A Study of Allogenic Natural Killer Cells in Combination With Trastuzumab and Pertuzumab in Adult Patients With Refractory Metastatic Her2 Positive Breast Cancer. NK-ACT-BC_2020

Patient Inclusion Criteria:

1. Histologically confirmed locally advanced and/or metastatic breast adenocarcinomasthat have progressed on standard therapy (must have received pertuzumab,trastuzumab, and ado-trastuzumab emtansine in the neoadjuvant, adjuvant, ormetastatic setting) and have received at least two lines of therapy in themetastatic setting. Prior neoadjuvant or adjuvant therapy presenting relapse within 6 months of completion will be considered as a line of treatment for metastaticdisease. Hormonal therapies will not be considered as previous lines of therapy.Eligible patients must have progressed while on or following the most recent line oftherapy.

2. Patient's provision of signed Informed Consent.

3. Patient has potential allogenic donors (alive parents, siblings, patient´s couple orchildren aged ≥ 18 years) who provide signed Donor Informed Consent. A trialphysician will address the suitability of the identified allogenic relative as anoptimal candidate.

4. Age ≥ 18 years.

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

6. Life expectancy ≥ 3 months.

7. Ability to comply with the protocol requirements.

8. Patients must have clinically and/or radiographically documented measurable disease.At least one lesion must be measurable as per RECIST v.1.1. Previously irradiatedlesions must not be counted as target lesions unless there has been demonstratedprogression in the lesion and no other target lesions are available. Tumors must be accessible for pre-planned biopsies. Lesions that are intended to bebiopsied must not be counted as target lesions.

9. Adequate hematologic and organ function defined by the following laboratory resultsobtained within 7 days prior to the first study treatment (cyclophosphamide dose):

• ANC ≥1.500 cells/microL o Lymphocyte count ≥ 1.000 cells/microL

• Platelet count ≥ 100.000 cells/microL

• Hemoglobin ≥ 9.0 g/dL (patients may be transfused to meet this criterion atleast 7 days before).

• Total bilirubin ≤ 1.5 x ULN (except for patients with known Gilbert's syndromeand serum bilirubin level ≤ 3 x ULN).

• AST and ALT ≤ 3 x ULN (except for patients with documented liver metastases, inwhich case AST and ALT is allowed up to ≤ 5 x ULN).

• Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min based on theCockcroft-Gault glomerular filtration rate estimation.

• INR ≤ 1.5 x ULN

• Serum albumin ≥ 25 g/dL

10. Female patient of childbearing potential must have a negative pregnancy test (serum)within 7 days prior to the first study drug administration and agreement to remainabstinent or use of contraceptive measures that result in a failure rate of <1%/year (bilateral tubal ligation, male sterilization, established proper use of hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterine devices,copper intrauterine devices) during the treatment period or within 12 months afterthe administration of cyclophosphamide, 7 months after the last dose of trastuzumab,or 6 months after the last dose of pertuzumab, whichever occurs last.

A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a post-menopausal state (>12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of both ovaries and/or uterus).

Patient Exclusion Criteria:

1. Other primary cancers apart from non-melanoma localized skin cancer, carcinoma insitu of the cervix, localized prostate cancer or ductal in situ carcinoma of thebreast treated surgically, or prior cancer treated with curative intent at leastmore than 3 years ago and with no evidence of relapse.

2. Major surgical procedures within 4 weeks prior to the cyclophosphamide dose, oranticipation of need for a major surgical procedure during the course of the study.

3. Less than 3 weeks since last dose of approved systemic anti-cancer therapy (chemotherapy, hormonal therapy, tyrosine kinase inhibitors, immunotherapy,radiotherapy) prior to the cyclophosphamide dose. Less than 6 weeks since last doseof mitomycin C and nitrosoureas. However, non-extended palliative radiotherapy forbone metastases ≤ 2 weeks prior to the cyclophosphamide dose is allowed.

4. Treatment with investigational agent within 4 weeks prior to the cyclophosphamidedose.

5. Prior treatment with adoptive cellular therapy.

6. History of severe allergic, anaphylactic or other hypersensitivity reactions totrastuzumab and/or pertuzumab.

7. Prior G4-3 toxicity to trastuzumab and/or pertuzumab.

8. Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1,except for any grade of alopecia.

9. Administration of a live attenuated vaccine within 4 weeks before thecyclophosphamide dose.

10. Signs or symptoms of systemic infection within 2 weeks prior the cyclophosphamidedose (requiring antibiotics).

11. Patients with active tuberculosis, patients with HIV infection or syphilis, activechronic or acute hepatitis B infection or hepatitis C infection, herpes simplexvirus, cytomegalovirus, HTLV or Epstein-Barr virus infection. Patients with priorallogenic bone marrow transplantation or prior solid organ transplantation.

12. Systemic steroid therapy or other immune-suppressants or immune-stimulatory agents (including but not limited to prednisone, azathioprine, methotrexate, thalidomide,anti-TNF agents) within 4 weeks prior to the cyclophosphamide dose.

13. Patients who have received acute, low-dose dexamethasone for nausea, may be enrolledafter discussion with the principal investigator.

14. The use of inhaled corticosteroids or mineralocorticoids for orthostatichypotension/adrenocortical insufficiency (not related with autoimmune disease) isallowed.

15. Corticosteroids as premedication in case of dye allergy prior to imaging tests areallowed.

16. History of autoimmune diseases including but not limited to systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated to antiphospholipid syndrome, granulomatosis, Sjögren's syndrome,multiple sclerosis, vasculitis or glomerulonephritis. Any other potential autoimmunedisorders may be accepted after consultation with the principal investigator.

• Patients with history of autoimmune hypothyroidism on a stable dose of thyroidreplacement hormone may be eligible.

• Patients with controlled type 1 diabetes mellitus on a stable insulin regimenmay also be eligible.

17. New York Heart Association (NYHA) functional class ≥ 2, history within the past 6months of myocardial infarction, unstable angina, coronary artery bypass grafting orstenting, stroke or clinically-significant cardiac arrhythmia (isolated bundlebranch blockade in an ECG is not considered relevant).

18. Uncontrolled (persistent) hypertension defined as systolic blood pressure (SBP) >180mmHg or diastolic blood pressure (DBP) >100 mmHg.

19. LVEF < 50% by echocardiogram or multi-gated acquisition (MUGA) scan.

20. Uncontrolled pleural effusion, pericardial effusion, or ascites that requiresrecurrent drainage procedures (once monthly or more frequently).

21. Known hereditary or acquired coagulopathies (e.g., hemophilia, von Willebrand'sdisease, cancer-associated diffuse intravascular coagulation).

22. Concomitant treatment with therapeutic anticoagulants (oral, heparin). Low dosemolecular weight heparin for prophylactic purposes is allowed.

23. Current dyspnea at rest due to complications of advanced malignancy or requirementfor continuous oxygen therapy.

24. Known primary CNS malignancy or symptomatic or untreated CNS metastases. Patientswith asymptomatic or treated CNS metastases may be enrolled after consultation withthe Medical Monitor, provided they have improved upon completion of CNS-directedtherapy (radiotherapy or surgical removal).

25. Pregnancy or lactation within the past 3 months and throughout the trial.

26. Substance abuse, medical, psychological, or social conditions that may interferewith the subject's participation in the trial or, as per the investigator'sjudgment, may jeopardize the interpretation of the results or render the patient athigh risk from treatment complications.