NGRhTNF, a new vascular targeting agent with a dual mechanism of action: preliminary clinical results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13052-13052
Author(s):  
C. Bordignon ◽  
F. Caligaris Capio ◽  
S. Toma ◽  
L. Manenti ◽  
P. Rizzardi ◽  
...  
Keyword(s):  
Phase I ◽  
Anticancer Activity ◽  
Vascular Permeability ◽  
Mechanism Of Action ◽  
Phase I Study ◽  
Low Dose ◽  
Moderate Intensity ◽  
Vascular Targeting ◽  
Dce Mri ◽  
Vascular Targeting Agent

13052 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding solid tumor (lung, renal, and colorectal) neovasculature. NGRhTNF specific binding relies on dynamic interactions with TNF-receptors, aminopeptidase N (CD13) and a specific integrin: a combination of receptors expressed by the tumor neovasculature endothelium, but not on normal vessels. This combination provides NGRhTNF with unique biological properties: at low dose, increased tumor vascular permeability, and massive tumor necrosis at high dose. Mouse preclinical data confirmed these properties, revealing also strong synergy between low dose NGRhTNF and cytotoxic agents (antracyclines, platinum based compounds, etc.). Methods: Based on these data, a series of studies were designed. A multicentre phase I study with NGRhTNF as single agent -still in progress- aims at defining MTD and preliminary anticancer activity, within the EORTC network (EORTC 16041). A single center phase I study exploiting the low dose range (0.2–1.6 μg/m2) aims at defining safety and NGRhTNF activity on the tumor vascular permeability using DCE MRI (HSR NGR002). Results: Twelve advanced neoplastic patients were enrolled in the HSR NGR002 study. Up to the dose of 1.6 μg/m2, the only common toxicity was represented by constitutional symptoms such as infusion-associated chills (40%) of mild to moderate intensity. At the tested doses, NGRhTNF increased vascular permeability, as shown by changes in DCE MRI parameters (Ktrans and Kep), and modulated the expression of chemokines possessing antiangiogenic activity. NGRhTNF achieved stable disease in about 45% of highly refractory treated patients, and still ongoing long lasting disease control in 2 cases (7 and 9 months along with sharp decline of CA125 and VEGF). Conclusions: NGR-hTNF, a VTA with a unique mechanism of action, combines activity on tumor vascular permeability and direct anti-cancer effect. Preliminary data in humans confirm its favourable safety profile along with remarkable anticancer activity, thus rendering the agent suitable for a development program alone or in combination with chemotherapeutics. Phase II low dose combination studies will begin in 2006. [Table: see text]

Safety and anticancer activity of low dose regimen of NGRhTNF, a new vascular targeting agent, in solid advanced malignancies (NGR002 phase I trial)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3540-3540 ◽  
Author(s):  
C. Gallo-Stampino ◽  
G. Rizzardi ◽  
S. Toma ◽  
A. Corti ◽  
P. Scifo ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Vascular Permeability ◽  
Drug Exposure ◽  
Low Dose ◽  
Biological Effects ◽  
Cytotoxic Agents ◽  
Vascular Targeting ◽  
Frequent Event ◽  
Over Time ◽  
Vascular Targeting Agent

3540 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumours where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Methods: 4 dose levels of NGRhTNF (0.2 up to 1.6 mcg/sqm) have been administered q 3 w in 16 patients. Main end-points included safety, anticancer activity and pharmacokinetic.Measurement of circulating tumor and endothelial cells (CTC and CEC), sTNFRI and s TNFRII, along with plasma cyto-chemokine profile have been performed. Results: 16 patients were enrolled (6F/10M);median age 60,range 43–73). Toxicity was limited to constitutional symptoms, and chills were the most frequent event (40%). Over a median follow-up of 15 weeks, stable disease was achieved in 44% of patients, with long lasting disease control in 2 cases (27 and 75 weeks, with establishment of indication to radical surgery after 75 weeks, presently tumor free after removal of the residual tumor mass). In these 2 patients, VEGF, MMP-9, CA125, significantly decreased over time. DCE-MRI indicates that NGRhTNF increases vascular permeability after first drug exposure, particularly at the dose of 0.4 mcg/sqm, while following multiple infusions it exerts an antivascular effect, as demonstrated by the decrease of Ktrans values. Moreover NGRhTNF is able to elicit inflammatory and immune responses over time, as indicated by the modulation of expression of multiple cyto-chemokines. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Low dose NGRhTNF has an optimal safety profile along with anticancer activity acting on tumour vasculature and inducing relevant biological effects, thus rendering the agent suitable for a development both as monotherapy and in combination with chemotherapeutics. The phase II program is due to start in early 2007. [Table: see text]

A phase I study to define the optimal low dose of NGR-hTNF, a novel vascular targeting agent (VTA), in combination with cisplatin in patients (pts) with solid tumors

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 14647-14647 ◽  
Author(s):  
F. G. De Braud ◽  
V. Gregorc ◽  
T. M. De Pas ◽  
G. Citterio ◽  
R. Scalamogna ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Low Dose ◽  
Vascular Targeting ◽  
Vascular Targeting Agent

Phase I and DCE-MRI evaluation of NGR-TNF, a novel vascular targeting agent, in patients with solid tumors (EORTC 16041)

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 3521-3521 ◽  
Author(s):  
H. van Laarhoven ◽  
W. Fiedler ◽  
I. M. Desar ◽  
S. van Asten ◽  
S. Marreaud ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Vascular Targeting ◽  
Dce Mri ◽  
Mri Evaluation ◽  
Vascular Targeting Agent

366 POSTER Phase I study of NGR-TNF, a novel vascular targeting agent, in patients with refractory solid tumours (EORTC 16041)

2006 ◽  
Vol 4 (12) ◽  
pp. 113
Author(s):  
C. Van Herpen ◽  
W. Fiedler ◽  
S. Toma ◽  
S. Marreaud ◽  
H. Van Laarhoven ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Solid Tumours ◽  
Vascular Targeting ◽  
Vascular Targeting Agent

scholarly journals Phase I Study of NGR-hTNF, a Selective Vascular Targeting Agent, in Combination with Cisplatin in Refractory Solid Tumors

2011 ◽  
Vol 17 (7) ◽  
pp. 1964-1972 ◽  
Author(s):  
Vanesa Gregorc ◽  
Filippo G. De Braud ◽  
Tommaso M. De Pas ◽  
Roberto Scalamogna ◽  
Giovanni Citterio ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Vascular Targeting ◽  
Vascular Targeting Agent

Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

2015 ◽  
Vol 33 (7) ◽  
pp. 732-739 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Siegel ◽  
David H. Vesole ◽  
Peter Lee ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Concentration ◽  
Phase I ◽  
Phase I Study ◽  
Low Dose ◽  
Single Agent ◽  
Phase Iii ◽  
Maximum Plasma ◽  
Irreversible Inhibitor ◽  
Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

A phase I study of daily everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors

2011 ◽  
Vol 69 (3) ◽  
pp. 591-598 ◽  
Author(s):  
Matthew G. Fury ◽  
Eric Sherman ◽  
Sofia Haque ◽  
Susan Korte ◽  
Donna Lisa ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Low Dose ◽  
Advanced Solid Tumors ◽  
Weekly Cisplatin
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