Tiragolumab, Atezolizumab and Chemotherapy in Triple Negative Breast Cancer

Inclusion Criteria:

1. Age ≥ 18 years old
2. Female
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Histological diagnosis of carcinoma of the breast, according to AJCC 8th edition thatis estrogen receptor negative (ER-), progesterone receptor negative (PR-) and HER2-negative according to local testing on the most recent tumor sample examined.
5. ER-negative and PR-negative are defined as having an immunohistochemistry (IHC) < 10%
6. HER2 negative is defined as per the 2018 American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines, indeed as having anIHC of 0 or 1+ without ISH OR IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells OR ISHnon-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells [without IHC]; Note: a IHC of 3+ is always considered HER2positive, independently of the ISH result. Cohort A (early setting): patients will be enrolled regardless of their tumor PD-L1status. Cohort B (metastatic setting): patients will be enrolled regardless of their tumorPD-L1 status but participants with PD-L1 negative tumor status (i.e.<1% defined byImmunohistochemistry with Ventana SP142) will be capped at 40%. i.e.<1% defined byimmunohistochemistry with Ventana SP142) will be capped at 40%.
7. Agreement to perform new study-related biopsies and blood sampling as described in thestudy schedule of activity.
8. Tumor considered as accessible by biopsy, according to the investigator. Fine-needleaspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavagesamples are not acceptable. Tumor tissue from bone metastases is not acceptable.
9. For female of childbearing potential (WCBP): negative serum or urinary pregnancy testwithin 2 weeks prior to first dose of study administration.
10. Women of childbearing potential must agree to use one highly effective method ofcontraception during the screening period, during the course of the study and at least 12 months after the last administration of study treatment (see appendix 7) .
11. Adequate bone marrow function as defined below: Absolute neutrophil count ≥1500/μL, i.e., 1.5x109/L Hemoglobin ≥ 9.0 g/dL Platelets ≥100000/μL, i.e., 100x109/L
12. Adequate liver function as defined below: Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert's syndrome ≤ 3 x UNL isallowed AST ≤ 3.0 x ULN, ALT ≤ 3.0 x ULN
13. Adequate renal function as defined below: Creatinine ≤ 1.5 x UNL and eGFR≥40ml/min/1.73m²
14. Adequate coagulant function as defined below: International Normalized Ratio (INR) ≤ 1.5 x ULN
15. Completion of all necessary screening procedures within 28 days prior to inclusion
16. Signed Informed Consent form (ICF) obtained prior to any study related procedure
17. Patients must be covered by a health insurance system Inclusion criteria #16 to #18 are applicable to cohort A (early setting):
18. For tumor stage T1c, nodal stage N1-2, by at least one radiographic or clinicalmeasurement. For tumor stage T2-4, nodal stage N0-2, by at least one radiographic or clinicalmeasurement.
19. Multifocal, multicentric unilateral or bilateral breast adenocarcinoma tumors areallowed provided that all foci are ER-/PR-/HER2- according to local testing.
20. Left ventricular ejection fraction (LVEF) ≥ 50%. Inclusion criteria #19 to 23 are applicable to cohort B (metastatic setting):
21. No prior line of chemotherapy / or systemic therapy for metastatic disease (patientswith known germline BRCA1 or BRCA2 mutations may have been treated with one prior lineof therapy with PARP inhibitor).
22. Radiation therapy for metastatic disease is permitted. There is no required washoutperiod for radiation therapy. Patients should be recovered from the effects ofradiation.
23. Prior chemotherapy in the neoadjuvant or adjuvant setting is allowable if treatmentwas completed 12 months prior to inclusion.
24. Patients with documented liver metastases: AST and ALT Patients with documented livermetastases: AST and ALT less than 5 x ULN
25. Have a life expectancy of at least 3 months.

Exclusion Criteria:

1. Pregnant and/or lactating women.
2. Contra-indications to 18F-FDG PET/CT and/or 68Ga-FAPI-46 PET/CT.
3. Patients in whom tumor deposits are not detected by 18F-FDG PET/CT.
4. Subject with a significant medical, neuro-psychiatric, substance abuse or surgicalcondition, currently uncontrolled by treatment, which, in the principal investigator'sopinion, may interfere with completion of the study.
5. TNM stage T4d breast cancer (inflammatory breast cancer).
6. Known HIV
7. Active infection including: Hepatitis B (known positive HBV surface antigen (HBsAg)result). Subjects with a past or resolved HBV infection (defined as the presence ofhepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; Hepatitis C.Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA.
8. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, active tuberculosis, symptomatic congestive heart failure, uncontrolledhypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease,serious chronic gastrointestinal conditions associated with diarrhea, or psychiatricillness/social situations that would limit compliance with study requirement,substantially increase risk of incurring AEs or compromise the ability of the subjectto give written informed consent.
9. Concomitant use of other investigational drugs.
10. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia. Subjects with Grade ≥2 neuropathy will be evaluated on acase-by-case basis after consultation with the Study Physician.
11. Active or prior documented autoimmune disease (including inflammatory bowel disease,celiac disease, Wegener's granulomatosis) within the past 3 years. Note: Subjects with childhood atopy or asthma, vitiligo, alopecia, Grave's disease,Hashimoto's thyroiditis, on a stable dose of thyroid replacement hormone or psoriasisnot requiring systemic treatment (within the past 2 years), and patients withcontrolled Type 1 diabetes mellitus on a stable insulin regimen are not excluded.
12. Known history of, or any evidence of active, non-infectious pneumonitis. (Note:History of radiation pneumonitis in the radiation field [fibrosis] is permitted).
13. History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins.
14. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamsterovary (CHO) cells or any component of the atezolizumab formulation.
15. Any live (attenuated) vaccine within 30 days of planned start of study therapy.
16. Treatment with systemic immunosuppressive medications (including but not limited tocorticosteroids, cyclophosphamide, azathioprine, cyclosporine, methotrexate,thalidomide, and antitumor necrosis factor [TNF] agents) within 2 weeks prior toinclusion, or anticipated requirement for systemic immunosuppressive medicationsduring the trial.
17. Patients who have received acute, low-dose (≤ 10 mg oral prednisone orequivalent), systemic immunosuppressant medications may be enrolled in the study.
18. The use of corticosteroids (≤10 mg oral prednisone or equivalent) for chronicobstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) forpatients with orthostatic hypotension, and low dose supplemental corticosteroidsfor adrenocortical insufficiency are allowed.
19. Prior treatment with anti-PD-1 or anti-PD-L1 therapeutic antibody within 6 months.
20. Prior allogeneic stem cell or solid organ transplantation
21. Known active EBV
22. Known lymphoepithelioma-like carcinoma
23. Patients with an obstruction of urine flow (according to the current SmPc ofcyclophosphamide)
24. Oligometastatic patients if they require locoregional treatment. Exclusion criteria #23 to #25 are applicable to cohort A (early setting):
25. Presence of any distant metastasis.
26. Known germline BRCA1 or BRCA2 mutation.
27. Contra-indication for treatment by nab-paclitaxel, doxorubicin, cyclophosphamide,carboplatin or known allergy to any tested substances or any excipients (e.g;chemotherapy or immunotherapy formulations). Exclusion criteria #26 to #28 are applicable to cohort B (metastatic setting):
28. Contra-indication for treatment by nab-paclitaxel or known allergy to any testedsubstances or any excipients (e.g; chemotherapy or immunotherapy formulations).
29. Leptomeningeal disease and known CNS disease, except for treated asymptomatic CNSmetastases, provided all of the following criteria are met: Only supratentorial and cerebellar metastases allowed (i.e., no metastases tomidbrain, pons, medulla, or spinal cord) Treated and stable CNS metastases since atleast 4 weeks before inclusion No ongoing requirement for corticosteroids as therapyfor CNS disease No stereotactic radiation within 7 days or whole brain radiationwithin 14 days prior to inclusion No evidence of interim progression between thecompletion of CNS-directed therapy and the screening radiographic study Note:asymptomatic brain metastases discovered during the screening, by e.g. 68Ga-FAPI-46PET/CT and deemed accessible to stereotactic radiation therapy could remain in thestudy after discussion with the study medical monitors.
30. Prior malignancy other than breast cancer active within the previous 5 years, exceptfor localized cancers that are considered to have been cured and in the opinion of theinvestigator present a low risk for recurrence. Examples include basal or squamouscell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix orbreast.