Efficacy and Safety of L19TNF in Previously Treated Patients with Advanced Stage or Metastatic Soft-tissue Sarcoma

Inclusion Criteria:

1. Male or female, 18 to 80 years of age.

2. Histologically or cytologically confirmed advanced unresectable or metastatic softtissue sarcoma (STS), Grade 2 - 3 according to the FNLCC grading system.Participants with bone sarcomas including Ewing sarcoma, Kaposi's sarcoma andgastrointestinal stromal tumors (GIST) will be excluded.

3. Subjects who received at least two prior systemic therapies (e.g., anthracyclines,taxanes, ifosfamide, gemcitabine, trabectedin, pazopanib, eribulin) for advanced ormetastatic disease including at least one prior therapy based on anthracyclines asmonotherapy or in combination. Neoadjuvant and adjuvant therapies can be consideredas a prior line of treatment if the time to recurrence from completion of treatmentwas ≤ 12 months. Previous therapy with anthracyclines is not compulsory insituations of contraindications to this class of drugs. All previous therapies musthave completed ≥ 3 weeks (21 days) prior to study treatment start.

4. Evidence of disease progression after prior line of therapy for advanced ormetastatic disease.

5. Patients must have at least one unidimensionally measurable lesion by computedtomography as defined by RECIST criteria v.1.1. If only one lesion is present atscreening this lesion should not have been irradiated during previous treatments.

6. Life expectancy of at least 3 months in the judgment of the investigator.

7. ECOG ≤ 2.

8. Documented negative test for HIV-HBV-HCV. For HBV serology: the determination ofHBsAg and anti-HBcAg-Ab is required. In patients with serology documenting previousexposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBcAb), 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-RNAindicating no current infection are eligible.

9. Female patients: negative serum pregnancy test at screening for women ofchildbearing potential (WOCBP)*. WOCBP must agree to use, from the screening to sixmonths following the last study administration of L19TNF and/or DTIC, highlyeffective contraception methods, as defined by the "Recommendations forcontraception and pregnancy testing in clinical trials" issued by the Head ofMedicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) andwhich include, for instance, progesterone-only or combined (estrogen- andprogesterone-containing) hormonal contraception associated with inhibition ofovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateraltubal occlusion, vasectomized partner or sexual abstinence. Male patients: Malesubjects able to father children must agree to use two acceptable methods ofcontraception throughout the study from the screening to six months following thelast administration of L19TNF and/or DTIC (e.g. condom with spermicidal gel).Double-barrier contraception is required.

10. Evidence of a personally signed and dated informed consent document indicating thatthe subject has been informed of all pertinent aspects of the study.

11. 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 analternative medical cause) and are not permanently sterilized (e.g., tubalocclusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).

Exclusion Criteria:

1. Anti-cancer treatment with radiation therapy (with the exception of radiation ofsingle lesions for palliative reasons, e.g. pain management which then are not takenas indicator lesions for iRECIST response), chemotherapy, targeted therapies,immunotherapy, hormones or other antitumor therapies within 3 weeks prior to studytreatment start.

2. Subjects who participated in an investigational drug or device study within 3 weeksprior to study treatment start.

3. Previous treatment with TNF or L19TNF or DTIC.

4. Known history of allergy to intravenously administered humanproteins/peptides/antibodies and any other constituent of the product.

5. Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L andhemoglobin (Hb) < 9.0 g/dl, with the exception of values lower than these due tocytologically or histologically proven marrow metastasis, which will not constituteexclusion criteria.

6. Chronically impaired renal function as expressed by creatinine clearance < 60 mL/minor serum creatinine > 1.5 ULN.

7. Inadequate liver function (ALT or AST ≥ 3 x ULN or ALP or GGT ≥ 2.5 x ULN, or totalbilirubin ≥ 1.5 x ULN). For patients with metastatic lesions in the liver ALT, AST,GGT or ALP ≥ 5 x ULN.

8. Any severe concomitant condition which in the opinion of investigators makes itundesirable for the patient to participate in the study or which could jeopardizecompliance with the protocol.

9. History within the last year of cerebrovascular disease and/or acute or subacutecoronary syndromes including myocardial infarction, unstable or severe stable anginapectoris.

10. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).

11. Clinically significant cardiac arrhythmias.

12. Abnormalities observed during baseline ECG and echocardiogram investigations thatare considered as clinically significant by the investigator.

13. Uncontrolled hypertension.

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. Serious, non-healing wound, ulcer or bone fracture.

23. Allergy to study medication or excipients in study medication.

24. Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6months

25. Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) andvitamin K antagonists (e.g., phenprocoumon, warfarin).

26. Concurrent use of other anti-cancer treatments or agents other than studymedication.

27. Protected adults (i.e., persons referred to as adults who are under legal protectionmeasure or unable to express their consent) or persons under the protection ofjustice.