Inclusion
1) Female or male, age >= 18 years.
2) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
3) Previously untreated non-metastatic (M0) TNBC meeting Stage I or II criteria according to AJCC Cancer Staging Manual, 8th Edition, 2017 as assessed by the local investigator on the basis of mammogram (MMG) and/or ultrasound (US) of the breasts, and US or clinical examination of the axilla.
a) Stage I cT1c cN0;
Stage IIA cT1 cN1; cT2 cN0;
Stage IIB cT2 cN1; cT3 cN0.
b) Contralateral in situ only disease is permitted;
c) In the event of abnormal imaging of the axilla, nodal status should be confirmed by cytology.
4) Clinically node positive participants should undergo computed tomography (CT) scan or PET CT of chest/abdomen (and bone scan if clinically indicated) to exclude metastases. Those participants with equivocal finding on staging should have biopsies performed to confirm or exclude metastatic disease if possible.
5) Non-metastatic, potentially operably, unilateral triple negative breast cancer, histologically defined as:
a) ER negative: with < 1% of tumour cells positive for ER by IHC irrespective of staining intensity; AND
b) PR negative: with < 10% tumour cells positive for PR by IHC irrespective of staining intensity; AND
c) HER2 negative:
i) IHC 0, as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within <= 10% of the invasive tumour cells; OR
ii) IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumour cells; OR
iii) ISH (FISH or SISH) negative based on:
* Single-probe average HER2 copy number < 4.0 signals/cell; OR
* Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell; OR
* As per ASCO-CAP 2018 Guidelines.
6) Able to commence study treatment within 14 days of randomisation.
7) Surgery is able to be undertaken within 4 weeks of final dose of neoadjuvant IV therapy. Pre-operative radiation is not permitted for any participant with operable cancer after final paclitaxel.
8) Adequate organ function. All screening laboratory tests should be performed within 14 days of randomisation.
9) Screening laboratory values must meet the following criteria (using NCI-CTCAE V5.0):
a) WBC >= 2 x 10^9/L;
b) Neutrophils >= 1.5 x 10^9/L;
c) Platelets >= 100 x 10^3/µL;
d) Haemoglobin >= 9.0 g/dL;
e) Serum creatinine <= 1.5 x ULN or calculated creatinine clearance >= 50 mL/min (using the Cockcroft Gault formula);
f) AST/ALT <= 3.0 x ULN;
g) Total bilirubin <= 1.5 x ULN except participants with Gilbert Syndrome who must have a total bilirubin level <= 3.0 x ULN.
10) Left ventricular ejection fraction (LVEF) of >= 50% assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening (no more than 4 weeks before study entry).
11) Negative pregnancy test or confirmation of post-menopausal status for female participants. Women who have undergone surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy/tubal ligation, or hysterectomy) do not require pregnancy testing.
a) Negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG within 14 days of randomisation and within 7 days before the first dose of study treatment. The pregnancy test will be repeated within 24 hours before the first dose if outside this window.
OR:
b) Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
i) Women < 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments with no Mirena® IUD in situ and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
ii) Women >= 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments with no Mirena IUD in situ or endometrial ablation. If Mirena IUD or endometrial ablation and age < 60 years, LH and FSH should be in the postmenopausal range.
12) Female participants of childbearing potential must agree to follow instruction for method(s) of contraception from the time of enrolment for the duration of treatment and for at least 5 months after completing Nivolumab treatment;
13) Be willing and able to provide written informed consent for the study. The participant may also provide consent for future unspecified biomedical research. However, the participant may participate in the main study without participating in future unspecified biomedical research.
14) The participant has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.
15) The participant agrees to make tumour (diagnostic core biopsy and surgical specimen) available for submission for central pathology review and to conduct translational studies as part of this protocol.
Exclusion
1) Confirmed presence of AJCC 8th edition anatomic Stage 3 or 4 disease.
2) Tumour of any size considered inoperable at presentation.
3) Multifocal* or bilateral invasive breast cancer. * Refer to AJCC 8th Edition: use clinical judgement if satellite nodes are close as to whether this represents truly multifocal disease.
4) Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy that target immune checkpoints, co-stimulatory or co-inhibitory pathways for T-cell receptors within the past 12 months.
5) Will be offered neoadjuvant breast radiation therapy.
6) Undergone or planned for sentinel lymph node biopsy before study therapy.
7) Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks before randomisation.
Note: participant will be excluded if he/she received an investigational agent with anticancer or anti-proliferative intent within the last 12 months.
8) Any concurrent anti-neoplastic therapy (i.e. chemotherapy, hormonal therapy, immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational agents for treatment of breast cancer) not already specified in the protocol.
9) Prior malignancy active within the previous 3 years before randomisation, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
10) Other active non-breast malignancy requiring concurrent intervention.
11) Has significant cardiovascular disease such as myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months, congestive cardiac failure (CHF) New York Heart Association (NYHA) classification IV or history of CHF NYHA III or IV.
12) Participants with an active, known or suspected autoimmune disease are not eligible. Participants with the following are eligible to participate:
a) Type I diabetes mellitus;
b) Hypothyroidism only requiring hormone replacement;
c) Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment; or
d) Conditions not expected to recur in the absence of an external trigger.
13) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomisation are not eligible. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted. Patients requiring steroids as a once-off, short term anti-emetics (such as that prescribed with chemotherapy) are eligible.
14) Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
15) Has a history of non-infectious pneumonitis requiring treatment with steroids.
16) Known medical condition that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
17) Treatment with botanical preparations (e.g. herbal supplements) and traditional Chinese medicines, intended for general health support or to treat the disease under study, within 7 days before randomisation.
18) Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
19) Pregnant; lactating participants must stop breast feeding before randomisation. Use of oral, injectable or implant hormonal contraceptives or medicated IUD must stop before randomisation.
20) Contraindications or known hypersensitivity to the study medication or excipients.
21) Administration of a a live vaccine within 30 days before randomisation
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed, however intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
22) Known history of testing positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS).
23) Active Hepatitis B virus (known positive Hepatitis B surface antigen (HBsAg) result or Hepatitis C virus (HCV). Participants with past or resolved HBV infection (defined as the presence of Hepatitis B core antibody (anti-HBc) and absence of HBsAg) are eligible if remaining on anti-viral medication. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
24) Active tuberculosis infection (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice).