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

Inclusion Criteria:

Patients are eligible to be enrolled for randomization in the study only if they meet all of the following criteria:

1. Written informed consent prior to any specific study procedures, showing patientwillingness to comply with all study procedures.

2. Histologically or cytologically documented locally recurrent inoperable ormetastatic breast cancer with HER2+ status based on local laboratory determination,preferably on the most recent available FFPE tumor sample, and according to AmericanSociety of ClinicalOncology (ASCO)/College of American Pathologists (CAP)international guidelines valid at the time of the assay. In case of discordance inHER2+ status in different biopsies, we will consider the result from the most recentbiopsy one will be used.

3. Documented HR status based on local laboratory, preferably on the most recentavailable FFPE tumor sample, and according to ASCO/CAP international guidelinesvalid at the time of the assay. In case of discordance in HR status in differentbiopsies, the result from the most recent biopsy will be used. HR+ will be definedas ≥1% positive cells by immunohistochemistry for Estrogen Receptor (ER) and/orProgesterone Receptor (PgR). HR- will be defined as <1% positive cells byimmunohistochemistry for both ER and PgR. Considering that there are limited data onendocrine 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 eligiblefor inclusion in the HR- cohort.

4. Patients with a PIK3CA tumor mutation at central laboratory determination,preferably on the most recent available FFPE tumor sample.

5. At least 1 but no more than 5 prior lines of anti-HER2 based therapy for metastaticbreast cancer (MBC). Maintenance therapy will not count as an additional line oftherapy.

6. 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 6months after completing adjuvant trastuzumab).

7. Female or male patient is at least 18 years of age.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

9. Patients can be either males or premenopausal/perimenopausal or postmenopausalfemales. In the HR+ cohort, males and females who are not post-menopausal must havebeen on a gonadotropin-releasing hormone (GnRH) agonist (e.g. goserelin orleuprorelin) 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, plasmaestradiol is ≥ 10 pg/mL and follicle-stimulating hormone (FSH) ≤ 40 IU/l or inthe 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 laboratorydefinition. Postmenopausal status is defined as either:

• Natural (spontaneous) amenorrhea lasting more than 12 months and either agefrom49 to 59 years and/or history of vasomotor symptoms (e.g., hot flush) inthe absence of other medical justification, or Levels of plasma estradiol ≤ 20pg/mL and follicle-stimulating hormone (FSH) ≥ 40 IU/l or in the postmenopausalrange, according to local laboratory definition, or Surgical bilateraloophorectomy. Perimenopausal status is defined as neither premenopausal nor postmenopausal.

10. Measurable disease or at least one evaluable bone lesion, lytic or mixed (lytic+blastic), which has not been previously irradiated and is assessable bycomputer tomography (CT)/magnetic resonance imaging (MRI) in the absence ofmeasurable disease according to RECIST 1.1 criteria.

11. Life expectancy ≥ 12 weeks.

12. 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 significantby the investigator.

• Creatinine <1.5 x upper limit of normal (ULN) or creatinine Clearance ≥ 35mL/min using Cockcroft-Gault formula (if creatinine is ≥1.5 ULN).

• Total bilirubin < 2 x ULN (any elevated bilirubin should be asymptomatic atenrollment) except for patients with Gilbert's syndrome who may only beincluded 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 xULN. If patient has liver metastasis, AST and ALT ≤ 5.0 x ULN (elevated AST or AST valuesmust 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 glycosylatedhemoglobin (HbA1c) < 6.5%.

13. Resolution of all acute toxic effects of prior anti-cancer therapy or surgicalprocedures to NCI-CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicitiesnot considered a safety risk for the patient at investigator´s discretion).

14. Adequate cardiac function as defined by left ventricular ejection fraction (LVEF) of ≥ 50% measured by echocardiography or multi-gated acquisition (MUGA) scans.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Have received more than 5 previous lines of anti-HER2 based therapy for MBC, orprior fulvestrant.

2. Symptomatic visceral disease or any disease burden that makes the patient ineligiblefor experimental therapy per the investigator's best judgment.

3. Symptomatic central nervous system (CNS) metastases. However, patients with CNSmetastases who have been adequately treated, are asymptomatic and do not requirecorticosteroid or anti-epileptic medication are eligible.

4. Presence of leptomeningeal carcinomatosis.

5. Other invasive malignancy (different from the current breast cancer) at the time ofenrollment or previous diagnosis of a completely removed malignancy within 3 yearsprior to randomization except for adequately treated (including complete surgicalremoval) of International Federation of Gynecology and Obstetrics (FIGO) stage Igrade 1 endometrial cancer, basal or squamous cell carcinoma of the skin, thyroidcancer limited to thyroid gland, in situ carcinoma of the cervix, and grade 1-2early stage bladder cancer defined as T1 or less, without nodal involvement (N0).

6. Patients with an established diagnosis of diabetes mellitus type I or not controlledtype II (FPG ≥ 140 mg/dL [7.7 mmol/L] or HbA1c ≥ 6.5%), or history of gestationaldiabetes (as per American College of Obstetricians and Gynecologists (ACOG)guidelines) or documented steroid-induced diabetes mellitus.

7. Prior treatment with any mTOR, AKT or PI3K inhibitor.

8. 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).

9. Patients who received before randomization:

• Any investigational agent within 4 weeks.

• Chemotherapy within a period of time that is shorter than the cycle durationused 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 priorto starting study treatment.

• Corticosteroids within 2 weeks prior to starting study treatment. Note: thefollowing uses of corticosteroids are permitted at any time: single doses,topical applications(e.g., for rash), inhaled sprays (e.g., for obstructiveairways diseases), eye drops or local injections (e.g., intra-articular).

• Radiotherapy within 2 weeks prior to starting study treatment (all acute toxiceffects must be resolved to NCI-CTCAE version 5.0 grade <1, except toxicitiesnot considered a safety risk for the patient at investigator´s discretion).Patients who received prior radiotherapy to >25% of bone marrow are noteligible regardless of when it was administered.

• Major surgery or other anti-cancer therapy not previously specified within 4weeks prior to starting study treatment, (all acute toxic effects, includingperipheral neurotoxicity must be resolved to NCI-CTCAE version 5.0 grade ≤ 1,except toxicities not considered a safety risk for the patient at theinvestigator´s discretion).

10. Patient has clinically significant, uncontrolled heart disease and/or recent cardiacevents including any of the following:

• History of angina pectoris, coronary artery bypass graft (CABG), symptomaticpericarditis or myocardial infarction within 6 months of randomization.

• History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV).

• Clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia),complete left bundle branch block, high grade AV block (e.g. bifascicularblock, Mobitz type II and third degree AV block without pacemaker in place).

• Uncontrolled hypertension defined by a Systolic Blood Pressure ≥ 160 mmHgand/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or withoutanti-hypertensive medication. Initiation or adjustment of antihypertensivemedication(s) is allowed prior to screening.

• Long QT syndrome, family history of idiopathic sudden death or congenital longQT 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 notinterpretable) or QTcF > 460 msec for females (using Fridericia's correction).All as determined by screening ECG.

11. Bleeding diathesis (i.e., Disseminated Intravascular Coagulation (DIC), clottingfactor deficiency) or long-term (> 6 months) anticoagulant therapy, other thanantiplatelet therapy and low dose coumarin derivatives, provided that theInternational Normalised Ratio (INR) is less than 1.5.

12. History of clinically significant bowel disease including abdominal fistula, orgastrointestinal perforation.

13. Difficulties to swallow tablets, malabsorption syndrome disease significantlyaffecting gastrointestinal function, resection of the stomach or small bowel, oractive inflammatory bowel disease (e.g., ulcerative diseases).

14. Known hypersensitivity to trastuzumab, alpelisib or fulvestrant or any of theirexcipients. If known hypersensitivity to either vinorelbine, capecitabine, eribulinor any of their excipients, patient will be eligible as long as the investigator'schoice avoids that drug in the control arm. If known hypersensitivity to all three cytostatics (vinorelbine, capecitabine anderibulin), the patient will not be eligible.

15. Known positive serology for Human Immunodeficiency Virus (HIV), or active infectionfor hepatitis B or hepatitis C.

16. Other severe acute or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation or studytreatment administration or may interfere with the interpretation of study resultsand, in the judgment of the investigator, would make the patient inappropriate forentry into this study.

17. Patients with currently documented pneumonitis/interstitial lung disease (the chestComputed Tomography [CT] scan performed at screening for the purpose of tumorassessment should be reviewed to confirm that there are no relevant pulmonarycomplications present).

18. Patient with liver disease with a Child Pugh score B or C.

19. Patient with a history of acute pancreatitis within 1 year of screening or pastmedical history of chronic pancreatitis.

20. Patient has a history of Steven-Johnson-Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN).

21. Patient is nursing (lactating) or is pregnant as confirmed by a positive serum humanChorionic Gonadotropin (hCG) test prior to initiating study treatment.

22. Patient is a woman of child-bearing potential or a partner of a woman ofchild-bearing potential, unless agreement to remain abstinent or use single orcombined 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 doseof study treatment, except for patients receiving fulvestrant in which this periodshould be of at least 2 years.

• Abstinence is only acceptable if it is in line with the preferred and usuallifestyle of the patient.

• Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpost-ovulation methods) and withdrawal are not acceptable methods ofcontraception.

• Examples of non-hormonal contraceptive methods with a failure rate of < 1% peryear include tubal ligation, male sterilization (only if he is the sole partnerand have been performed at least 6 months prior to screening), and certainintrauterine devices.

• Alternatively, two methods (e.g., two barrier methods such as a condom and acervical 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 periodspecified above.