This trial will Study a type of sarcoma defined metastatic soft-tissue sarcoma (STS). Participants will be treated with bexmarilimab, a CLEVER-1 antibody plus doxorubicin, a chemotherapy. The main purpose of the Study is to analyze the safety (to find out how safe or toxic a treatment is to appropriately manage the risks) and efficacy (to find out how effective a treatment is) of bexmarilimab combined with doxorubicin in participants who have STS.

The main purpose of the Study is to analyze the safety and efficacy of bexmarilimab combined with doxorubicin in participants who have STS. The safety of bexmarilimab and doxorubicin will be determined by assessing the safe dose of bexmarilimab when administered with doxorubicin, defined as the dose-limiting toxicities and adverse events. Bexmarilimab plus doxorubicin treatment efficacy will be determined by assessing the PFS, defined as the period from treatment initiation/randomization to the first occurrence of disease progression or death from any cause.

Inclusion Criteria:

1. Participant, or legal representative (if applicable), must be capable to understand the purpose of the Study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.

2. Female or male participants ≥ 18 years of age at the time of signing ICF.

3. For phase Ib (dose escalation):

   • Histologically documented metastatic STS with no more than 3 lines of treatment.
   • Participant has not received doxorubicin, but doxorubicin could be indicated for metastatic disease as per institutional guidelines.

   For phase Ib (dose expansion) and for phase II:

   • Metastatic STS with any of the following histologies: undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), dedifferentiated liposarcoma (DDLPS), myxoid liposarcoma (MLPS), leiomiosarcoma (LMS) with no prior treatment in the advanced setting. Capped to 33% of participants with UPS/MFS, 33% of participants with DDLPS/MLPS, and 33% of participants with LMS.

4. Measurable disease according to RECIST v.1.1.

5. Participant has adequate bone marrow, liver, and renal function:

   • Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 7 days before first Study treatment dose): Absolute neutrophil count (ANC) ≥ 1,000/mm3, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9.0 g/dL.
   • Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 ×ULN if Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 ×ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 ×ULN in participants with no liver metastasis and 5.0 ×ULN in participants with liver metastasis; partial thromboplastin [PT]-INR/activated partial thromboplastin time [PTT] <1.5×ULN (≤ 2.0×ULN for participants on anticoagulation prophylactic regimen).
   • Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min/1.73 m2 based on Cockcroft-Gault glomerular filtration rate estimation for participants with creatinine levels above institutional normal.

6. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 (v.6.0) (except for alopecia or other toxicities not considered a safety risk for the participant at investigator's discretion).

7. Participants must be able to provide blood samples for PK analysis (for phase Ib), and blood samples and the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks at the time of the inclusion for translational studies (for phase Ib and phase II). Archival tissue sample should have preferably be taken ≤ 24 months before screening. If archival tissue is not available, a newly obtained baseline biopsy of an accessible tumor lesion is required prior to start of Study treatment.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

9. Minimum life expectancy of ≥ 12 weeks at screening.

10. Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before Study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 7 months after the last dose of Study treatments. Female participants must refrain from egg cell donation and breastfeeding during this same period.

11. Male participants who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening until 4 months after the last administration of the Study drug. Male participants must not donate or bank sperm during this same period.

12. Participant must be accessible for treatment and follow-up.

Exclusion Criteria:

1. Participation in another clinical trial, interventional or observational, until the Study's safety visit. Note: participation in retrospective studies or data analysis is allowed.

2. Treatment with approved or investigational cancer therapy within 14 days prior to initiation of Study drug.

3. Prior treatment with anthracyclines for localized or advanced disease.

4. Prior treatment with immunocheckpoint inhibitors for localized or advanced disease.

5. For phase Ib (dose expansion) and phase II: participant has received prior treatment in the advanced setting.

6. Known active uncontrolled or symptomatic central nervous system (CNS) metastases and/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Participants with a history of a CNS metastasis previously treated with curative intent (for example, stereotactic radiation or surgery) that have not progressed on follow-up imaging, have been asymptomatic for at least 60 days and are not receiving systemic corticosteroids and or/anticonvulsants, are eligible. Participants with signs or symptoms of neurological compromise should have appropriate radiographic imaging performed before randomization to rule out brain metastasis.

7. Participants diagnosed with bone sarcomas, locally-aggressive sarcomas, GIST or Kaposi sarcoma.

8. Have a concurrent malignancy or malignancy within 5 years of Study enrollment with the exception of carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor's Medical Monitor is required.

9. Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances.

10. Major surgical procedure or significant traumatic injury within 14 days before the first dose of Study treatment or anticipation of need for major surgery within the course of the Study treatment.

11. The patient requires systemic corticosteroid (≥10 mg/day prednisone or equivalent) or other immunosuppressive treatment. Topical, nasal, inhaled, and ophthalmic corticosteroids are allowed.

12. Has an active cardiac disease or a history of cardiac dysfunction or conduction abnormalities including, but not confined, to any of the following:

    • History and/or signs of active coronary artery disease/ischemia with or without angina pectoris, documented myocardial infarction, or symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) within six months prior to Study entry.
    • Symptomatic pericarditis.
    • Left ventricular ejection fraction (LVEF) < 50% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO).
    • History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia), which is symptomatic or requires treatment (NCI-CTCAE grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers will be permitted to enroll.
    • QT Interval Corrected by Fridericia's formula (QTcF) prolongation to > 470 ms based on average of the screening triplicate 12-lead ECG.
    • Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.

13. Participants with a history of chronic ulcers or clinically relevant liver disease leading to Child Pugh Score C or higher. If the history of abnormal liver function is related to previous hematologic malignancy or it's treatment, the participant may be enrolled after discussing with the Medical Monitor.

14. Pregnant or lactating women or participants not willing to apply highly effective contraception as defined in the protocol.

15. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the Study.

16. Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV). Participants with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

17. Has active primary immunodeficiency, known human immunodeficiency virus (HIV) infection with positive viral load. Note: HIV-infected participants on effective anti-retroviral therapy with undetectable viral load are eligible for inclusion, provided their therapy does not include CYP3A4 inhibitors or inducers (such as nevirapine or atazanavir).

18. Other active uncontrolled infection at the time of enrollment.

19. Receipt of live or attenuated vaccine within 30 days prior to the first dose of Study treatment.

20. A history of uncontrolled seizures, central nervous system (CNS) disorders, or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to Study drugs or interfering with participant safety.

21. Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, contraindicate participant participation.

22. Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator.