A Study Comparing the Efficacy of L19TNF+Doxorubicin vs Doxorubicin Alone as First-line Therapy in Patients With Advanced or Metastatic Soft Tissue Sarcoma

Inclusion Criteria:

1. Patients aged 18-75 years.
2. Patients must have histological evidence of advanced unresectable and/or metastatichigh-grade soft tissue sarcoma (grade 2 - 3 according to the FNCLCC grading system)not amenable to curative treatment with surgery or radiotherapy and for whichdoxorubicin treatment is considered appropriate. Participants with Osteosarcoma,Chondrosarcoma, Ewing Sarcoma/ Primitive Neuroectodermal Tumor (PNET), Kaposi'sSarcoma, Dermatofibrosarcoma protuberans, and Gastrointestinal Stromal Tumors (GIST)will be excluded
3. Patients must have at least one unidimensionally measurable lesion by computedtomography as defined by RECIST criteria 1.1. This lesion should not have beenirradiated during previous treatments.
4. Life expectancy of at least 3 months.
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
6. Documented negative test for HIV-HBV-HCV. For HBV serology: the determination ofHBsAg, anti-HBsAg-Ab and anti-HBCAg-Ab is required. In patients with serologydocumenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccinationand/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV-RNA or HCVantibody test. Subjects with a positive test for HCV antibody but no detection ofHCV-RNA indicating no current infection are eligible.
7. Female patients: negative serum pregnancy test at screening for women of childbearingpotential (WOCBP)*. WOCBP must agree to use, from the screening to six monthsfollowing the last administration of L19TNF and/or Doxorubicin, highly effectivecontraception methods, as defined by the "Recommendations for contraception andpregnancy testing in clinical trials" issued by the Head of Medicine Agencies'Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, forinstance, progesterone-only or combined (estrogen- and progesterone-containing)hormonal contraception associated with inhibition of ovulation, intrauterine devices,intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomizedpartner or sexual abstinence. Male patients: Male subjects able to father childrenmust agree to use two acceptable methods of contraception from the screening to fourmonths following the last administration of L19TNF and/or Doxorubicin (e.g. condomwith spermicidal gel). Double-barrier contraception is required.
8. Informed consent signed and dated to participate in the study.
9. Willingness and ability to comply with the scheduled visits, treatment plan,laboratory tests and other study procedures.

Exclusion Criteria:

1. Prior therapy (except surgery and radiation) for unresectable or metastatic malignantsoft tissue sarcoma.
2. Previous treatment with anthracycline-containing chemotherapy.
3. Radiotherapy within 4 weeks prior to therapy.
4. Known history of allergy to TNFα, anthracyclines or other intravenously administeredhuman proteins/peptides/antibodies.
5. Previous therapy with recombinant TNF.
6. Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl.
7. Chronically impaired renal function or creatinine ≥ 2.0 x ULN.
8. Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN.
9. Any severe concomitant condition which makes it undesirable for the patient toparticipate in the study or which could jeopardize compliance with the protocol.
10. History within the last year of acute or subacute coronary syndromes includingmyocardial infarction, unstable or severe stable angina pectoris.
11. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
12. Clinically significant cardiac arrhythmias or requiring permanent medication.
13. Uncontrolled hypertension, despite optimal therapy.
14. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaineclassification).
15. Severe diabetic retinopathy such as severe non-proliferative retinopathy andproliferative retinopathy.
16. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery)within 4 weeks of administration of study treatment.
17. Pregnancy or breast-feeding.
18. Requirement of chronic administration of corticosteroids or other immunosuppressantdrugs. Limited use of corticosteroids to treat or prevent acute hypersensitivityreactions is not considered an exclusion criterion.
19. Presence of active and uncontrolled infections or other severe concurrent disease,which, in the opinion of the investigator, would place the patient at undue risk orinterfere with the study.
20. Known active or latent tuberculosis (TB).
21. Concurrent malignancies other than Soft Tissue Sarcoma, unless the patient has beendisease-free for at least 2 years.
22. Growth factors or immunomodulatory agents within 7 days prior to the administration ofstudy treatment.
23. Serious, non-healing wound, ulcer or bone fracture.
24. Allergy to study medication or excipients in study medication.
25. Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6months.
26. Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) andvitamin K antagonists (e.g., phenprocoumon, warfarin).
27. Concurrent use of other anti-cancer treatments or agents other than study medication.