The present study is an open-label, randomized, controlled, two-arm multi-center study of the efficacy of L19TNF treatment in combination with doxorubicin versus doxorubicin alone in metastatic leiomyosarcoma patients.

In the study, 122 patients will be randomized in a 1:1 ratio to receive doxorubicin treatment (Arm 1) or L19TNF treatment in combination with doxorubicin (Arm 2).

The primary objective of the trial is to evaluate if L19TNF in combination with doxorubicin (Arm 2) given for metastatic leiomyosarcoma improves efficacy measured as progression free survival, as compared to doxorubicin alone (Arm 1).

Anti-cancer activity will be assessed every 6 weeks during therapy and every 12 weeks thereafter.

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 growth plates).

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 le Cancer (FNCLCC) grading system) not amenable to curative treatment with surgery or radiotherapy.

3. Patients must have at least one unidimensionally measurable lesion by computed tomography 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 irradiated during 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 of HBsAg and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV, 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.

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 the screening to six months following the last study drug administration, 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.

8. Male patients: Male subjects able to father children must agree to use two acceptable methods 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 experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical 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 the following criteria:

1. Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma (STS).

2. Patients with primary tumor localized to the extremities and a single resectable synchronous 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/min or serum creatinine > 1.5 ULN.

9. Inadequate liver function (ALT, AST, GGT, ALP or total bilirubin ≥ 1.5 x ULN) or total bilirubin ≥ 1.5 x ULN).

10. International normalized ratio (INR) > 1.5 ULN.

11. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.

12. History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.

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 are considered as clinically significant by the investigator. Subjects with current, or a history of QT/QTc prolongation would be excluded. In particular:

    • patients with a marked prolongation of QT/QTc interval (e.g., repeated demonstration 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., heart failure, hypokalemia, family history of prolonged QT syndrome) are excluded;
    • patients who require the use of concomitant medications that prolong the QT/QTc interval are excluded.

17. Uncontrolled hypertension, despite optimal therapy.

18. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).

19. Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative 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 immunosuppressant drugs. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions 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 or interfere with the study.

24. Known active or latent tuberculosis (TB).

25. Concurrent malignancies other than soft tissue sarcoma (STS), unless the patient has been disease-free for at least 2 years.

26. Growth factors or immunomodulatory agents within 7 days prior to the administration of study 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 receive vaccination during the study.