Treatments and/or Procedures

Study Criteria

Inclusion Criteria:

  -  Patients with histologically or cytologically confirmed advanced solid cancer deemed
     suitable for combination therapy of L19TNFα and doxorubicin.

  -  Patients aged ≥18 years old with advanced or metastatic solid tumor in whom standard
     anticancer therapies have been exhausted and who are amenable for a doxorubicin
     monotherapy according to the discretion of the Principal Investigators and previously
     treated with a cumulative dose of anthracyclines (≤ 300 mg/m2).

  -  Eastern cooperative oncology group (ECOG) performance status ≤ 2.

  -  Patients may have received previous chemotherapy (>4 weeks prior therapy) or radiation
     therapy (>6 weeks prior therapy), but they must be amenable for doxorubicin treatment
     according to the discretion of the Principal Investigator.

  -  Patients must have at least one unidimensionally measurable lesion by computed
     tomography as defined by RECIST criteria version 1.1. This lesion must not have been
     irradiated during previous treatments.

  -  Previous anthracycline therapy, including liposomal doxorubicin, for metastatic and/or
     adjuvant disease is allowed. However, patients must not have received a cumulative
     anthracycline dose of more than 300 mg/m2 of doxorubicin, nor more than 500 mg/m2 of
     epirubicin, nor more than 600 mg/m2 of pegylated or non-pegylated liposomal
     doxorubicin prior to study entry, in order to avoid anthracycline-associated
     cardiotoxicity.

  -  Life expectancy more than 3 months.

  -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L and haemoglobin
     (Hb) ≥ 9.5 g/dl.

  -  All acute adverse effects (excluding alopecia) of any prior therapy (including
     surgery, radiation therapy, chemotherapy) must have resolved to ≤ Grade 1, except
     elevated liver transaminases judged to be associated with tumor infiltration (see
     below) (graded according to the National Cancer Institute CTCAE v.4.02 dated September
     15, 2009).

  -  Alkaline phosphatase (AP), alanine aminotransferase (ALT) and/or aspartate
     aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 2.0
     mg/dL, unless liver involvement by the tumor, in which case the transaminase levels up
     to 5 x ULN are allowed.

  -  Creatinine ≤ 1.5 ULN or 24 h creatinine clearance ≥ 60 mL/min.

  -  Testing negative for acute or chronic infection with hepatitis B or C virus, or human
     immunodeficiency virus 1 or 2.

  -  Negative pregnancy test for females of childbearing potential at the screening visit.

  -  Commitment from patient to practice medically appropriate/acceptable method of birth
     control beginning 30 days before study entry and continuing until 6 months following
     the last treatment with study drug. Excluding women without childbearing potential;
     menopause at least 2 years earlier, tubal ligation at least 1 year earlier, or total
     hysterectomy. The definition of effective contraception will be based on the
     guidelines ICH M3 rev2.

  -  Evidence of a personally signed and dated EC-approved ICF indicating that the patient
     (or legally acceptable representative) has been informed of all pertinent aspects of
     the study.

  -  Willingness and ability to comply with the scheduled visits, treatment plan,
     laboratory tests and other study procedures.

ICF must be obtained for all the patients before enrollment into the study.

Exclusion Criteria:

  -  Pregnancy or breast-feeding. Patients must agree to use effective contraception, or be
     surgically sterile or postmenopausal. The definition of effective contraception will
     be based on the guidelines ICH M3 rev2.

  -  Presence of active infections (e.g. requiring antimicrobial therapy) or other severe
     concurrent disease, which, in the opinion of the investigator, would place the subject
     at undue risk or interfere with the study.

  -  Presence of known brain metastases. If patient is symptomatic, negative CT scan within
     two months before study beginning is required. However, presence of controlled brain
     metastases (i.e., evaluated as SD of PR after radiotherapy) is allowed.

  -  Known cancer of other primary origin within the prior 5 years.

  -  History of chronic hepatitis B or C, or chronic active hepatitis or active autoimmune
     diseases.

  -  Cardiac disease as manifested by any of the following:

       -  > Grade II heart failure, graded per New York Heart Association (NYHA) criteria.

       -  History within the last year of acute or subacute coronary syndromes including
          myocardial infarction, unstable or severe stable angina pectoris.

       -  Irreversible cardiac arrhythmias requiring permanent medication.

       -  Ejection fraction less than the institutional lower limit of normal as assessed
          by MUGA scan or echocardiogram.

  -  Uncontrolled hypertension.

  -  Ischemic peripheral vascular disease (Grade IIb-IV).

  -  Severe rheumatoid arthritis.

  -  Severe diabetic retinopathy.

  -  History of allograft or stem cell transplantation.

  -  Major surgery or trauma within 4 weeks prior to start of study treatment.

  -  Known history of allergy to TNFα, Anthracyclines or other intravenously administered
     human proteins/peptides/antibodies.

  -  Chemotherapy (standard or experimental), or therapy with an investigational agent
     within 4 weeks prior to start of study treatment, and radiation within 6 weeks prior
     therapy.

  -  Cumulative exposure to anthracycline-containing chemotherapy (patients received a
     cumulative anthracycline dose of more than 300 mg/m2 of doxorubicin or of more than
     500 mg/m2 of epirubicin or pegylated or non-pegylated liposomal doxorubicin), prior to
     study entry precluding the application of at least an additional 150 mg/m2 doxorubicin
     (total dose for 2 cycles of study therapy).

  -  Treatment with an investigational study drug within six weeks before beginning of
     treatment with L19TNFα.

  -  Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6
     weeks before administration of study treatment.

  -  Growth factors or immunomodulatory agents within 7 days prior to the administration of
     study treatment.

  -  Neuropathy > Grade 1.

  -  Patient requires or is taking corticosteroids or other immunosuppressant drugs on a
     long-term basis. Limited use of corticosteroids to treat or prevent acute
     hypersensitivity reactions is not considered an exclusion criterion.

  -  Concurrent therapy with anticoagulants at full dose .

  -  Participation in another interventional clinical trial during participation in this
     trial.

  -  Expectation that the patient will not be able to complete at least 6 weeks of therapy.

  -  Any conditions that in the opinion of the investigator could hamper compliance with
     the study protocol.