1, except toxicities not considered a safety risk for the patient at the investigator´s discretion).
  • Patient has clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following:
  • History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis or myocardial infarction within 6 months of randomization.
  • History of documented congestive heart failure (New York Heart Association functional classification III-IV).
  • 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).
  • Uncontrolled hypertension defined by a Systolic Blood Pressure ≥ 160 mmHg 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.
  • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) > 470msec.
  • Bradycardia (heart rate < 50 at rest), by electrocardiogram (ECG) or pulse.
  • Inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 460 msec for females (using Fridericia's correction). All as determined by screening ECG.
  • Bleeding diathesis (i.e., Disseminated Intravascular Coagulation (DIC), clotting factor deficiency) or long-term (> 6 months) anticoagulant therapy, other than antiplatelet therapy and low dose coumarin derivatives, provided that the International Normalised Ratio (INR) is less than 1.5.
  • History of clinically significant bowel disease including abdominal fistula, or gastrointestinal perforation.
  • Difficulties to swallow tablets, malabsorption syndrome disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or active inflammatory bowel disease (e.g., ulcerative diseases).
  • Known hypersensitivity to trastuzumab, alpelisib or fulvestrant or any of their excipients. If known hypersensitivity to either vinorelbine, capecitabine, eribulin or any of their excipients, patient will be eligible as long as the investigator's choice avoids that drug in the control arm.
  • If known hypersensitivity to all three cytostatics (vinorelbine, capecitabine and eribulin), the patient will not be eligible.
  • Known positive serology for Human Immunodeficiency Virus (HIV), or active infection for hepatitis B or hepatitis C.
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
  • Patients with currently documented pneumonitis/interstitial lung disease (the chest Computed Tomography [CT] scan performed at screening for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
  • Patient with liver disease with a Child Pugh score B or C.
  • Patient with a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
  • Patient has a history of Steven-Johnson-Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN).
  • Patient is nursing (lactating) or is pregnant as confirmed by a positive serum human Chorionic Gonadotropin (hCG) test prior to initiating study treatment.
  • Patient is a woman of child-bearing potential or a partner of a woman of child-bearing potential, unless agreement to remain abstinent or use single or combined non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study treatment, except for patients receiving fulvestrant in which this period should be of at least 2 years.
  • Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient.
  • Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  • Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization (only if he is the sole partner and have been performed at least 6 months prior to screening), and certain intrauterine devices.
  • Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide.
  • Male participants must not donate sperm during study and up to the time period specified above.

Trial locations and contacts

106 sites in 6 countries.

106 sites in 6 countries

Spain54 sites

  • Centro Oncoloxico de Galicia

    A Coruña

  • Complexo Hospitalario Universitario A Coruña

    A Coruña

  • Hospital Clínico Universitario de Santiago CHUS

    A Coruña

  • Complejo Hospitalario Universitario de Albacete

    Albacete

  • Hospital General Universitario de Alicante

    Alicante

  • Hospital Universitario de Badajoz

    Badajoz

  • ICO Badalona - Hospital Universitario Germans Trias i Pujol

    Badalona

  • Hospital Clínic de Barcelona

    Barcelona

  • Hospital de La Santa Creu I Sant Pau

    Barcelona

  • Hospital del Mar

    Barcelona

  • Hospital Universitario Basurto

    Bilbao, 48013

  • Hospital Galdakao-Usansolo

    Bilbao

  • Hospital Universitario de Cruces

    Bilbao

  • Hospital San Pedro de Alcántara

    Cáceres

  • Hospital Universitario Puerta del Mar

    Cadiz

  • Hospital Universitario Donostia

    Donostia / San Sebastian

  • Hospital General Universitario de Elche

    Elche

  • ICO de Girona - Hospital Josep Trueta

    Girona

  • Hospital Universitario Clínico San Cecilio

    Granada

  • Hospital Universitario Virgen de las Nieves

    Granada

  • Hospital Universitario Juan Ramón Jiménez

    Huelva

  • Hospital Universitario de Jaen

    Jaén

  • Hospital Universitario de Jerez de la Frontera

    Jerez de la Frontera

  • Hospital Universitario Arnau de Vilanova de Lleida

    Lleida

  • Hospital Universitario Lucus Augusti

    Lugo

  • Hospital Universitario Fundación Jiménez Díaz

    Madrid, 28040

  • Hospital Clínico San Carlos

    Madrid

  • Hospital General Universitario Gregorio Marañon

    Madrid

  • Hospital Universitario de Fuenlabrada

    Madrid

  • Hospital Universitario HM Sanchinarro - CIOCC Clara Campal

    Madrid

  • Hospital Universitario Puerta de Hierro Majadahonda

    Madrid

  • Hospital Universitario Ramon Y Cajal

    Madrid

  • Hospital Universitario Severo Ochoa

    Madrid

  • Hospital Universitario Regional de Malaga

    Málaga

  • Althaia Xarxa Assistencial de Manresa

    Manresa

  • Hospital de Mataró

    Mataró

  • Hospital Clinico Universitario Virgen de La Arrixaca

    Murcia

  • Hospital Universitario Son Espases

    Palma de Mallorca

  • Hospital Universitario Son Llatzer

    Palma de Mallorca

  • Complejo Hospitalario de Navarra

    Pamplona

  • Corporació Sanitaria Parc Taulí

    Sabadell

  • Hospital Universitario de Canarias

    Santa Cruz de Tenerife

  • Hospital Universitario Nuestra Señora de la Candelaria

    Santa Cruz de Tenerife

  • Hospital Universitario Virgen de Valme

    Seville

  • Hospital Universitario Virgen Del Rocio

    Seville

  • Hospital Universitario Virgen Macarena

    Seville

  • Hospital Universitario Sant Joan de Reus

    Tarragona

  • Hospital de Terrassa - Consorci Sanitari de Terrassa

    Terrassa

  • Hospital Virgen de la Salud

    Toledo

  • Consorcio Hospital General Universitario de Valencia

    Valencia

  • Hospital Clínico Universitario de Valencia

    Valencia

  • Hospital Universitario Arnau de Vilanova de Valencia

    Valencia

  • Hospital Provincial de Zamora (Complejo Asistencial de Zamora)

    Zamora

  • Hospital Universitario Miguel Servet

    Zaragoza

Other trials in Spain

Italy25 sites

  • A.O. "SS Antonio e Biagio e Cesare Arrigo"

    Alessandria

  • Clinica Oncologica, AOU Riuniti

    Ancona

  • Ospedale di Bolzano Azienda Sanitaria Alto Adige

    Bolzano

  • Ospedale MultiMedica Castellanza

    Castellanza

  • Cannizzaro Hospital

    Catania

  • ASST Cremona

    Cremona

  • Azienda Ospedaliero-Universitaria Careggi, University of Florence

    Florence

  • IRCCS Policlinico San Martino

    Genoa

  • Mater Salutis Hospital

    Legnago

  • ASST-Mantova- Hospital Carlo Poma

    Mantua

  • Istituto Scientifico Romagnolo per lo Studio e la Cura dei tumori

    Meldola

  • IRCCS Ospedale San Raffaele

    Milan

  • IEO - Istituto Europeo di Oncologia

    Milan

  • Ospedali Riuniti Monselice Padova

    Monselice

  • AOU Maggiore della Caritá

    Novara

  • Casa di Cura La Maddalena S.P.A.

    Palermo

  • Azienda Ospedaliero-Universitaria di Parma

    Parma

  • Istituti Clinici Scientifici Maugeri SpA-SB

    Pavia

  • AUSL Romagna/Oncology Department

    Rimini

  • Istituti Fisioterapici ospitaliersi - IFO - Istituti Regina Elena

    Roma

  • Policlinico Umberto I

    Roma

  • UOSD AUSL Modena

    Sassuolo

  • Santa Chiara Hospital

    Trento

  • Sant'Anna Hospital - Città della salute e della scienza

    Turin

  • Department of Oncology, ASUFC, PO Sm Misericordia

    Udine

Other trials in Italy

Netherlands9 sites

  • Meander Medisch Centrum

    Amersfoort

  • Adrz Medisch Centrum

    Goes

  • Martini Ziekenhuis

    Groningen

  • Maastricht UMC

    Maastricht

  • Radboud Medical Center

    Nijmegen, Gelderland, 6525 GA

  • ZorgSaam Ziekenhuis

    Terneuzen

  • HagaZiekenhuis

    The Hague

  • Diakonessenhuis Utrecht

    Utrecht

  • VieCuri Medisch Centrum

    Venlo

Other trials in Netherlands

Austria8 sites

  • Medizinische Universität Innsbruck - Univ.Klinik f. Frauenheilkunde Innsbruck

    Innsbruck

  • LKH Hochsteiermark - Leoben

    Leoben

  • Ordensklinikum Linz GmbH - BHS

    Linz

  • Universitätsklinikum St. Pölten

    Pölten

  • Pyhrn - Eisenwurzen Klinikum Steyr

    Steyr

  • Klinik Hietzing Wien

    Vienna

  • Klinik Ottakring

    Vienna

  • Medizinische Universität Wien - Univ.klinikum AKH Wien

    Vienna

Other trials in Austria

France7 sites

  • Centre d'Oncologie et Radiothérapie 37

    Chambray-lès-Tours

  • Centre Jean Perrin

    Clermont-Ferrand

  • Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc

    Dijon

  • Centre hospitalier universitaire à Limoges

    Limoges

  • Institut Curie Hospital

    Paris

  • Centre hospitalier universitaire de Poitiers

    Poitiers

  • Institute Curie - Site Saint-Cloud

    Saint-Cloud, 92210

Other trials in France

Switzerland3 sites

  • Tumor Zentrum Aarau

    Aarau

  • Inselspital, Universitätsspital Bern

    Bern

  • Centre du sein Fribourg

    Fribourg

Other trials in Switzerland

About this study

Official title: A Randomized Phase III Trial of Trastuzumab + ALpelisib +/- Fulvestrant Versus Trastuzumab + Chemotherapy in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer. "ALPHABET Study".

Randomized phase III trial of trastuzumab + Alpelisib +/- fulvestrant versus trastuzumab + chemotherapy in patients with PIK3CA mutated previously treated HER2+ Advanced Breast cancer.

Read the detailed description

This is an international, multicenter, open-label, controlled phase III randomized clinical trial in HER2+ advanced breast cancer (ABC) patients harboring PIK3CA mutation.

Approximately 300 patients (144 in the Hormone Receptor (HR)- cohort and 156 in the HR+ cohort) will be enrolled.

Central screening of PIK3CA mutations on the most recent available formalin-fixed paraffinembedded (FFPE) tumor sample is required for the purpose of eligibility. Investigators will be encouraged to send the most recent tumor tissue, preferably from a metastatic lesion. However, if this is not possible, archived tissue samples either from primary tumor or metastatic lesion will be acceptable. Local screening of HR and HER2 status is required (although there will be a central confirmation done retrospectively).

Once the screening process (locally at each site and at the central laboratory) is completed, fully eligible patients will be randomized in a 1:1 fashion to the control arm with trastuzumab plus chemotherapy (CT) or to the experimental arm with trastuzumab + alpelisib +/- fulvestrant (depending on HR status). The two patient cohorts defined according to HR status will be randomized separately, with randomization in each cohort stratified by prior treatment with pertuzumab (yes vs no) and number of prior anti-HER2 based therapy lines for MBC (≤2 vs >2).

In both cohorts patients will continue to receive their assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.

After objective disease progression, patients in both treatment arms will be followed until death or withdrawal of consent.

In order to perform exploratory biomarker analysis, pre-treatment tumor and sequential blood samples (at baseline, at week 9, at the end of treatment (EOT), and at progressive disease (PD)) will be obtained. Additionally, blood samples from approximately 100 patients (50 HR+ and 50 HR-) screened and without PIK3CA mutation will be collected.

Keywords
Alpelisib, Metastatic Breast Cancer, PIK3CA mutated, HER2 positive
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TrastuzumabBiological

    Also called Herceptin

    6 mg/kg IV every 3 weeks (3-weekly schedule), or 4 mg/kg IV loading dose, followed by 2mg/kg IV weekly (weekly schedule)*, or 600 mg SC every 3 weeks.

    • If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.

  • AlpelisibDrug

    Also called Piqray

    300 mg oral once daily.

  • FulvestrantDrug

    Also called Faslodex

    500 mg intramuscular every 4 weeks plus loading dose on day 15 cycle 1.

  • VinorelbineDrug

    Also called Navelbine

    Oral (60 mg/m2) or IV (25 or 30 mg/m2 per investigator preference) on days 1 and 8, every 3 weeks.

  • CapecitabineDrug

    Also called Xeloda

    1250 or 1000 mg/m2 (per investigator preference) twice a day (BID) oral, 2 weeks on, 1 week off, every 3 weeks.

  • EribulinDrug

    Also called Halaven

    1.23 mg/m2 IV on days 1 and 8, every 3 weeks.

Study groups in NCT05063786
Study groupRoleWhat they receive
Experimental Arm (Arm A) Cohort 1 (HER2+/HR-)ExperimentalTrastuzumab either intravenous (IV) or subcutaneous (SC): 6 mg/kg IV every 3 weeks (3-weekly schedule), or 2 mg/kg IV weekly (weekly schedule)*, or 600 mg SC every 3 weeks. Alpelisib 300 mg oral once daily. *If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.
Receives: Biological: Trastuzumab; Drug: Alpelisib
Experimental Arm (Arm A) Cohort 2 (HER2+/HR+)ExperimentalTrastuzumab either intravenous (IV) or subcutaneous (SC): 6 mg/kg IV every 3 weeks (3-weekly schedule), or 2 mg/kg IV weekly (weekly schedule)*, or 600 mg SC every 3 weeks. Alpelisib 300 mg oral once daily. Fulvestrant 500 mg intramuscular every 4 weeks plus loading dose on day 15 cycle 1. Males and females who are not post-menopausal must have been on a gonadotropin-releasing hormone (GnRH) agonist (e.g. goserelin or leuprorelin) for at least 28 days prior to starting study treatment, and should continue with this therapy. *If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.
Receives: Biological: Trastuzumab; Drug: Alpelisib; Drug: Fulvestrant
Control Arm (Arm B ) Cohorts 1 and 2Active comparatorTrastuzumab either intravenous (IV) or subcutaneous (SC): 6 mg/kg IV every 3 weeks (3-weekly schedule), or 2 mg/kg IV weekly (weekly schedule)*, or 600 mg SC every 3 weeks. Chemotherapy (CT): vinorelbine, capecitabine or eribulin (according to investigator preference): * Vinorelbine either oral (60 mg/m2) or IV (25 or 30 mg/m2 per investigator preference) on days 1 and 8, every 3 weeks. * Capecitabine: 1250 or 1000 mg/m2 (per investigator preference) twice a day (BID) oral, 2 weeks on, 1 week off, every 3 weeks. * Eribulin: 1.23 mg/m2 IV on days 1 and 8, every 3 weeks. * If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.
Receives: Biological: Trastuzumab; Drug: Vinorelbine; Drug: Capecitabine; Drug: Eribulin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free Survival (PFS)

    Time from randomization to objective disease progression based on the investigator's assessment according to the response evaluation criteria for solid tumors (RECIST) version 1.1., or death from any cause.

    Measured: The accumulation of targeted PFS events is estimated at 44 and 38 months since first patients randomized, in the HR- and HR+ cohorts, respectively.

Secondary outcomes (3)

  1. Overall Survival (OS)

    Time from randomization to death from any cause.

    Measured: Approximately 59 months from the inclusion of the first patient.

  2. Objective Response (OR)

    Complete or partial response as best overall response based on the investigator's assessment according to RECIST version 1.1.

    Measured: Through study completion, an average of 59 months from the inclusion of the first patient.

  3. Safety and tolerability

    Adverse events (AEs) grades will be defined by the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 5.0. AE terms will be coded according to the MedDRA dictionary.

    Measured: During the study treatment period or within 30 days of the last dose of study treatment.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Oct 2021
  2. Study start14 Sep 2021
  3. Primary completion23 Dec 2025
  4. Study completion23 Dec 2025

Why it stopped: Study prematurely terminated due to recruitment challenges, low incidence of the target population, evolving treatment landscape, ethical considerations, and inability to ensure funding through study completion.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
27 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05063786
Sponsor's protocol ID
GEICAM/2017-01_IBCSG 62-20_BIG
Other IDs
2020-005639-65
Acronym
ALPHABET
Status last verified
Oct 2026
First submitted
21 Jul 2021
Last updated
15 Oct 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Perez-Fidalgo JA, Criscitiello C, Carrasco E, Regan MM, Di Leo A, Ribi K, Adam V, Bedard PL. A phase III trial of alpelisib + trastuzumab +/- fulvestrant versus trastuzumab + chemotherapy in HER2+ PIK3CA-mutated breast cancer. Future Oncol. 2022 Jun;18(19):2339-2349. doi: 10.2217/fon-2022-0045. Epub 2022 Apr 25.

    PubMed 35465733

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Trastuzumab, Alpelisib and Fulvestrant in people with Advanced Breast Cancer, run by Spanish Breast Cancer Research Group at 106 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 34 inclusion and 45 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 15 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 106 sites in Spain, Italy, Netherlands, Austria, France and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Study prematurely terminated due to recruitment challenges, low incidence of the target population, evolving treatment landscape, ethical considerations, and inability to ensure funding through study completion.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression Free Survival (PFS) (time frame: The accumulation of targeted PFS events is estimated at 44 and 38 months since first patients randomized, in the HR- and HR+ cohorts, respectively.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05063786, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2026.

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