Intratumoral INT230-6 Followed by Neoadjuvant Immuno-chemotherapy in Patients With Early TNBC. INVINCIBLE-4-SAKK

Inclusion Criteria:

• Written informed consent according to country specific law and ICH GCP E6(R2)regulations before registration and prior to any trial specific procedures.

• Newly histologically diagnosed, previously untreated locally advanced non-metastaticTNBC as defined by the most recent American Society of Clinical Oncology (ASCO) /College of American Pathologist (CAP) guidelines .

• The following stages according to staging per American Joint Committee on Cancer (AJCC) for breast cancer staging criteria version 8 are included: cT2-4c N0-3 M0.

• Multifocal and multicentric primary tumors are allowed and the tumor with the mostadvanced T stage should be used to assess the eligibility. If multifocal ormulticentric disease TNBC needs to be confirmed for each focus.

• Measurable disease in the breast with at least one lesion with a diameter ≥2cm thatis evaluable per RECIST v1.1, visible in ultrasound and injectable.

• Male or female subject Age ≥ 18 years.

• ECOG performance status 0-1

• Adequate bone marrow function (administration of G-CSF, EPO and/or blood transfusionwithin 14 days before registration is not allowed):

• neutrophil count ≥ 1.5 x 109/L

• platelet count ≥ 100 x 109/L

• hemoglobin ≥ 90 g/L

• Adequate hepatic function:

• total bilirubin ≤ 1.5 x ULN, or direct bilirubin ≤ ULN for subjects with totalbilirubin levels > 1.5 x ULN

• AST and ALT ≤ 2.5 x ULN,

• Albumin 30 ≥ g/L

• Lactate Dehydrogenase (LDH) <2.5 ULN

• Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 50ml/min/1.73 m2 (according to CKD-EPI formula or serum creatinine ≤ 1.5x ULN.

• Adequate cardiac function: Left ventricular Ejection Fraction (LVEF) ≥ 50% asdetermined by echocardiography (ECHO)

• Adequate coagulation function:

• INR ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy

• aPTT ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy

• If patient is receiving anticoagulant therapy, the treating physician mustdetermine that the anticoagulation can be stopped at least 24 hours prior toinjection.

• Women of childbearing potential must use highly effective contraception, are notpregnant or lactating and agree not to become pregnant during trial treatment anduntil 6 months after the last dose of INT230-6 or standard of care treatment. Anegative pregnancy test before inclusion into the trial is required for all women ofchildbearing potential. (www.swissmedicinfo.ch).

• Men agree not to donate sperm or to father a child during trial treatment and until 6 months after the last dose of INT230-6 or standard of care treatment (www.swissmedicinfo.ch).

Exclusion Criteria:

• Inflammatory Breast Cancer cT4d

• The following histological subtypes of TNBC are excluded: Classic adenoid cysticcarcinoma, secretory carcinoma, low-grade adenosquamous carcinoma, tall cellcarcinoma with reversed polarity, high-grade metaplastic

• History of invasive malignancy ≤3 years prior to signing informed consent (excepttreated basal cell or squamous cell skin cancer or in situ cervical cancer)

• Prior chemotherapy, targeted therapy, radiation therapy or anti-PD-L1 agent forprevious breast cancer or Ductal Carcinoma in Situ (DCIS) on the same side.

• Concurrent bilateral breast cancer

• Concomitant treatment with any other experimental drug for recent breast cancerdiagnosis in another clinical trial.

• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA II orIV; unstable angina pectoris, history of myocardial infarction and acute coronarysyndrome requiring stenting/bypass surgery within the last six months, seriousarrhythmias requiring medication (with exception of atrial fibrillation orparoxysmal supraventricular tachycardia), significant QT-prolongation, uncontrolledhypertension.

• Known history of human immunodeficiency virus (HIV) or active chronic hepatitis C orhepatitis B virus infection or any uncontrolled active systemic infection requiringintravenous (iv) antimicrobial treatment.

• Active autoimmune disease that required systemic treatment in past 2 years (e.g.,with use of disease modifying agents, corticosteroids or immunosuppressive drugs).Replacement therapy (e.g., thyroid hormone replacement, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency) is notconsidered a form of systemic treatment.

• History of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

• Known history of tuberculosis.

• Known history of allogeneic organ or stem cell transplant.

• Receipt of live attenuated vaccine within 30 days prior to registration.

• Diagnosis of immunodeficiency, concomitant or prior use of immunosuppressivemedication within 7 days before registration, with the exceptions of local (intranasal, topical and inhaled) corticosteroids, or systemic corticosteroids whichmust not exceed 10 mg/day of prednisone or a dose equivalent corticosteroid, and thepremedication for chemotherapy.

• Concomitant anticoagulation with warfarin or equivalent vitamin K antagonists (e.g.phenprocoumon), factor Xa inhibitors (e.g. rivaroxaban, apixaban), direct thrombininhibitors (e.g. dabigatran) or platelet inhibitors/antiplatelet agents that cannotbe stopped 24 hours before the administration of INT230-6. Aspirin (up to 300mg/day) is allowed.

• Any concomitant drugs contraindicated for use with the trial drug according to theInvestigator Brochure (IB) and the immuno-chemotherapy treatment according to theapproved product information.

• Known hypersensitivity to trial drug or to any component of the trial drug orimmuno-chemotherapy treatment.

• Any other serious underlying medical, psychiatric, psychological, familial orgeographical condition, which in the judgment of the investigator may interfere withthe planned staging, treatment and follow-up, affect patient compliance or place thepatient at high risk from treatment-related complications.