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

Sponsor

AGC Biologics S.p.A. (Industry)

Overall Status

Completed

CT.gov ID

NCT00484341

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

9.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Adult Soft Tissue Sarcoma	Drug: low-dose NGR-hTNF Drug: high-dose NGR-hTNF Drug: Doxorubicin	Phase 2

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

69 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

NGR016: Randomized Phase II Study Evaluating Two Doses of NGR-hTNF Administered Either as Single Agent or in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma (STS)

Actual Study Start Date :

Oct 1, 2010

Actual Primary Completion Date :

May 1, 2016

Actual Study Completion Date :

May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A: low-dose NGR-hTNF 0.8 mcg/m² of NGR-hTNF	Drug: low-dose NGR-hTNF NGR-hTNF: 0.8 mcg/m² as 60-minutes intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs Other Names: NGR-hTNF
Experimental: B: high-dose NGR-hTNF 45 mcg/m² of NGR-hTNF	Drug: high-dose NGR-hTNF NGR-hTNF: 45 mcg/m² as 60-minutes intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs Other Names: NGR-hTNF
Experimental: C: low-dose NGR-hTNF + doxorubicin 0.8 mcg/m² of NGR-hTNF + doxorubicin	Drug: low-dose NGR-hTNF NGR-hTNF: 0.8 mcg/m² as 60-minutes intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs Other Names: NGR-hTNF Drug: Doxorubicin Doxorubicin: 60 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) on day 1 every 3 weeks for a maximum of 6 cycles or until cumulative dose of 550 mg/m²
Experimental: D: high-dose NGR-hTNF + doxorubicin 45 mcg/m² of NGR-hTNF + doxorubicin	Drug: high-dose NGR-hTNF NGR-hTNF: 45 mcg/m² as 60-minutes intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs Other Names: NGR-hTNF Drug: Doxorubicin Doxorubicin: 60 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) on day 1 every 3 weeks for a maximum of 6 cycles or until cumulative dose of 550 mg/m²

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre Leon Berard	Lyon		France	69373
2	Institut de Cancérologie Gustave Roussy	Villejuif		France	94805
3	Istituto Ortopedico Rizzoli	Bologna		Italy	40136
4	Fondazione IRCCS Istituto Nazionale dei Tumori di Milano	Milan		Italy	20133
5	IRCCS Policlinico S. Matteo	Pavia		Italy	27100
6	Università Campus Bio-Medico	Rome		Italy	00128
7	Clatterbridge Centre for Oncology	Bebington	Wirral	United Kingdom	BA11 3