TY - JOUR
T1 - Phase I study of NGR-hTNF, a selective vascular targeting agent, in combination with cisplatin in refractory solid tumors
AU - Gregorc, Vanesa
AU - De Braud, Filippo G.
AU - De Pas, Tommaso M.
AU - Scalamogna, Roberto
AU - Citterio, Giovanni
AU - Milani, Alessandra
AU - Boselli, Sabrina
AU - Catania, Chiara
AU - Donadoni, Giovanni
AU - Rossoni, Gilda
AU - Ghio, Domenico
AU - Spitaleri, Gianluca
AU - Ammannati, Cristina
AU - Colombi, Scialini
AU - Caligaris-Cappio, Federico
AU - Lambiase, Antonio
AU - Bordignon, Claudio
PY - 2011/4/1
Y1 - 2011/4/1
N2 - Purpose: NGR-hTNF exploits the tumor-homing peptide asparagine-glycine- arginine (NGR) for selectively targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity. Experimental Design: NGR-hTNF was escalated using a doubling-dose scheme (0.2-0.4-0.8-1.6 μg/m
2) in combination with fixed-dose of cisplatin (80 mg/m
2), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles. Results: Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m
2 (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m
2. This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m
2 (n=3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m
2. At the dose level of 0.8 μg/m
2, expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months. Conclusions: The combination of NGR-hTNF 0.8 μg/m
2 with cisplatin 80 mg/m
2 showed favorable toxicity profile and promising antitumor activity.
AB - Purpose: NGR-hTNF exploits the tumor-homing peptide asparagine-glycine- arginine (NGR) for selectively targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity. Experimental Design: NGR-hTNF was escalated using a doubling-dose scheme (0.2-0.4-0.8-1.6 μg/m
2) in combination with fixed-dose of cisplatin (80 mg/m
2), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles. Results: Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m
2 (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m
2. This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m
2 (n=3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m
2. At the dose level of 0.8 μg/m
2, expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months. Conclusions: The combination of NGR-hTNF 0.8 μg/m
2 with cisplatin 80 mg/m
2 showed favorable toxicity profile and promising antitumor activity.
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U2 - 10.1158/1078-0432.CCR-10-1376
DO - 10.1158/1078-0432.CCR-10-1376
M3 - Article
C2 - 21307147
AN - SCOPUS:79953306455
VL - 17
SP - 1964
EP - 1972
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 7
ER -