Personalised Neoantigen-targeting Cancer Vaccine NECVAX-NEO1 in Neoadjuvant Triple-negative Breast Cancer

Inclusion Criteria:

1. Patients able to understand and follow instructions during the trial.

2. Patients able and willing to give written informed consent, signed and dated.

3. Female and male patients.

4. Patients aged at least 18 years old at the time of ICF signature.

5. cT2-4 N0 or any N-positive (stage II-III) triple-negative breast cancer patientsdiagnosed as candidates for neoadjuvant anti-PD1 monoclonal antibody andanthracycline/taxane based chemotherapy

6. Patients with tumor accessible for biopsy and surgery and showing at least 30% oftumoral cells on the biopsy.

7. Patients with adequate bone marrow function at Screening, confirmed at Baseline,including:

8. ANC ≥ 1.5 × 109/L; patients with documented benign cyclical neutropenia areeligible if white blood cell count is ≥ 1.5 × 109/L, with ANC ≥ 1.0 × 109/L,leukocytes ≥ 4.0 × 109/L, and lymphocytes ≥ 0.6 × 109/L;

9. platelets ≥ 100 × 109/L;

10. hemoglobin ≥ 9 g/dL (may have been transfused);

11. International Normalized Ratio (INR) < 1.5×Upper Limit of Normal (ULN); patientstreated with vitamin K antagonist are eligible if INR < 3.

12. Patients with adequate hepatic function at Screening, confirmed at Baseline, definedby

13. total bilirubin level ≤1.5×ULN; patients with documented Gilbert disease areallowed if total bilirubin ≤3×ULN;

14. aspartate aminotransferase (AST) level ≤2.5×ULN, and alanine aminotransferase (ALT) level ≤2.5×ULN, or, for patients with documented metastatic disease tothe liver, AST and ALT levels ≤5×ULN.

15. Patients with adequate renal function at Screening, confirmed at Baseline, definedby eGFR ≥ 30 mL/min using 2021 CKD-EPI creatinine equation.

16. Patients must be able to undergo MRI/Ultrasound imaging procedures for tumorfollow-up.

17. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

18. Life expectancy of at least 12 months according to the Investigator's judgement.

Exclusion Criteria:

Medical and surgical history, and diseases

1. Patients with a history of any disease, metabolic dysfunction, physical examinationfinding, or clinical laboratory finding that, based on the Investigator's judgement,provides a reasonable suspicion of a disease or condition that contraindicates theuse of the IMP or that might affect the interpretation of the trial results orrender the patient at high risk for treatment complications.

2. Patients with CTCAE v 5.0 Grade 3 or higher not having resolved to Grade 1 within 6weeks before Baseline.

3. Patients with any significant co-morbidity which, according to the Investigator'sjudgement, makes patient compliance to trial conditions unlikely.

4. Patients with previous malignant disease (other than the tumor disease for thistrial) within the last five (5) years (except adequately treated non-melanoma skincancers and carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, orprostate) unless a complete remission without further recurrence was achieved atleast two (2) years prior to Screening, and the patient is deemed to have been curedwith no additional therapy required or anticipated to be required.

5. Patients who underwent prior organ transplantation, including allogeneic stem celltransplantation.

6. Patients with congenital or any other immunodeficiency syndromes, or any activeautoimmune disease that might deteriorate when receiving an immunostimulatory agent,except for: a. Patients with vitiligo, psoriasis, alopecia not requiring immunosuppressivetreatment, are eligible. b. Administration of steroids through a route known to result in a minimal systemicexposure (topical, intranasal, intro-ocular, or inhalation), is acceptable.

7. Patients with history of uncontrolled intercurrent illness, including but notlimited to uncontrolled hypertension (high blood pressure defined as BPD>=140 mmHgor BPS >=90 mmHg despite of combination therapy with diuretic/CCB/ACE or ARB).

8. Patients with a known prior hypersensitivity or contraindications to any of the IMPsor any component in its formulations or any other drug scheduled or likely to begiven during the trial, including known severe hypersensitivity reactions tomonoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3).

9. Patients with severe acute or chronic medical conditions, including

10. Immune colitis

11. Inflammatory bowel disease

12. History of severe vomiting or diarrhea not having resolved to Grade 1 atBaseline

13. Immune pneumonitis

14. Pulmonary fibrosis

15. Psychiatric conditions including recent (within the last year) or activesuicidal ideation or behavior

16. Laboratory abnormalities that may increase the risk associated with trialparticipation or trial treatment administration or may interfere with theinterpretation of trial results and, in the judgement of the Investigator,would make the patient inappropriate for entry into this trial.

17. Patients with a history of small intestine resection surgery or other majorgastrointestinal surgery

18. Patients with active infection requiring systemic therapy with antibiotics (at bothScreening and Baseline).

19. Patients with a known history of human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome or multi-drug resistant gram-negative bacteria.

20. Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection atScreening (positive HBV surface antigen or HCV RNA if anti-HCV antibody Screeningtest positive).

21. Patients with increased anesthesiological risk (e.g. known or predicted difficultairway) if general anesthetic is required .

22. Patients with increased bleeding risk (e.g. coagulopathies) and patients onanticoagulants.

23. Women who are pregnant or breastfeeding, or women of childbearing potential (definedas any woman who is not surgically sterile with a hysterectomy and/or bilateraloophorectomy or ≥ 12 months of amenorrhea and at least 50 years of age) not willingto use highly effective methods of birth control. Highly effective birth control isdefined as follows:

24. combined (estrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation 1: • oral • intravaginal • transdermal

25. progestogen-only hormonal contraception associated with inhibition of ovulation 1: • oral • injectable

• implantable 2

3. intrauterine device (IUD) 2

4. intrauterine hormone-releasing system (IUS) 2

5. bilateral tubal occlusion 2

6. vasectomised partner 2,3

7. sexual abstinence 4

NOTES:

1. Hormonal contraception may be susceptible to interaction with the IMP, which mayreduce the efficacy of the contraception method (see section 4.3)

2. Contraception methods that in the context of this guidance are considered to havelow user dependency.

3. Vasectomised partner is a highly effective birth control method provided thatpartner is the sole sexual partner of the WOCBP trial participant and that thevasectomised partner has received medical assessment of the surgical success.

4. In the context of this guidance sexual abstinence is considered a highly effectivemethod only if defined as refraining from heterosexual intercourse during the entireperiod of risk associated with the study treatments. The reliability of sexualabstinence needs to be evaluated in relation to the duration of the clinical trialand the preferred and usual lifestyle of the subject.

Males of child-bearing potential are to use a highly effective method of birth control to avoid pregnancy with any partner during the study and until the end of the Follow-up period (EoT) or 30 calendar days after the last dose of IMP.

17. Patients with a known history of drug/substance abuse.

Prior and concomitant medication

18. Patients who received any live vaccines within 30 days prior to trial treatment.

19. Patients participating Treatment in any other clinical trial within 30 days beforeScreening.

20. Patients receiving any other treatment that, in the opinion of the Investigator,might interfere with the trial

21. Patients with a current drug or substance abuse.

22. Patients with chronic concurrent therapy within 2 weeks before the trial treatmentor expected therapy during the trial treatment period with:

23. Corticosteroids (except systemic corticosteroids up to 10 mg prednisolone orequivalent daily dose).

24. Immunosuppressive agents.

25. Antibiotics. Any other anticancer therapy or concurrent anticancer treatment exceptthe neoadjuvant chemotherapy / anti-PD1 checkpoint inhibitor standard of carebackground therapy as per study protocol.

Other 23. Patients unable to understand the Protocol requirements, instructions and trial-related restrictions, the nature, scope, and possible consequences of the trial.

24. Patients who are unlikely to comply with the Protocol requirements, instructions andtrial-related restrictions, e.g., uncooperative attitude, inability to return forfollow-up visits, and improbability of completing the trial.

25. Patients with legal incapacity or limited legal capacity. 26. Patients with anycondition which results in an undue risk for the patient during the trialparticipation according to the Investigator.