Phase II Study of NGR-hTNF in Combination With Doxorubicin in Patients Affected by Soft Tissue Sarcomas.

Considering the safety/toxicity profile of NGR-hTNF characterized by mild-to-moderate constitutional symptoms when given either every three weeks or weekly both at low (0.8 µg/m^2) and high dose (45 µg/m^2); the reversibility of these adverse events generally occurring only during the infusion time; the absence of overlapping toxicities with chemotherapeutic agents; and the safety and preliminary antitumor activity observed in phase Ib trial with doxorubicin, seems justified to evaluate in a randomized 4-arm phase II trial the preliminary antitumor activity of two doses of NGR-hTNF (0.8 µg/m^2 and 45 µg/m^2) administered weekly either alone or in combination with a standard dose of doxorubicin (60 mg/m^2 every three weeks).

Inclusion criteria

• Patients ≥ 18 years
• Histologically-proven, locally advanced, or metastatic STS (excluding extraosseus Ewing sarcoma)
• Patients not amenable to surgery, radiotherapy, or combined-modality therapy with curative intent
• Patients untreated or previously treated with one or more systemic regimen
• ECOG Performance status 0-2 (Appendix A)
• At least one untreated (not previously irradiated) target lesion that could be measured in one dimension, according to RECIST criteria
• A life expectancy of 12 weeks or more
• Adequate baseline bone marrow, hepatic and renal function, defined as follows:

• Neutrophils > 1.5 x 109/L and platelets > 100 x 109/L
• Bilirubin < 1.5 x ULN
• AST and/or ALT < 2.5 x ULN in absence of liver metastasis or < 5 x ULN in presence of liver metastasis
• Serum creatinine < 1.5 x ULN
• Creatinine clearance (estimated according to Cockcroft-Gault formula) ≥ 50 ml/min
• Patients may have had prior treatment providing the following conditions are met before treatment start:

• Surgery and radiation therapy: wash-out period of 14 days
• Systemic therapy: wash-out period of 21 days
• Patients must give written informed consent

Exclusion criteria

• Patients may not receive any other investigational agents while on study
• Patients with myocardial infarction within the last six (6) months, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication
• LVEF < 55% (only for patients candidate for doxorubicin treatment)
• Uncontrolled hypertension
• Prolonged QTc interval (congenital or acquired) > 450 ms
• History or evidence upon physical examination of CNS disease unless adequately treated (e.g., primary brain tumor, any brain metastasis, seizure not controlled with standard medical therapy) or history of stroke
• Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol
• Known hypersensitivity/allergic reaction or contraindications to human albumin preparations or to any of the excipients
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol
• Pregnancy or lactation. Patients - both males and females - with reproductive potential (i.e. menopausal for less than 1-year and not surgically sterilized) must practice effective contraceptive measures throughout the study. Women of child-bearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration