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

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

Exclusion Criteria

• Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma.
• Previous treatment with anthracycline-containing chemotherapy.
• Radiotherapy within 4 weeks prior to therapy.
• Known history of allergy to TNFα, anthracyclines or other intravenously administered human proteins/peptides/antibodies.
• Previous therapy with recombinant TNF.
• Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl.
• Chronically impaired renal function or creatinine ≥ 2.0 x ULN.
• Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN.
• Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
• Clinically significant cardiac arrhythmias or requiring permanent medication.
• Uncontrolled hypertension, despite optimal therapy.
• Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
• Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy.
• Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment.
• Pregnancy or breast-feeding.
• Requirement of chronic administration of corticosteroids or other immunosuppressant drugs. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
• 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 or interfere with the study.
• Known active or latent tuberculosis (TB).
• Concurrent malignancies other than Soft Tissue Sarcoma, unless the patient has been disease-free for at least 2 years.
• Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment.
• Serious, non-healing wound, ulcer or bone fracture.
• Allergy to study medication or excipients in study medication.
• Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6 months.
• Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and vitamin K antagonists (e.g., phenprocoumon, warfarin).
• Concurrent use of other anti-cancer treatments or agents other than study medication.