PIK3CA/PTEN-altered Advanced Breast Cancer Treated With MEN1611 Monotherapy or in Combination With Eribulin

General inclusion criteria

PRE-SCREENING PHASE

The following criteria must be met to be eligible to entry into the pre-screening:

1. Patient must be able to sign written pre-screening form prior to any moleculardetermination during the pre-screening phase.

2. Being male or female aged ≥ 18 years.

• Histologically confirmed metaplastic or non-metaplastic TNBC as per localassessment. or

• Histologically confirmed HR-positive/HER2-negative metaplastic breast cancer

4. Known HR status according to the updated American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2020 guidelines and HER2-negativebreast cancer (BC) as per ASCO/CAP 2018 criteria based on local testing on the mostrecently analyzed biopsy.

5. Prior treatment with at least one, but no more than four, prior lines of systemictherapy for advanced disease. Earlier adjuvant or neoadjuvant therapy for morelimited disease will be considered as one of the required prior regimens if thedevelopment of unresectable locally advanced metastatic disease occurred within a 6-month period after completion of chemotherapy.

6. No prior treatment with a PI3K/AKT/mTOR inhibitors, nor with eribulin.

7. Patient must consent to give a tumor sample or/and a blood sample for testing of theprior mentioned alterations (or if needed and deemed safe by the Investigator, ableto provide a fresh tumor sample).

8. Unknown PIK3CA mutational and/or PTEN loss status. SCREENING PHASE Patients must meet inclusion criteria 2 to 7 of the pre-screening phase and thefollowing inclusion criteria of the screening phase to be eligible for enrollmentinto the Study:

9. Patient must be able to sign written main informed consent form (ICF) prior toparticipation in any Study-related activities.

10. Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 whichthe Investigator believes is stable at the time of screening.

11. Life expectancy greater or equal to 12 weeks.

12. Unresectable locally advanced/metastatic HR-positive/HER2-negative metaplasticbreast cancer or triple negative breast cancer documented by computed tomography (CT) scan or magnetic resonance imaging (MRI), that is not amenable to resectionwith curative intent.

13. Patient has a PIK3CA mutation confirmed by MEDSIR's designated central lab,determined in the pre-screening phase or patient has a pathology report confirmingPIK3CA mutant status by a certified laboratory (using validated PIK3CA mutationassay) either from tissue or blood, And/or Patient has evidence of PTEN loss by immunohistochemistry (IHC) confirmed byMEDSIR's designated central lab in the pre-screening phase or patient has apathology report confirming PTEN loss by a certified laboratory, preferably on themost recent available tumor sample. Note: PI3KCA mutations should have been evaluated at least at hot spots, E542, E545and H1047. PTEN staining should have been evaluated by assessing both intensity of staining andpercentage of positive cells. Both nuclear and cytoplasmic staining should beevaluated. Staining of normal cells such as benign breast epithelium, stromal cellsand/or endothelial cells should have been evaluated as an internal control. Anytumor nuclear or cytoplasmic staining showing similar intensity with internalcontrol cells should have been considered positive staining (no PTEN loss). Completelack of staining or faint staining (cytoplasmic or nuclear) in up to 50% of tumorcells should have been considered as PTEN loss. If there was no staining in internalcontrol cells, the staining should have been considered inconclusive.

14. Patients with clinically stable metastatic central nervous system (CNS) tumors areeligible if:

15. Stereotactic radiotherapy ≥ 7 days prior to initiation of study treatment.

16. Whole-brain radiotherapy ≥ 7 days prior to initiation of study treatment.

17. Neurosurgical resection ≥ 28 days prior to initiation of study treatment.

18. Not receiving steroid therapy or anticonvulsant at Baseline.

19. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 asdetermined by the US National Cancer Institute-Common Terminology Criteria forAdverse Events (NCI-CTCAE) version 5.0 (v.5.0). Note: Except for alopecia or other toxicities not considered a safety risk for thepatient at Investigator's discretion.

20. Available archival tumor sample (formalin-fixed paraffin-embedded [FFPE] tissue) ofthe most recent biopsy/surgery since last progression. Note: Subjects for whom the most recent tumor biopsy since last progression couldnot be obtained (e.g., inaccessible tumor or subject safety concern) may submitarchival pathological material from either metastatic or primary sites.

21. Adequate hematologic and organ function within 14 days before the first Studytreatment on Day 1 of Cycle 1, defined by the following:

22. Hematological (without platelet, red blood cell transfusion, and/or granulocytecolony-stimulating factor support within 7 days before first Study treatmentdose): 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 (≥ 5.6 mmol/L).

23. Hepatic: Serum albumin ≥ 3 g/dL; total bilirubin ≤ 1.5 times the upper limit ofnormal (ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartatetransaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case ofliver metastases ≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN inthe case of liver and/or bone metastases).Note: If total bilirubin is increased, assessment of direct bilirubin levels isrecommended.

24. Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min basedon Cockcroft-Gault glomerular filtration rate estimation.

25. Urinalysis: including dipstick (specific gravity, pH, glucose, protein,ketones, and blood) and microscopic examination (sediment, red blood cells [RBCs], WBCs, casts, crystals, epithelial cells, and bacteria).

26. For women of childbearing potential: agreement to remain abstinent (must refrainfrom heterosexual intercourse) or use highly effective contraceptive methods, or twoeffective contraceptive methods, as defined in the clinical study protocol (CSP),during the treatment period and for at least 7 months after the last dose of Studytreatment, whichever is longer. Women of childbearing potential must have a negativeserum pregnancy test within 7 days before Study treatment initiation and must agreeto refrain from donating eggs during the entire Study treatment period and for 3months after the last administration of the Study drug.

27. Being male subjects, surgically sterile or having agreed with true abstinence (mustrefrain from heterosexual intercourse), or whose female partners are willing toagree with true abstinence or use barrier contraceptive measures as defined in theCSP during the entire Study treatment period and for 7 months after the lastadministration of the Study drug. Males must agree to refrain from donating spermduring the entire Study treatment period and for 3 months after the lastadministration of the Study drug.

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

29. Measurable, or non-measurable but evaluable, disease as defined by the local siteInvestigator as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) criteria.

Note: Patients with bone lesions as the only sites of metastatic disease are eligible.

Exclusion criteria:

Any patient meeting ANY of the following criteria will be excluded from the Study:

1. Current participation in another therapeutic clinical trial.

2. Extra-cranial radiotherapy or limited-field palliative radiotherapy within 7 daysprior to Study enrolment, or patients who have not recovered fromradiotherapy-related toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% ofthe bone marrow has been previously irradiated.

3. Major surgery (defined as requiring general anesthesia) or significant traumaticinjury within 21 days of start of Study drug, or patients who have not recoveredfrom the side effects of any major surgery.

4. Patient with a concurrent malignancy or malignancy within 5 years of Studyenrollment except for carcinoma in situ of the cervix, non-melanoma skin carcinoma,or stage I uterine cancer. Note: For other cancers considered to have a low risk of recurrence, discussion withthe Medical Monitor is required.

5. Treatment with approved chemotherapy/immunotherapy/ targeted agents within 21 daysprior to initiation of Study, or treatment with an investigational cancer therapyfor 21 days or 5 half-lives (whichever is longer) prior to initiation of any Studytreatment.

6. Patient with cerebrovascular accident or transient ischemic attack within 6 monthsprior to the start of any Study treatment.

7. Congenital long QT syndrome or screening QT interval corrected using Fridericia'sformula (QTcF) > 480 milliseconds.

8. Patient with an active cardiac disease or a history of cardiac dysfunction orconduction abnormalities including any of the following:

• Unstable angina pectoris or documented myocardial infarction within 6 monthsprior to Study entry.

• Symptomatic pericarditis.

• Documented congestive heart failure (New York Heart Association functionalclassification III- IV).

• Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gatedacquisition (MUGA) scan or echocardiogram (ECHO).

• Ventricular arrhythmias except for benign premature ventricular contractions.

• Supraventricular and nodal arrhythmias requiring a pacemaker or not controlledwith medication.

• Conduction abnormality requiring a pacemaker.

• Other cardiac arrhythmia not controlled with medication.

9. Patient with uncontrolled hypertension.

10. Uncontrolled diabetes mellitus (glycated haemoglobin [HbA1c] >7%) and/or fastingplasma glucose (FPG) >120 mg/dL or 6.7 mmol/L. Note: Patients who have diabetes mellitus adequately managed regardless FPG or HbA1cmay be considered eligible as per the Medical Monitor assessment and criteria.

11. Known concurrent severe and/or uncontrolled concomitant medical conditions (i.e.influenza or any other active infections) that could cause unacceptable safety risksor compromise compliance with the protocol.

12. Known active or uncontrolled pulmonary dysfunction.

13. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBVinfection (defined as having a negative hepatitis B surface antigen [HBsAg] test anda positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNAtest) are eligible. Patients positive for HCV antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV RNA.

14. Known hypersensitivity reaction to any investigational or therapeutic compound ortheir incorporated substances.

15. Patient with serious and/or unstable pre-existing psychiatric or neurologic illnessor other conditions that could interfere with subject safety.

16. History of significant gastrointestinal disease, including but not limited toabdominal fistula, gastrointestinal perforation or other malabsorption syndromesthat would impact on drug absorption. Grade ≥2 diarrhea should resolve at least 7days prior to the start of any Study treatment.

17. Subject receiving chronic treatment with steroids, as immunosuppressant, or anotherimmunosuppressive agent.

18. Subject receiving treatment with drugs known to be moderate and strong inhibitors orinducers of isoenzyme CYP3A as well as moderate or strong inducers of CYP1A2 within 2 weeks of the first administration of MEN1611.

19. Breastfeeding or pregnancy as determined by a serum pregnancy test (β-HCG) atscreening, prior to the administration of MEN1611 in combination with eribulin.Since β-HCG over expression can be also elevated in some tumor types, a positiveresult should be confirmed with a validated alternative test (e.g., ultrasound).