Treatment of Metastatic Soft Tissue Sarcoma (STS) Patients (FIBROSARC USA)

Inclusion Criteria: Patients may be included in the study if they meet all of the following criteria:

1. Age ≥ 16 years. Patients under 18 years, should be fully grown (proof of fused growthplates).
2. Patients with histological evidence of stage IV metastatic high-grade leiomyosarcoma (grade 2 - 3 according to the Federation Nationale des Centres de Lutte Contre leCancer (FNCLCC) grading system) not amenable to curative treatment with surgery orradiotherapy.
3. Patients must have at least one unidimensionally measurable lesion by computedtomography as defined by Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1.If only 1 lesion is present at screening this lesion should not have been irradiatedduring previous treatments.
4. Life expectancy of at least 3 months in the judgment of the investigator.
5. ECOG ≤ 1.
6. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination ofHBsAg and anti-HBcAg-Ab is required. In patients with serology documenting previousexposure to HBV, negative serum HBV-DNA is required. For HCV: HCV-RNA or HCV antibodytest. Subjects with a positive test for HCV antibody but no detection of HCV-RNAindicating no current infection are eligible.
7. Female patients: negative serum pregnancy test for women of childbearing potential (WOCBP)* within 14 days of starting treatment. WOCBP must agree to use, from thescreening to six months following the last study drug administration, 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.
8. Male patients: Male subjects able to father children must agree to use two acceptablemethods of contraception throughout the study (e.g., condom with spermicidal gel).Double-barrier contraception is required.
9. Informed consent signed and dated to participate in the study.
10. Willingness and ability to comply with the scheduled visits, treatment plan,laboratory tests and other study procedures.

• Women of childbearing potential are defined as females who have experiencedmenarche, are not postmenopausal (12 months with no menses without an alternativemedical cause) and are not permanently sterilized (e.g., tubal occlusion,hysterectomy, bilateral oophorectomy or bilateral salpingectomy).

Exclusion Criteria: Patients will be excluded from participating in this study if they meet one or more of thefollowing criteria:

1. Prior therapy (except surgery and radiation) for unresectable or metastatic malignantsoft tissue sarcoma (STS).
2. Patients with primary tumor localized to the extremities and a single resectablesynchronous distant metastatic lesion.
3. Patients eligible for neoadjuvant preoperative treatment.
4. Previous treatment with anthracycline-containing chemotherapy.
5. Radiotherapy within 4 weeks prior to start of therapy.
6. Known history of allergy to TNFα, anthracyclines or other intravenously (IV)administered human proteins/peptides/antibodies.
7. Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl.
8. Chronically impaired renal function as expressed by creatinine clearance < 60 mL/minor serum creatinine > 1.5 ULN.
9. Inadequate liver function (ALT, AST, GGT, ALP or total bilirubin ≥ 1.5 x ULN) or totalbilirubin ≥ 1.5 x ULN).
10. International normalized ratio (INR) > 1.5 ULN.
11. Any severe concomitant condition which makes it undesirable for the patient toparticipate in the study or which could jeopardize compliance with the protocol.
12. History within the last year of cerebrovascular disease and/or acute or subacutecoronary syndromes including myocardial infarction, unstable or severe stable anginapectoris.
13. Heart insufficiency (any grade, New York Heart Association (NYHA) criteria).
14. Left Ventricular Ejection Fraction (LVEF) < 50%.
15. Clinically significant cardiac arrhythmias or requiring permanent medication.
16. Abnormalities observed during baseline ECG and Echocardiogram investigations that areconsidered as clinically significant by the investigator. Subjects with current, or ahistory of QT/QTc prolongation would be excluded. In particular:

• patients with a marked prolongation of QT/QTc interval (e.g., repeateddemonstration of QTc >480 milliseconds using Fredricia's QT correction formula)are excluded;
• patients with a history of risk factors for Torsades de Pointes (e.g., heartfailure, hypokalemia, family history of prolonged QT syndrome) are excluded;
• patients who require the use of concomitant medications that prolong the QT/QTcinterval are excluded.

17. Uncontrolled hypertension, despite optimal therapy.
18. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaineclassification).
19. Severe diabetic retinopathy such as severe non-proliferative retinopathy andproliferative retinopathy.
20. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery)within 4 weeks of administration of study treatment.
21. Pregnancy or breast-feeding.
22. 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.
23. 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.
24. Known active or latent tuberculosis (TB).
25. Concurrent malignancies other than soft tissue sarcoma (STS), unless the patient hasbeen disease-free for at least 2 years.
26. Growth factors or immunomodulatory agents within 7 days prior to the administration ofstudy treatment.
27. Serious, non-healing wound, ulcer or bone fracture.
28. Allergy to study medication or excipients in study medication.
29. Concurrent therapy with anticoagulants.
30. Concurrent use of other anti-cancer treatments or agents other than study medication.
31. Any recent live vaccination within 4 weeks prior to treatment or plan to receivevaccination during the study.