Olinvacimab With Pembrolizumab in Patients With mTNBC

Inclusion Criteria:

1. Female patients ≥19 years old
2. Histologically proven mTNBC* irrespective of PD-L1 status. *Histological or cytological diagnosis of relapsed/metastatic TNBC. TNBC is defined bythe negative expression of estrogen receptors (ER), progesterone receptors and humanepidermal receptor-2 (HER2). If there is a pathology report of the metastasis, takethe histopathology of the metastases as standard. Negative for ER and progesteronereceptors is defined as the expression of ER and progesterone receptors in <1% of thetumor cells by immunohistochemistry (IHC). HER2-negative is defined as a score of 0and 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH) negative. Ifthe HER2 test result is 0 or 1+ by IHC, FISH detection is optional, but the resultmust be negative.
3. Has provided archival tumor tissue sample or newly obtained core or excisional biopsyof a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)tissue blocks are preferred to slides. Newly obtained biopsies are preferred toarchived tissue.

• Note: If submitting unstained cut slides, newly cut slides should be submitted tothe testing laboratory within 14 days from the date slides are cut

4. Has measurable disease per RECIST 1.1 as assessed by the local siteinvestigator/radiology. Lesions situated in a previously irradiated area areconsidered measurable if progression has been demonstrated in such lesions
5. Has received at least one prior line of systemic therapy for metastatic or inoperablelocally advanced TNBC. Patients who have failed adjuvant chemo within 12 months shouldbe considered as fulfilling a line of systemic therapy.
6. No previous therapy with anti-VEGF, anti-VEGFR or anti-PD-1 antibody for theirmetastatic disease. The use of anti-VEGF, anti-VEGFR, anti-PD-1 or anti-PD-L1 antibodyin neoadjuvant or adjuvant setting will be allowed if there was no progression ofdisease within 6 months after the completion of treatment.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
8. Adequate hematologic, renal, and hepatic function tests performed within 7 days priorto initiation of study treatment:

• Hematologic tests
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Haemoglobin ≥ 9.0 g/dL (This must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stabledose of erythropoietin, e.g. ≥ approximately 3 months)
• Blood coagulation tests
• Prothrombin time (PT) ≤ 1.5 x Upper limit of normal (UNL)
• Activated partial thromboplastin time (aPTT) ≤ 1.5 x UNL
• Hepatic function tests
• Total bilirubin ≤ 1.5 x UNL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 xULN (≤ 5 x ULN in case of liver metastasis)
• Renal function test - Creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥30mL/min for patients with creatinine levels >1.5 × institutional ULN

9. HIV-infected participants must be on anti-retroviral therapy (ART) and have awell-controlled HIV infection/disease defined as:

• Participants on ART must have a CD4+ T cell count >350 cells/mm3 at time ofscreening
• Participants on ART must have achieved and maintained virologic suppressiondefined as confirmed HIV RNA level below 50 copies/mL or the lower limit ofqualification (below the limit of detection) using the locally available assay atthe time of screening and for at least 12 weeks prior to screening
• Participants on ART must have been on a stable regimen, without changes in drugsor dose modification, for at least 4 weeks prior to study entry (day 1)

10. Participants who are HBsAg positive are eligible if they have received HBV anti-viraltherapy for at least 4 weeks and have undetectable HBV viral load prior torandomization.

• Note: Participants should remain on anti-viral therapy throughout studyintervention and follow local guidelines for HBV anti-viral therapy postcompletion of study intervention.
• Hepatitis B screening tests are not required unless:
• Known history of HBV infection
• As mandated by local health authority

11. Participants with history of HCV infection are eligible if HCV viral load isundetectable at screening.

• Note: Participants must have completed curative anti-viral therapy at least 4weeks prior to randomization.
• Hepatitis C screening tests are not required unless:
• Known history of HCV infection
• As mandated by local health authority

12. The patient should provide written informed consent

Exclusion Criteria:

1. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first dose ofstudy treatment.

• Note: Participants who have entered the follow-up phase of an investigational studymay participate as long as it has been 4 weeks after the last dose of the previousinvestigational agent.

2. Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinicallystable and without requirement of steroid treatment for at least 14 days prior tofirst dose of study treatment
3. Treatment with systemic chemotherapy, hormonal therapy, immunotherapy or biologictherapy within 4 weeks or five half-lives (which is shorter) prior to the baselinevisit
4. Has received prior radiotherapy within 2 weeks of start of study treatment. Patientsmust have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 2-week washout is permittedfor palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
5. Not recovered below National Cancer Institute (NCI) CTCAE (v5.0) Grade 1 or baselinefrom AEs due to previous therapy (patient with ≤ Grade 2 neuropathy or alopecia may beeligible)
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior the first dose of study drug
7. Has an active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)is not considered a form of systemic treatment and is allowed.
8. Has a known additional malignancy that is progressing or has required active treatmentwithin the past 2 years. (Note: Patients with basal cell carcinoma of the skin,squamous cell carcinoma of the skin, or carcinoma in situ [e.g., breast carcinoma,cervical cancer in situ] controlled by curative therapy are not excluded).
9. Has a history of (non-infectious) pneumonitis/interstitial lung diseases that requiredsteroids or current pneumonitis/interstitial lung disease
10. Has an active infection requiring systemic antibiotics
11. HIV-infected participants with a history of Kaposi sarcoma and/or MulticentricCastleman Disease.
12. Active psychiatric disorder (schizophrenia, major depressive disorder, bipolardisorder etc.) or substance abuse disorder that would interfere with the participant'sability to cooperate with the requirements of the study. Treated depression withongoing antidepressant medication is not an exclusion criterion
13. Female who is pregnant* or lactating and of childbearing potential who does not agreeto a reliable and adequate method of contraceptiona. A women of childbearing potential (WOCBP) must agree to use contraception during thetreatment period and for at least 6 months (for females) after the last dose of studytreatment. aAdequate contraception allowed in this trial is as follows

• Hormonal contraceptives such as combined oral contraceptive pill
• Intrauterine devices (IUD) or the implantation of intrauterine system
• Blockage methods (spermicides and condoms/spermicides and [vaginal] diaphragm forcontraception, vaginal sponges or cervical cap)
• Sterilization surgery such as tubal ligation in females *A WOCBP who has apositive urine pregnancy test (within 72 hours) prior to treatment. If the urinetest is positive or cannot be confirmed as negative, a serum pregnancy test willbe required.

14. Uncontrolled hypertension (systolic blood pressure [SBP]> 150 or diastolic bloodpressure [DBP]> 90 mmHg) or seizure
15. Class III or IV heart failure by New York Heart Association (NYHA) classification
16. Requiring therapeutic anticoagulation treatment (prophylactic therapy withlow-molecular weight heparin is allowed)
17. Serious Grade 4 venous thromboembolic event including pulmonary embolism
18. Moderate to severe proteinuria as demonstrated by urine dipstick for proteinuria ≥2+.For patients with ≥2+ proteinuria on dipstick urinalysis, a urine protein: creatinine (UPC) ratio will be determined, or a 24-hour urine collection will be done. Patientswith a UPC ratio <1 or a 24-hour urine protein <1 gram are eligible.
19. History of abdominal fistula or gastrointestinal perforation, or serious GI bleedingwithin 6 months
20. History of severe arterial thromboembolic event within 12 months of start of studydrug
21. Major surgery within 4 weeks prior to initiation of study treatment. (If theparticipant had major surgery, the participant must have recovered adequately from theprocedure and/or any complications from the surgery prior to starting studyintervention).
22. A known history of severe hypersensitivity (≥Grade 3) to study drugs and/or any of itsexcipients.
23. Has had an allogenic tissue/solid organ transplant.
24. Unable to participate in the trial according to the investigator's decision.
25. Have received a live vaccine within 30 days prior to enrollment. Seasonal flu vaccinesthat do not contain live virus are permitted
26. Have had a serious or non-healing wound, ulcer, or bone fracture within 28 days priorto enrollment