Restoring Sensitivity To Immunotherapy In Advanced Triple Negative Breast Cancer Exploiting Ceralasertib Priming Followed By Combined Durvalumab/Nab-Paclitaxel

Inclusion Criteria:

1. ATRiBRAVE trial written informed consent, prior to any study specific procedures

2. Age ≥18 years old

3. Ability to comply with the study protocol in the investigator's judgment.

4. Ability to swallow and retain oral medication

5. Availability of a formalin-fixed, paraffin-embedded block (FFPE) containing primarytumor tissue or at least 10-20 unstained tumor slides

6. Metastatic TNBC patients who have not received prior systemic cytotoxic therapy inthe advanced setting and whose tumor have relapsed from treatment with curativeintent for early disease, which must have included ICI and chemotherapy as part ofradical locoregional therapy

7. Documented disease progression (e.g., with biopsy sample, pathology or imagingreport) since the last treatment in the early setting with curative intent (neo/adjuvant regimen)

8. Negative ER/PgR (defined as <10% of tumor cells expressing ER and PgR hormonalreceptors) and HER2 status (HER2 IHC score 0, 1+ or 2+ non-amplified by in situhybridization) must be confirmed in the most recent tumor sample (primary and/ormetastatic)

9. Evaluable disease, as defined by RECIST 1.1

10. ECOG performance status 0-1 (refer to Appendix 1)

11. Patients must have a life expectancy ≥ 3 months from proposed first dose date.

12. Patients must have acceptable bone marrow, liver and renal functions measured within 28 days prior to administration of study treatment

13. Body weight > 30kg

14. Women with childbearing potential should complete a pregnancy test with negativeresult within 28 days of study treatment and be willing to use effectivecontraceptive methods from screening to 90 days after the last dose of durvalumab

15. For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures and agreement to refrain from donating sperm fromscreening to 90 days after the last dose of durvalumab.

Exclusion Criteria:

1. Diagnosis of ataxia telangiectasia.

2. Any previous treatment with ATR inhibitors, DNA-damage repair inhibitors.

3. Patients, who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 therapy:

4. Must not have experienced a toxicity that led to permanent discontinuation ofprior immunotherapy.

5. All AEs while receiving prior immunotherapy must have completely resolved orresolved to baseline prior to screening for this study.

6. Must not have experienced a ≥ Grade 3 immune related AE or an immune relatedneurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:Patients with endocrine AE of ≤ Grade 2 are permitted to enroll if they arestably maintained on appropriate replacement therapy and are asymptomatic.

7. Must not have required the use of additional immunosuppression other thancorticosteroids infliximab or Cellcept for the management of an AE, not haveexperienced recurrence of an AE if re-challenged, and not currently requiremaintenance doses of > 10 mg prednisone or equivalent per day.

8. Treatment with any investigational product during the last 28 days before theenrollment.

9. Patients must have had a washout period of 3 weeks for any prior cancer therapyprior to the start of study drug. The following intervals between the end of theprior treatment and first dose of study drug must be observed: ≥ 4 weeks forradiotherapy (patients who receive palliative radiation for nontarget lesions neednot have a 4 week washout period and can be enrolled immediately); patients mayreceive a stable dose of bisphosphonates or denosumab for bone metastases, beforeand during the study; ≥ 4 weeks for major surgery; ≥ 7 days for minor surgicalprocedures; ≥ 14 days (or 5 half-lives whoever is longest) for any investigationalproduct.

10. Current or prior use of immunosuppressive medication within 4 weeks prior to thefirst dose of durvalumab, with the exceptions of intranasal, topical, inhaledcorticosteroids, and systemic corticosteroids ≤ 10 mg prednisone / day orequivalent.

11. Patients with second primary cancer, except: adequately treated non-melanoma skincancer, or other solid tumours curatively treated with no evidence of disease for ≤3years.

12. Any gastrointestinal condition that would preclude adequate absorption ofceralasertib, including but not limited to inability to swallow oral medication,refractory nausea and vomiting, chronic gastrointestinal diseases or previoussignificant bowel resection, intestinal obstruction or CTCAE grade 3 or grade 4upper GI bleeding within 4 weeks before the enrollment.

13. Active or prior documented autoimmune or inflammatory disorders (including IBD [e.g.Crohn's disease, ulcerative colitis or diverticulitis], SLE, sarcoidosis syndrome,tuberculosis, Wegener syndrome, myasthenia gravis, Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, history of primary immunodeficiency or HIVinfection, known hepatitis B or hepatitis C infection, glomerulonephritis, nephriticsyndrome, Fanconi Syndrome or renal tubular acidosis within the past 2 years priorto the start of treatment. The following are exceptions to this criterion: i)Subjects with vitiligo or alopecia; ii) hypothyroidism (e.g., following Hashimotosyndrome) stable on hormone replacement; iii) any chronic skin condition that doesnot require systemic therapy; iv) patients with coeliac disease controlled by dietalone and patients without active disease in the last 5 years may be included butonly after consultation with the study physician.

14. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody,hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), atscreening. Participants with a past or resolved HBV infection (defined as thepresence of anti-HBc and absence of HbsAg) are eligible. Participants positive forHCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

15. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that mayinclude clinical history, physical examination and radiographic findings, ortuberculosis testing in line with local practice).

16. Receipt of a live, attenuated vaccine within 30 days prior to the first dose ofstudy treatment.

17. Patients with confirmed COVID-19 infection by PCR test who have not made a fullrecovery

18. History of allogeneic organ transplantation.

19. Untreated central nervous system (CNS) metastatic disease or cord compression. Note:Patients with asymptomatic central nervous system (CNS) metastases are eligible,provided that all of the following criteria are met: (a) The metastases are limitedto the supratentorial region or cerebellum (i.e., no metastases to midbrain, pons,medulla, or spinal cord are allowed); (b) No ongoing requirement for corticosteroidsas therapy for CNS disease; (c) No stereotactic radiation within 7 days orwhole-brain radiation or neurosurgical resection within 2 weeks before the start ofstudy treatment; (d) Radiographic demonstration of interim stability (i.e., noprogression) between the completion of CNS-directed therapy and the screeningimaging study

20. History of leptomeningeal disease

21. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia or vitiligo

22. Resting ECG with measurable QTcF > 470 msec on 2 or more time points within a 24-hour period or family history of long QT syndrome.

23. Patients with cardiac problem as follows: uncontrolled hypertension or hypotension (BP ≥150/95 mmHg despite medical therapy, BP <90/60 mmHg or orthostatic hypotensionfall in BP >20 mmHg), Left ventricular ejection fraction <55% measured byechocardiography, Atrial fibrillation with a ventricular rate >100 bpm on ECG atrest or any clinically important abnormalities in rhythm, conduction or morphologyof resting ECG (e.g. complete left bundle branch block , third degree heart block,second degree heart block), Symptomatic heart failure (NYHA grade II-IV), Prior orcurrent cardiomyopathy, Severe valvular heart disease, Uncontrolled angina (CanadianCardiovascular Society grade II-IV despite medical therapy), Acute coronary syndromewithin 6 months prior to starting treatment.

24. Stroke or transient ischemic attack in the last 6 months prior to screening.

25. Uncontrolled symptomatic pleural effusion, pericardial effusion, or ascites.

26. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL orcorrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued useof bisphosphonate therapy.

27. Severe infection within 4 weeks prior to the first dose of study treatment (Cycle 1,Day 1), including but not limited to hospitalization for complications of infection,bacteraemia, or severe pneumonia.

28. Treatment with oral or IV antibiotics within 2 weeks prior to initiation of studytreatment (Cycle 1, Day 1).

29. Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronicobstructive pulmonary disease exacerbation, urinary tract infection or for dentalextraction) are eligible.

30. As judged by the Investigator, any evidence of severe or uncontrolled systemicdiseases that places the patient at unacceptable risk of toxicity or non-compliance.Examples include, but are not limited to, diabetes type I and II, active bleedingdiatheses, renal transplant, uncontrolled seizures, severe COPD, superior vena cavasyndrome, extensive bilateral lung disease on High Resolution CT scan, severeParkinson's disease, refractory nausea or vomiting, irritable bowel syndrome,chronic gastrointestinal disease, significant bowel resection, psychiatriccondition, or active infection including any patient known to have tuberculosis,hepatitis B, hepatitis C and human immunodeficiency virus (HIV) or requiringsystemic antibiotics, antifungals or antiviral drugs. Screening for chronicconditions is not required.

31. Concomitant use of known potent cytochrome P (CYP) 3A inhibitors (e.g.,ketoconazole,itraconazole, telithromycin, clarithromycin, protease inhibitorsboosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir,telaprevir). The required washout period prior to starting study treatment is 2weeks.

32. Concomitant use of known strong CYP3A inducers (e.g., phenobarbital, enzalutamide,phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and StJohn's Wort). The required washout period prior to starting study treatment is 5weeks for enzalutamide or phenobarbital and 3 weeks for other agents.

33. Receiving or having received, concomitant medications, herbal supplements, and/orfoods that significantly modulate Pgp activity (washout periods of 5 half-lives).

34. Known hypersensitivity to ceralasertib, durvalumab or nab-paclitaxel or any of theirexcipients