Citation: European Journal of Cancer Supplements, Vol 7 No 2, September 2009, Page 128

G. Citterio¹, F.G. De Braud², V. Gregorc¹, T.M. De Pas², C. Noberasco², S. Boselli², M. Giovannini¹, F. Caligaris Cappio¹, A. Lambiase³, C. Bordignon<sup>3

1</sup>Istituto Scientifico San Raffaele, Department of Oncology, Milan, Italy
²European Institute of Oncology, New Drugs Development Unit, Milan, Italy
³MolMed, Clinical Development, Milan, Italy

Background: NGR-hTNF is a VTA consisting of TNF-a fused to the tumour-homing peptide (NGR) able to selectively binds an aminopeptidase N overexpressed on tumour blood vessels. Low-dose NGR-hTNF displayed significant preclinical synergism with cisplatin.
Methods: Pts with resistant/refractory solid tumours received NGR-hTNF given with a low-dose, doubling-dose scheme (0.2–0.4–0.8–1.6 μg/sqm) as 1-hour intravenous infusion, in combination with a fixed-dose of cisplatin 80 mg/sqm. Both drugs were given every 3 weeks. A 3+3 design was followed. Any grade 3–4 toxicity related to NGR-hTNF was defined dose-limiting toxicity (DLT). Sampling for pharmacokinetics (PK) and pharmacodynamics (soluble TNF-receptors, sTNF-R1 and 2) was done during the first 3 cycles.
Results: 22 pts (median age, 60 years; M/F 14/8; PS 0/1 12/10) with various solid tumors were evaluated over 77 cycles (range, 1–10). The median number of prior regimens was 3 (range, 1–6) and 12 pts (55%) were platinum-pretreated. NGR-hTNF C_max and AUC increased dose-proportionally (r² = 0.91, p = 0.0001 and r² = 0.67, p = 0.001, respectively). No shedding of sTNF-Rs was noted up to 0.8 μg/sqm. Higher and faster peaks of sTNF-R1 (p = 0.001) and sTNF-R2 (p = 0.0001) were observed at 1.6 μg/sqm than at lower doses. A correlation was detected between first-cycle NGR-hTNF exposure and sTNF-R2 AUC (r = 0.64, p = 0.005), while no relationship was noted for sTNF-R1. The combination was safely administered without PK interaction or worsening of platinum toxicity. Consistently with the low doses tested, MTD was not reached. No DLTs were recorded at 0.2 μg/sqm (n = 4), 0.4 μg/sqm (n = 3) and 1.6 μg/sqm (n = 3). At 0.8 μg/sqm, a transient grade 3 infusion reaction was registered. This cohort was expanded to 6 pts for safety check with no further DLT, and to 12 pts for activity assessment. At this dose, 2 lung cancer pts, both platinum-pretreated, achieved a partial response (-79%) and a significant tumor shrinkage (-28%), lasting 7.2 and 6.7 months, respectively. An additional 4 pts had stable disease for a median time of 6.4 months. The median progression-free survival for all pts (n = 22), for pts enrolled at 0.8 μg/sqm (n = 12), and for platinum-pretreated pts (n = 9) were 2.7, 4.7, and 4.3 months, respectively.
Conclusion: The combination of NGR-hTNF 0.8 μg/sqm with cisplatin is well-tolerated and shows promising activity.