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

Phase 2

Completed

Interventions: Drug: high-dose NGR-hTNF
Drug: low-dose NGR-hTNF
Drug: Doxorubicin

Brief Summary: 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.

Detailed Description: 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).

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
B: high-dose NGR-hTNF	high-dose NGR-hTNF	45 mcg/m² of NGR-hTNF
D: high-dose NGR-hTNF + doxorubicin	high-dose NGR-hTNF	45 mcg/m² of NGR-hTNF + doxorubicin
C: low-dose NGR-hTNF + doxorubicin	low-dose NGR-hTNF	0.8 mcg/m² of NGR-hTNF + doxorubicin
A: low-dose NGR-hTNF	low-dose NGR-hTNF	0.8 mcg/m² of NGR-hTNF
C: low-dose NGR-hTNF + doxorubicin	Doxorubicin	0.8 mcg/m² of NGR-hTNF + doxorubicin
D: high-dose NGR-hTNF + doxorubicin	Doxorubicin	45 mcg/m² of NGR-hTNF + doxorubicin

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	every 6-12 weeks	Defined as the time from the date of randomization until disease progression, or death

Secondary Outcome Measures

Name	Time	Method
Response rate	every 6-12 weeks	Measured both according to RECIST criteria and by FDG-PET
Duration of Disease Control	every 6-12 weeks	Measured from the date of randomization until disease progression, or death due to any cause
Safety and Toxicity according to NCI-CTCAE criteria (version 4.02)	during the study	To evaluate safety and toxicity profile related to NGR-hTNF
Overall survival (OS)	every 6-12 weeks	Defined as the time from the date of randomization until the date of death due to any cause or the last date the patient was known to be alive
Tumor response	every 6-12 weeks	Evaluated by a centralized review of changes in tumor density on CT scan and/or perfusion MRI

Locations (7): Institut de Cancérologie Gustave Roussy
🇫🇷
Villejuif, France
Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
🇮🇹
Milan, Italy
Centre Leon Berard
🇫🇷
Lyon, France
Istituto Ortopedico Rizzoli
🇮🇹
Bologna, Italy
Università Campus Bio-Medico
🇮🇹
Rome, Italy
Clatterbridge Centre for Oncology
🇬🇧
Bebington, Wirral, United Kingdom
IRCCS Policlinico S. Matteo
🇮🇹
Pavia, Italy