PHESGO Maintenance After T-DXd Short Induction for HER2+ Unresectable Locally Recurrent or Metastatic Breast Cancer

Inclusion Criteria:

To be eligible to participate in this trial, an individual must meet ALL the following criteria:

1. Patient must be capable to understand the purpose of the study and have signedwritten informed consent form (ICF) prior to beginning specific protocol procedures.

2. Male or female patients ≥ 18 years of age at the time of signing ICF.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

4. Life expectancy of ≥ 12 weeks at screening.

5. Evidence of HER2-overexpressing tumor status confirmed by any MEDSIR's designatedcentral lab or patient has a pathology report confirming HER2-overexpression bylocal testing, preferably on the most recent available metastatic sample. In thelatest case, tumor tissue or blood must be sent to any MEDSIR's designated centrallab for confirmation of HER2 status. Analysis of the primary tumor sample will beaccepted if the metastatic tissue is inaccessible.

6. Must have known estrogen receptor (ER) and progesterone receptor (PgR) statuslocally determined prior to study entry.

7. Unresectable locally recurrent or MBC documented by computerized tomography (CT)scan or magnetic resonance imaging (MRI) that is not amenable to resection withcurative intent.

8. Evaluable disease as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v.1.1) criteria.

9. Willingness and ability to provide the most recently available formalin-fixedparaffin-embedded (FFPE) tumor tissue blocks at the time of the inclusion (mandatory). If archival tissue is not available, a newly obtained baseline biopsyof an accessible tumor lesion is required prior to start of study treatment.

10. No prior chemotherapy and/or HER2-targeted therapy for advanced disease (one priorline of endocrine therapy is allowed for MBC).

11. May have received adjuvant or neoadjuvant chemotherapy and/or HER2-targeted therapybefore study treatment initiation, with a disease-free interval (DFI) fromcompletion of the systemic treatment (excluding hormonal therapy) to metastaticdiagnosis of at least 12 months.

12. Adequate hematologic and organ function, defined by the following:

13. Hematological (without platelet, red blood cell transfusion, and/or granulocytecolony-stimulating factor support within seven days before first studytreatment dose): White blood cell (WBC) count > 3.0 x 109/L, absoluteneutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x 109/L, andhemoglobin (Hb) ≥ 9.0 g/dL.

14. Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times the upper limitof normal (x ULN) (≤ 3 x ULN in patients with known history of Gilbert'sdisease); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 × ULN in patients withliver and/or bone metastases); aspartate transaminase (AST) and alaninetransaminase (ALT) ≤ 1.5 x ULN (≤ 3 x ULN in patients with liver metastases).

15. Renal: Creatinine clearance ≥ 50 mL/min as determined by Cockcroft Gault (usingactual body weight).

16. Coagulation: International normalized ratio or prothrombin time and eitherpartial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.

17. Resolution of all acute toxic effects of prior anticancer therapy to grade ≤ 1 asdetermined by the NCI-CTCAE v.5.0 criteria (except for alopecia or other toxicitiesnot considered a safety risk for the patient at Investigator's discretion).

18. For women of childbearing potential who are sexually active with a non-sterilizedmale partner: must have a negative serum pregnancy test within 14 days before studytreatment initiation. In addition, agreement to remain abstinent (refrain fromheterosexual intercourse) or use one highly effective method of birth control or twoeffective contraceptive methods, as defined in the protocol from the time ofscreening until 7 months after the last dose of study treatments. Female patientsmust agree to refrain from egg cell donation and breastfeeding during this sameperiod.

19. Male participants who intend to be sexually active with a female partner ofchildbearing potential must be surgically sterile or use highly effectivecontraceptive methods, or two effective contraceptive methods, as defined in theprotocol from the time of screening until 4 months after the last dose of T-DXd or 7months after the last dose of PHESGO to prevent pregnancy in a partner. Maleparticipants must not donate or bank sperm during this same period. Not engaging inheterosexual activity (sexual abstinence) for the duration of the study and drugwashout period is an acceptable practice if this is the preferred usual lifestyle ofthe participant the last dose of study treatments.

20. Patient must be accessible for treatment and follow-up.

Exclusion Criteria:

An individual who meets ANY of the following criteria will be excluded from participation in this trial:

1. Current participation in another therapeutic clinical trial, except othertranslational studies.

2. Treatment with approved or investigational cancer therapy within 14 days prior toinitiation of study drugs.

3. Has previously been treated with T-DXd in the adjuvant or neoadjuvant setting.

4. Known active uncontrolled or symptomatic central nervous system (CNS) metastasesand/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema,and/or progressive growth. Note: Patients with a history of CNS metastases are eligible if they have beenpreviously treated with local therapy, are clinically stable, and offanticonvulsants and steroids for at least 14 days before the first dose of studytreatment.

5. Concurrent malignancy or malignancy within 5 years of study enrollment with theexception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stageI uterine cancer. For other cancers considered to have a low risk of recurrence,discussion with the Sponsor's Medical Monitor is required.

6. Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances.

7. Palliative radiotherapy with a limited field of radiation within 2 weeks or withwide field of radiation or to more than 30% of the bone marrow within 4 weeks priorto start of study treatment.

8. Major surgical procedure or significant traumatic injury within 14 days before thefirst dose of study treatment or anticipation of need for major surgery within thecourse of the study treatment.

9. Has an active cardiac disease or a history of cardiac dysfunction or severeconduction abnormalities including, but not confined, to any of the following:

10. Unstable angina pectoris, documented myocardial infarction, or symptomaticcardiac heart failure (CHF) (New York Heart Association [NYHA] Class II-IV)within six months prior to study entry.

11. Poorly controlled hypertension (i.e., systolic blood pressure ≥ 180 mmHg ordiastolic blood pressure ≥ 100 mmHg).

12. Symptomatic pericarditis.

13. Left ventricular ejection fraction (LVEF) < 55 % as determined by multigatedacquisition (MUGA) scan or echocardiogram (ECHO).

14. History of arrhythmia (multifocal premature ventricular contractions, bigeminy,trigeminy, or ventricular tachycardia), which is symptomatic or requirestreatment (NCI-CTCAE grade 3), symptomatic or uncontrolled atrial fibrillationdespite treatment, asymptomatic sustained ventricular tachycardia, orhigher-grade atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz 2] or third-degree AV-block). Participants with atrial fibrillationcontrolled by medication or arrhythmias controlled by pacemakers will bepermitted to enroll.

15. QT Interval Corrected by Fridericia's formula (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead ECG.

16. History of QT prolongation associated with other medications that requireddiscontinuation of that medication, or any current concomitant medication knownto prolong the QT interval and cause Torsades de Pointes.

17. Congenital long QT syndrome, family history of long QT syndrome, or unexplainedsudden death under 40 years of age in first-degree relatives.

18. Clinically severe pulmonary compromise resulting from intercurrent pulmonaryillnesses including, but not limited to, any underlying pulmonary disorder (e.g.,pulmonary emboli within three months of the study enrolment, severe asthma, severechronic obstructive pulmonary disease [COPD], restrictive lung disease, pleuraleffusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connectivetissue or inflammatory disorders with pulmonary involvement (e.g., rheumatoidarthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.

19. Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis thatrequired steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitisthat cannot be ruled out by imaging at screening.

20. Pregnant or lactating women or patients not willing to apply highly effectivecontraception as defined in the protocol.

21. Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV).Patients with past HBV infection or resolved HBV infection (defined as having anegative hepatitis B surface antibody [HBsAg] test and a positive hepatitis B coreantibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible.Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

22. Has active primary immunodeficiency, known human immunodeficiency virus (HIV)infection.

23. Other active uncontrolled infection at the time of enrollment.

24. Receipt of live or attenuated vaccine within 30 days prior to the first dose ofstudy treatment.

25. A history of uncontrolled seizures, CNS disorders or serious and/or unstablepre-existing psychiatric disability judged by the investigator to be clinicallysignificant and adversely affecting compliance to study drugs or interfering withsubject safety.

26. Has any other concurrent severe and/or uncontrolled medical condition that would, inthe Investigator's judgment contraindicate patient participation in the clinicalstudy.

27. Known substance abuse or any other concurrent severe and/or uncontrolled medicalcondition that would, in the investigator's judgment, contraindicate patientparticipation.

28. Inability or unwillingness to comply with study and follow-up procedures in theopinion of the Investigator.