Trastuzumab + Alpelisib +/- Fulvestrant vs Trastuzumab + CT in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer (ALPHABET)

NCT05063786 | Active Not Recruiting Phase 3 DMC

• 2 other identifiers: GEICAM/2017-01_IBCSG 62-20_BIG2020-005639-65
• Study Type: interventional
• Target: 27
• Locations: 6 countries
• Sites: 106

Brief Summary

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

Conditions

Advanced Breast Cancer

Keywords

Alpelisib; Metastatic Breast Cancer; PIK3CA mutated; HER2 positive

Outcome Measures

Primary Outcomes (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.

  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)

• Overall Survival (OS)

  Approximately 59 months from the inclusion of the first patient.

• Objective Response (OR)

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

• Safety and tolerability

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

Other Outcomes (5)

• Time to first subsequent therapy (TFST)

  After disease progression or unacceptable toxicity up approximately 59 months from the inclusion of the first patient.

• Time to first subsequent therapy cessation (TFSTC)

  At the finalization of the first subsequent line of systemic therapy after study treatment estimated to be approximately 59 months from the inclusion of the first patient.

• Change in the National Comprehensive Cancer Network - Functional- Breast Cancer Symptom Index-16 (NFBSI) summary score from baseline to 9 weeks after randomization

  Baseline and 9 weeks after randomization.

Study Arms (3)

Experimental Arm (Arm A) Cohort 1 (HER2+/HR-)

EXPERIMENTAL

Trastuzumab 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.

Biological: Trastuzumab; Drug: Alpelisib

Experimental Arm (Arm A) Cohort 2 (HER2+/HR+)

EXPERIMENTAL

Trastuzumab 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.

Biological: Trastuzumab; Drug: Alpelisib; Drug: Fulvestrant

Control Arm (Arm B ) Cohorts 1 and 2

ACTIVE COMPARATOR

Trastuzumab 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.

Biological: Trastuzumab; Drug: Vinorelbine; Drug: Capecitabine; Drug: Eribulin

Interventions

Trastuzumab BIOLOGICAL

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.

Also known as: Herceptin

Control Arm (Arm B ) Cohorts 1 and 2; Experimental Arm (Arm A) Cohort 1 (HER2+/HR-); Experimental Arm (Arm A) Cohort 2 (HER2+/HR+)

Alpelisib DRUG

300 mg oral once daily.

Also known as: Piqray

Experimental Arm (Arm A) Cohort 1 (HER2+/HR-); Experimental Arm (Arm A) Cohort 2 (HER2+/HR+)

Fulvestrant DRUG

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

Also known as: Faslodex

Experimental Arm (Arm A) Cohort 2 (HER2+/HR+)

Vinorelbine DRUG

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

Also known as: Navelbine

Control Arm (Arm B ) Cohorts 1 and 2

Capecitabine DRUG

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

Also known as: Xeloda

Control Arm (Arm B ) Cohorts 1 and 2

Eribulin DRUG

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

Also known as: Halaven

Control Arm (Arm B ) Cohorts 1 and 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.

You may not qualify if:

• 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).
• 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.

Sponsors & Collaborators

• Spanish Breast Cancer Research Group: lead
• ETOP IBCSG Partners Foundation: collaborator
• Breast International Group: collaborator
• Novartis Pharmaceuticals: collaborator

Study Sites (106)

Medizinische Universität Innsbruck - Univ.Klinik f. Frauenheilkunde Innsbruck

Innsbruck, Austria

Location

LKH Hochsteiermark - Leoben

Leoben, Austria

Location

Ordensklinikum Linz GmbH - BHS

Linz, Austria

Location

Universitätsklinikum St. Pölten

Pölten, Austria

Location

Pyhrn - Eisenwurzen Klinikum Steyr

Steyr, Austria

Location

Klinik Hietzing Wien

Vienna, Austria

Location

Klinik Ottakring

Vienna, Austria

Location

Medizinische Universität Wien - Univ.klinikum AKH Wien

Vienna, Austria

Location

Centre d'Oncologie et Radiothérapie 37

Chambray-lès-Tours, France

Location

Centre Jean Perrin

Clermont-Ferrand, France

Location

Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc

Dijon, France

Location

Centre hospitalier universitaire à Limoges

Limoges, France

Location

Institut Curie Hospital

Paris, France

Location

Centre hospitalier universitaire de Poitiers

Poitiers, France

Location

Institute Curie - Site Saint-Cloud

Saint-Cloud, 92210, France

Location

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

Alessandria, Italy

Location

Clinica Oncologica, AOU Riuniti

Ancona, Italy

Location

Ospedale di Bolzano Azienda Sanitaria Alto Adige

Bolzano, Italy

Location

Ospedale MultiMedica Castellanza

Castellanza, Italy

Location

Cannizzaro Hospital

Catania, Italy

Location

ASST Cremona

Cremona, Italy

Location

Azienda Ospedaliero-Universitaria Careggi, University of Florence

Florence, Italy

Location

IRCCS Policlinico San Martino

Genoa, Italy

Location

Mater Salutis Hospital

Legnago, Italy

Location

ASST-Mantova- Hospital Carlo Poma

Mantova, Italy

Location

Istituto Scientifico Romagnolo per lo Studio e la Cura dei tumori

Meldola, Italy

Location

IRCCS Ospedale San Raffaele

Milan, Italy

Location

IEO - Istituto Europeo di Oncologia

Milan, Italy

Location

Ospedali Riuniti Monselice Padova

Monselice, Italy

Location

AOU Maggiore della Caritá

Novara, Italy

Location

Casa di Cura La Maddalena S.P.A.

Palermo, Italy

Location

Azienda Ospedaliero-Universitaria di Parma

Parma, Italy

Location

Istituti Clinici Scientifici Maugeri SpA-SB

Pavia, Italy

Location

AUSL Romagna/Oncology Department

Rimini, Italy

Location

Istituti Fisioterapici ospitaliersi - IFO - Istituti Regina Elena

Roma, Italy

Location

Policlinico Umberto I

Roma, Italy

Location

UOSD AUSL Modena

Sassuolo, Italy

Location

Santa Chiara Hospital

Trento, Italy

Location

Sant'Anna Hospital - Città della salute e della scienza

Turin, Italy

Location

Department of Oncology, ASUFC, PO Sm Misericordia

Udine, Italy

Location

Radboud Medical Center

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

Meander Medisch Centrum

Amersfoort, Netherlands

Location

Adrz Medisch Centrum

Goes, Netherlands

Location

Martini Ziekenhuis

Groningen, Netherlands

Location

Maastricht UMC

Maastricht, Netherlands

Location

ZorgSaam Ziekenhuis

Terneuzen, Netherlands

Location

HagaZiekenhuis

The Hague, Netherlands

Location

Diakonessenhuis Utrecht

Utrecht, Netherlands

Location

VieCuri Medisch Centrum

Venlo, Netherlands

Location

Centro Oncoloxico de Galicia

A Coruña, Spain

Location

Complexo Hospitalario Universitario A Coruña

A Coruña, Spain

Location

Hospital Clínico Universitario de Santiago CHUS

A Coruña, Spain

Location

Complejo Hospitalario Universitario de Albacete

Albacete, Spain

Location

Hospital General Universitario de Alicante

Alicante, Spain

Location

Hospital Universitario de Badajoz

Badajoz, Spain

Location

ICO Badalona - Hospital Universitario Germans Trias i Pujol

Badalona, Spain

Location

Hospital Clínic de Barcelona

Barcelona, Spain

Location

Hospital de La Santa Creu I Sant Pau

Barcelona, Spain

Location

Hospital del Mar

Barcelona, Spain

Location

Hospital Universitario Basurto

Bilbao, 48013, Spain

Location

Hospital Galdakao-Usansolo

Bilbao, Spain

Location

Hospital Universitario de Cruces

Bilbao, Spain

Location

Hospital Universitario Puerta del Mar

Cadiz, Spain

Location

Hospital San Pedro de Alcántara

Cáceres, Spain

Location

Hospital Universitario Donostia

Donostia / San Sebastian, Spain

Location

Hospital General Universitario de Elche

Elche, Spain

Location

ICO de Girona - Hospital Josep Trueta

Girona, Spain

Location

Hospital Universitario Clínico San Cecilio

Granada, Spain

Location

Hospital Universitario Virgen de las Nieves

Granada, Spain

Location

Hospital Universitario Juan Ramón Jiménez

Huelva, Spain

Location

Hospital Universitario de Jaen

Jaén, Spain

Location

Hospital Universitario de Jerez de la Frontera

Jerez de la Frontera, Spain

Location

Hospital Universitario Arnau de Vilanova de Lleida

Lleida, Spain

Location

Hospital Universitario Lucus Augusti

Lugo, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Clínico San Carlos

Madrid, Spain

Location

Hospital General Universitario Gregorio Marañon

Madrid, Spain

Location

Hospital Universitario de Fuenlabrada

Madrid, Spain

Location

Hospital Universitario HM Sanchinarro - CIOCC Clara Campal

Madrid, Spain

Location

Hospital Universitario Puerta de Hierro Majadahonda

Madrid, Spain

Location

Hospital Universitario Ramon Y Cajal

Madrid, Spain

Location

Hospital Universitario Severo Ochoa

Madrid, Spain

Location

Althaia Xarxa Assistencial de Manresa

Manresa, Spain

Location

Hospital de Mataró

Mataró, Spain

Location

Hospital Universitario Regional de Malaga

Málaga, Spain

Location

Hospital Clinico Universitario Virgen de La Arrixaca

Murcia, Spain

Location

Hospital Universitario Son Espases

Palma de Mallorca, Spain

Location

Hospital Universitario Son Llatzer

Palma de Mallorca, Spain

Location

Complejo Hospitalario de Navarra

Pamplona, Spain

Location

Corporació Sanitaria Parc Taulí

Sabadell, Spain

Location

Hospital Universitario de Canarias

Santa Cruz de Tenerife, Spain

Location

Hospital Universitario Nuestra Señora de la Candelaria

Santa Cruz de Tenerife, Spain

Location

Hospital Universitario Virgen de Valme

Seville, Spain

Location

Hospital Universitario Virgen Del Rocio

Seville, Spain

Location

Hospital Universitario Virgen Macarena

Seville, Spain

Location

Hospital Universitario Sant Joan de Reus

Tarragona, Spain

Location

Hospital de Terrassa - Consorci Sanitari de Terrassa

Terrassa, Spain

Location

Hospital Virgen de la Salud

Toledo, Spain

Location

Consorcio Hospital General Universitario de Valencia

Valencia, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, Spain

Location

Hospital Universitario Arnau de Vilanova de Valencia

Valencia, Spain

Location

Hospital Provincial de Zamora (Complejo Asistencial de Zamora)

Zamora, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, Spain

Location

Tumor Zentrum Aarau

Aarau, Switzerland

Location

Inselspital, Universitätsspital Bern

Bern, Switzerland

Location

Centre du sein Fribourg

Fribourg, Switzerland

Location

Related Publications (1)

• 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.

  PMID: 35465733 RESULT

Related Links

• Spanish Breast Cancer Research Group (GEICAM) is a Spanish Breast Cancer Research Group

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Trastuzumab; Alpelisib; Fulvestrant; Vinorelbine; Capecitabine; eribulin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Study Director

  H. Clínico Universitario Valencia. Valencia, Spain.

  STUDY DIRECTOR

• Study Director

  Istituto Europeo di Oncologia. Milan, Italy.

  STUDY DIRECTOR

• Study Director

  Princess Margaret Cancer Center. Toronto, Canada

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2021
• First Posted: October 1, 2021
• Study Start: September 14, 2021
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: September 8, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (9); AU (8); FR (7); IT (25); ES (54); CH (3)