A Study to Explore Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of Novel Therapeutics in Patients With Early Relapsed Metastatic Triple-negative Breast Cancer

Inclusion Criteria:

1. Male or female patients (who are ≥18 years of age at the time of signing theinformed consent) who have a pathologically documented breast cancer that is:

• Advanced/unresectable (patients who can be treated with curative intent are noteligible) or metastatic.

• HER2-negative (IHC 0, 1+ or IHC 2+/ISH-) based on local assessment according toASCO/CAP guidelines 1.

• Documented as hormone receptor-negative (both oestrogen receptors andprogesterone receptors are negative [oestrogen receptors and progesteronereceptors < 10%]) as per GEFPICS guidelines in the metastatic setting 2.

2. Patients need to provide an adequate tissue sample: provided from either a newbiopsy of a metastatic site or the most recent archival biopsy taken at the time ofdiagnosis of metastatic disease, if performed within 1 month of the ICF signature.Additionally, an archival sample of the primary tumor may be submitted (ifavailable) in addition to any recent archival tissue provided.

3. Patients who have early relapsed triple negative breast cancer i.e.:

• Patients who have received neo/adjuvant chemotherapy in the localized stage.

• Radiological and anatomopathological evidence of disease recurrence ormetastasis while on (neo)adjuvant treatment or within 12 months from the end ofall treatments with curative intent.

4. Patients with germinal pathological BRCA1/2 mutations are eligible to the study ifthey have received prior treatment with PARP inhibitor.

5. ECOG PS of 0 to 2.

6. LVEF ≥ 50% within 28 days before enrolment.

7. Adequate organ and bone marrow function within 14 days prior to treatmentassignment.

8. At least one lesion, not previously irradiated (and different from the biopsy site),that qualifies as a RECIST 1.1 target lesion at baseline.

9. An adequate treatment washout period before randomization/enrolment.

10. Patients with leptomeningeal or brain metastases can be included in the trial ifsymptoms are controlled with corticosteroids until 10 mg/day of prednisone orequivalent. Patients with brain metastases must receive radiotherapy if indicated,before study entry. Anticonvulsant therapy must be stable for at least 14 days priorto C1D1. Reproduction

11. Evidence of post-menopausal status or negative serum pregnancy test for females ofchild-bearing potential who are sexually active with a non-sterilized male partner. For women of child-bearing potential, a negative result for a pregnancy test (Anegative serum pregnancy test at screening visit and a negative serum or urinepregnancy test within 72 hours prior to first study treatment administration). Women will be considered post-menopausal if they have been amenorrhoeic for at least 12 months without an alternative medical cause. The following age-specificrequirements apply:

• Women < 50 years of age would be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution.

• Women ≥ 50 years of age would be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of all exogenoushormonal treatments, had radiation-induced menopause with last menses> 1 yearago, had chemotherapy-induced menopause with last menses > 1 year ago).

12. Women who are surgically sterile (i.e., bilateral salpingectomy, bilateraloophorectomy, or complete hysterectomy) are eligible.

13. Female patients of child-bearing potential who are sexually active with anon-sterilized male partner must use at least one highly effective method ofcontraception from the time of screening and must agree to continue using suchprecautions for 7 months after the last dose of study treatment. Not all methods ofcontraception are highly effective. Female patients must refrain from egg celldonation and breastfeeding while on study and for 7 months after the last dose ofstudy treatment. Not engaging in sexual activity for the duration of the study anddrug washout period is an acceptable practice; however, periodic, or occasionalabstinence, the rhythm method, and the withdrawal method are not acceptable methodsof contraception.

14. Non-sterilized male patients who are sexually active with a female partner ofchild-bearing potential must use a condom with spermicide from screening to 4 monthsafter the final dose of study treatment. Not engaging in sexual activity for theduration of the study and drug washout period is an acceptable practice; however,periodic, or occasional abstinence, the rhythm method, and the withdrawal method arenot acceptable methods of contraception. It is strongly recommended for the femalepartners of a male patient to also use at least one highly effective method ofcontraception throughout this period. In addition, male patients should refrain fromfathering a child or donating sperm during the study and for 4 months after the lastdose of study treatment. Preservation of sperm should be considered prior toenrollment in this study.

15. Female patients must not donate, or retrieve for their own use, ova from the time ofscreening and throughout the study treatment period, and for at least 7 months afterthe final study treatment administration. Preservation of ova should be consideredprior to enrollment in this study Informed Consent

16. Patient must understand, sign and date the written informed consent form (ICF) priorto any protocol-specific procedures performed. Patient should be able and willing tocomply with study visits and procedure as per protocol.

17. Patient must be affiliated to a social security system or beneficiary of the same.

Exclusion Criteria:

1. Evidence of untreated spinal cord compression or with leptomeningeal or brainmetastases, requiring more than 10 mg/day of prednisone or equivalent. Note: Untreated spinal cord compression: patients can enter the study after adequatetreatment of spinal cord compression.

2. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, uncontrolled or significant cardiovascular disease, severe pulmonaryfunction compromise, serious chronic gastrointestinal conditions associated withdiarrhea, or psychiatric illness/social situations that would limit compliance withstudy requirements, substantially increase risk of incurring AEs or compromise theability of the patient to give written informed consent.

3. Has a clinically significant corneal disease.

4. Has a history of non-infectious ILD/pneumonitis including radiation pneumonitis thatrequired steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitisthat cannot be ruled out by imaging at screening.

5. Uncontrolled or significant lung disease or prior pneumonectomy.

6. Active connective tissue or inflammatory disorders requiring treatment, or active orprior documented autoimmune disease within the past 5 years. Of note, patients withvitiligo, Grave's disease or psoriasis not requiring systemic treatment (within thepast 2 years) are not excluded. Patients with type 1 diabetes or hypothyroidismstable under treatment or not requiring systemic treatment are eligible.

7. Active primary immunodeficiency.

8. Has active or uncontrolled hepatitis B or C virus infection. Patients are eligible if they:

9. Have been curatively treated for HCV infection as demonstrated clinically andby viral serologies

10. Have received HBV vaccination with only anti-HBs positivity and no clinicalsigns of hepatitis

11. Are HBsAg- and anti-HBc+ (i.e., those who have cleared HBV after infection) andmeet conditions i-iii of criterion d below:

12. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meetconditions i-iii below: i. HBV DNA viral load < 2000 IU/mL ii. Have normal transaminase values, or, if livermetastases are present, abnormal transaminases, with a result of AST/ALT <5× ULN,which are not attributable to HBV infection iii. Start or maintain antiviraltreatment if clinically indicated as per the investigator

13. Patients with known controlled HIV infection and undetectable HIV-DNA are eligibleto the trial. Note: all of the following criteria are required to define an HIV infection that iswell controlled: undetectable viral RNA, CD4+ count ≥ 350, no history ofAIDS-defining opportunistic infection within the past 12 months, and stable for atleast 4 weeks on the same anti-HIV medications (meaning there are no expectedfurther changes in that time to the number or type of antiretroviral drugs in theregimen). If an HIV infection meets the above criteria, monitoring of viral RNA loadand CD4+ count is recommended. Patients must be tested for HIV during the screeningperiod if acceptable by local regulations or an institutional review board (IRB)/ethics committee (EC).

14. Any concurrent systemic therapy (e.g. chemotherapy, targeted therapy,immunotherapy..), radiotherapy, investigational agent , or biological therapy forcancer treatment. Concurrent use of hormonal therapy for non-cancer-relatedconditions (e.g., hormone replacement therapy) is acceptable.

15. History of another primary malignancy except for:

16. Malignancy treated with curative intent and with no known active disease ≥ 5years before the first dose of study treatment.

17. Adequately treated non-melanoma skin cancer or Lentigo maligna without evidenceof disease.

18. Adequately treated carcinoma in situ without evidence of disease.

19. Has a history of severe hypersensitivity reactions to either the study treatment(s)or inactive ingredients (including but not limited to polysorbate 80 of Dato-DXd),or has a history of severe hypersensitivity reactions to other monoclonalantibodies.

20. Patients having received prior treatment with any antibody drug conjugates targetingTROP2 (eg, Sacituzumab govitecan) are not eligible to the study.

21. Judgment by the Investigator that the patients should not participate in the studyif the patient is unlikely to comply with study procedures, restrictions, andrequirements.

22. History of allogeneic organ transplantation.

23. Patient has clinically significant, uncontrolled heart disease and/or recent cardiacevents including any of the following:

24. History of angina pectoris, coronary artery bypass graft (CABG), symptomaticpericarditis, or myocardial infarction within 12 months prior to the start ofstudy treatment.

25. History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV).

26. Documented cardiomyopathy.

27. Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined byMultiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).

28. History of any cardiac arrhythmias (e.g., ventricular tachycardia), completeleft bundle branch block, high grade AV block (e.g., bifascicular block, Mobitztype II and third degree AV block), supraventricular, nodal arrhythmias, orconduction abnormality in the previous 12 months.

29. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHgand/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg, with or withoutantihypertensive medication. Initiation or adjustment of antihypertensivemedication(s) is allowed prior to screening.

30. Patients with prior use of immunosuppressive medications within 14 days prior tofirst study drug dose or anticipation of need for systemic immunosuppressivemedication during study treatment, except for intranasal and inhaled corticosteroidsor systemic corticosteroids at doses less than 10 mg/day of prednisone orequivalent.

31. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 7 months after the last dose of study treatment. (See contraceptionrequirements outlined in Appendix 7 of this protocol).

32. Administration of live attenuated vaccines within 30 days prior to the first dose ofstudy treatment, or anticipation that such a live, attenuated vaccine will berequired during the study or within 3 months after the last dose of study treatment.

33. Persons deprived of their freedom or under guardianship, or for whom it would beimpossible to undergo the medical follow-up required by the trial, for geographic,social or psychological reasons.

34. Participation in another clinical study with an investigational product during thelast 4 weeks prior to enrollment and while on study treatment.