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

The main objective of the trial is to document the preliminary antitumor activity of two doses of NGR-hTNF administered either alone or in combination with doxorubicin in locally advanced or metastatic soft-tissue sarcoma (STS) patients untreated or previously treated with one or more prior systemic regimen.

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).

Eligibility Criteria:
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