L19TNFα in Combination With Doxorubicin in Patients With Advanced Solid Tumours
L19TNFα in Combination With Doxorubicin in Patients With Advanced Solid Tumours
Prospective, open-label, non randomized, dose escalation study that will be conducted in
 sequential cohorts of patients.
In the clinical trial 3-6 patients will be assigned to L19TNFalfa at one of the following
 sequential dose levels (10.4 µg/kg, 13 µg/kg and 17 µg/kg) in combination with a fixed dose
 of doxorubicin.

 The RD will be defined following a traditional 3+3 design. The dose escalation will continue
 until the MTD is found, that is until at least two patients among a cohort of three to six
 patients experience a dose limiting toxicity (DLT).
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.