Doxorubicin With or Without DT-7012 in Advanced Soft Tissue Sarcoma

Inclusion Criteria: 1. Age ≥ 18 years at the time of signature of the informed consent form. 2. Written informed consent obtained before any study-specific procedure. The participant must be able to understand the study requirements and must be willing and able to comply with scheduled visits, treatment, laboratory tests, imaging assessments, translational sample collection, and other protocol procedures. 3. Histologically confirmed diagnosis of one of the following soft-tissue sarcoma subtypes: undifferentiated pleomorphic sarcoma (UPS) or dedifferentiated liposarcoma (DDLPS). Pathology review and/or confirmation by the French sarcoma reference pathology network (RRePS) or an equivalent expert sarcoma pathology review process is required whenever applicable according to national practice. \[1,2\] 4. Locally advanced/unresectable and/or metastatic disease not amenable to curative-intent surgery or curative-intent radiotherapy, as assessed by the Investigator in the context of multidisciplinary sarcoma management. 5. Assignment to the appropriate histology-specific cohort before randomization: UPS participants will be enrolled in Cohort A, and DDLPS participants will be enrolled in Cohort B. 6. Prior neoadjuvant and/or adjuvant systemic therapy is allowed if completed at least 6 months before randomization, provided that prior anthracycline exposure does not preclude safe administration of protocol doxorubicin according to institutional standards and cumulative lifetime anthracycline limits. 7. At least one measurable lesion according to RECIST v1.1. A measurable lesion must be accurately measurable in at least one dimension and have a longest diameter of ≥ 10 mm by CT scan or MRI, except for lymph nodes, which must have a short-axis diameter of ≥ 15 mm. Lesions located in a previously irradiated field may be considered measurable only if unequivocal progression has been documented after completion of radiotherapy. \[21\] 8. Baseline tumor assessment performed by CT scan and/or MRI according to RECIST v1.1 within the protocol-defined screening window before randomization. \[21\] 9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 10. Life expectancy \> 3 months according to the Investigator. 11. Eligible to receive doxorubicin-based first-line chemotherapy, including adequate cardiac function with left ventricular ejection fraction (LVEF) ≥ 50% by echocardiography or multigated acquisition scan (MUGA) performed during screening or within a period acceptable according to institutional practice, provided no intervening cardiac event has occurred. 12. Adequate hematologic and end-organ function, based on laboratory values obtained within 7 days prior to randomization unless otherwise specified. 1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL. Transfusion and/or growth factor support immediately before screening laboratory evaluation should be documented and should not be used to mask persistent inadequate bone marrow function. 2. Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for participants with Gilbert syndrome, for whom total bilirubin ≤ 3 x ULN is acceptable provided direct bilirubin is within normal range or clinically acceptable. 3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN, or ≤ 5 x ULN in the presence of liver metastases. 4. Alkaline phosphatase ≤ 2.5 x ULN, or ≤ 5 x ULN in the presence of liver and/or bone involvement attributable to disease. 5. Serum albumin ≥ 30 g/L. 6. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 30 mL/min according to Cockcroft-Gault or local institutional standard method. 7. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN, unless the participant is receiving anticoagulant therapy and coagulation parameters are within the expected therapeutic range for that treatment. 13. Adequate washout from prior anticancer therapy, if applicable: at least 5 half-lives or 28 days (whichever is longer) since the last dose of prior systemic chemotherapy or immunotherapy, and at least 2 weeks since the last radiotherapy or other local anticancer therapy, unless a shorter interval is clinically justified and approved by the Sponsor or Coordinating Investigator. Palliative radiotherapy to non-target lesions may be allowed if completed before randomization and if all acute toxicity has resolved to Grade ≤ 1. 14. Recovery to Grade ≤ 1 from prior treatment-related toxicities according to NCI CTCAE v 6.0, except alopecia of any grade, vitiligo of any grade, endocrinopathies controlled by replacement therapy, or non-painful peripheral neuropathy Grade ≤ 2. \[24\] 15. Patients shall be eligible to undergo IMP treatment and tumor biopsies. Patients who either do not consent to a tumor biopsy or do not have accessible lesions will not be eligible. 16. Availability of representative archival tumor material when feasible and willingness to allow its use for protocol-defined translational research. A fresh pretreatment biopsy is strongly recommended when clinically feasible and safe; refusal or inability to undergo a fresh biopsy should not preclude enrollment unless otherwise specified in the translational laboratory manual. 17. Willingness to provide protocol-defined blood samples for translational and pharmacodynamic research, including baseline and on-treatment samples, as specified in the schedule of assessments. 18. For women of childbearing potential \*: negative serum or certified highly sensittive urine pregnancy test within 72 hours before the first dose of study treatment (In the event of a positive or uninterpretable urine result, a confirmatory serum pregnancy test must be performed immediately) and willingness to use highly effective contraception\*\* during study treatment and after the last dose of study treatment for the period required by doxorubicin and DT-7012 risk management, i.e. at least 6 months after the last dose of doxorubicin and/or at least 6 months after the last dose of DT-7012, whichever is longer. \[8-10\] 19. For male participants with a partner of childbearing potential: willingness to use effective contraception during study treatment and for at least 6 months after the last dose of doxorubicin and/or at least 6 months after the last dose of DT-7012, whichever is longer. Male participants should refrain from sperm donation during this period. \[8-10\] . In addition, the female partner of childbearing potential should use highly effective method of contraception during trial participation starting with the Informed Consent Form signature and for at least 6 months after the last dose of DT-7012 20. Affiliation to a social security system, or beneficiary of such a system, in compliance with French law relating to biomedical research. Exclusion Criteria: 1. Diagnosis of a sarcoma subtype other than UPS or DDLPS, including well-differentiated liposarcoma without a dedifferentiated component, gastrointestinal stromal tumor, Kaposi sarcoma, desmoid tumor, Ewing sarcoma, rhabdomyosarcoma, bone sarcoma, or any other non-eligible histology. \[2\] 2. Disease considered amenable to curative-intent local therapy at the time of screening. 3. Prior systemic anticancer therapy for locally advanced/unresectable or metastatic disease. 4. Prior exposure to DT-7012 or any other CCR8-targeting agent. 5. Prior exposure to anthracyclines at or above the maximum cumulative dose allowed (550 mg/m²) according to the doxorubicin summary of product characteristics, institutional standards, or Investigator assessment, or any prior anthracycline-related cardiomyopathy. Participants for whom prior anthracycline exposure would prevent safe protocol doxorubicin administration are not eligible. 6. Known hypersensitivity or contraindication to doxorubicin, DT-7012, any of their excipients, or compounds of similar chemical or biological composition, including history of severe allergic, anaphylactic, or other hypersensitivity reactions to monoclonal antibodies or fusion proteins. \[8-10\] 7. Any contraindication to doxorubicin according to applicable product information, including but not limited to severe myocardial insufficiency, recent myocardial infarction, severe arrhythmia, severe persistent myelosuppression, severe hepatic impairment, or uncontrolled infection. 8. Active or uncontrolled autoimmune disease or immune deficiency requiring systemic treatment. Exceptions may include stable autoimmune-related hypothyroidism on hormone replacement, type 1 diabetes mellitus on insulin, stable adrenal or pituitary insufficiency on replacement therapy, vitiligo, psoriasis, or eczema not requiring systemic immunosuppressive therapy, after Investigator assessment. 9. Treatment with systemic immunosuppressive medication within 14 days prior to Cycle 1 Day 1, or anticipated need for systemic immunosuppressive medication during study treatment, with the exception of physiologic replacement corticosteroids, inhaled or topical corticosteroids, local steroid injections, premedication for hypersensitivity prophylaxis, or short-course steroids used for management of adverse events according to protocol. 10. Chronic systemic corticosteroid therapy at a dose \> 10 mg/day prednisone equivalent within 14 days prior to Cycle 1 Day 1, unless approved by the Sponsor or Coordinating Investigator for a non-immunosuppressive indication. 11. Any prior Grade ≥ 3 immune-related adverse event related to previous immunotherapy, or any unresolved immune-related adverse event \> Grade 1, except endocrinopathy controlled by replacement therapy. 12. Administration of a live attenuated vaccine within 30 days prior to the first dose of study treatment, or planned administration of a live attenuated vaccine during study treatment. Inactivated vaccines and non-live vaccines are permitted according to local recommendations. 13. Active infection requiring systemic therapy within 2 weeks prior to Cycle 1 Day 1, severe infection within 4 weeks prior to Cycle 1 Day 1, active tuberculosis, or any uncontrolled intercurrent infection. \[29\] 14. Known active hepatitis B infection, active hepatitis C infection, or uncontrolled HIV infection. Participants with resolved hepatitis B infection or controlled chronic viral infection may be eligible according to local standards and after appropriate specialist assessment, provided antiviral prophylaxis/monitoring is implemented when indicated. 15. Symptomatic, untreated, or unstable central nervous system metastases or leptomeningeal disease. Participants with previously treated CNS lesions may be eligible if clinically stable, off prohibited corticosteroids, and without evidence of progression according to Investigator assessment. 16. History of idiopathic pulmonary fibrosis, non-infectious pneumonitis requiring systemic corticosteroids, organizing pneumonia, drug-induced pneumonitis, immune-related pneumonitis, current interstitial lung disease, or evidence of active pneumonitis on screening imaging. Radiation-induced fibrosis confined to a prior radiation field is permitted if clinically stable. 17. Uncontrolled or clinically significant cardiovascular disease, including but not limited to myocardial infarction, acute coronary syndrome, coronary angioplasty/stenting or bypass grafting within 6 months; stroke or transient ischemic attack within 6 months; uncontrolled angina within 3 months; clinically significant arrhythmia; QTc \> 480 ms; congestive heart failure NYHA class III or IV; cardiomyopathy; clinically significant pericardial effusion; or poorly controlled venous thromboembolic disease. 18. Uncontrolled hypertension, defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 110 mmHg despite appropriate medical management. Participants with initial blood pressure elevation may be eligible if blood pressure is controlled before randomization. 19. Major surgery within 4 weeks prior to randomization or failure to recover adequately from surgery. Participants must have adequate wound healing before initiation of study treatment. 20. Pregnant or breastfeeding women, or participants intending to become pregnant or father a child during the study or within the protocol-defined post-treatment contraception period. 21. Prior or concurrent malignancy within the past 2 years, except malignancies with negligible risk of metastasis or death and treated with expected curative outcome, including adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, carcinoma in situ treated with curative intent, superficial/non-invasive bladder cancer, or endoscopically resected gastrointestinal neoplasia limited to the mucosa with no recurrence for more than 1 year. 22. Participation in another interventional clinical trial with an investigational medicinal product within 30 days before randomization or within 5 half-lives of the investigational product, whichever is longer. Participation in non-interventional studies or registries is permitted provided that it does not interfere with this protocol. 23. Known alcohol or drug abuse, psychiatric disorder, social situation, geographic constraint, or any other condition that, in the Investigator's opinion, may compromise participant safety, interfere with study treatment administration, impair compliance with study procedures, or affect interpretation of study results. 24. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent. 25. Any other condition that, in the Investigator's opinion, makes participation in the clinical trial undesirable or unsafe.