Phase Ib study of NGR-hTNF, a selective vascular targeting agent (VTA), in combination with cisplatin in patients with refractory solid tumors

3570 Background: NGR-hTNF is a VTA exploiting a tumor-homing-peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed on tumor blood vessels. In preclinical models, significant synergy between low-dose NGR-hTNF and cisplatin was shown. Methods: Patients with resistant/refractory solid tumors were treated with NGR-hTNF given with a low-dose, doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m2) as 1-hour intravenous infusion, in combination with cisplatin 80 mg/m2, both given every 3 weeks. A 3+3 escalation/de-escalation design was followed. PK sampling was performed after the first 3 cycles. DLT definition: any G3–4 toxicity related to NGR-hTNF. Results: 22 patients (median age: 60 years, range, 47–75; 14M/8F; ECOG PS 0/1 12/10) with different tumor types were evaluated over 77 cycles (range, 1–10). Median number of prior regimens was 3 (range, 1–6) and 12 patients (55%) were previously treated with platinum-based regimens. Both NGR-hTNF Cmax and AUC increased proportionally with dose. The combination was safe without PK interaction or exacerbation of platinum-associated toxicity profile. No shedding of soluble TNF receptors was observed up to 0.8 μg/m2. As expected for the low-dose range explored, MTD was not reached and no DLTs were registered at 0.2 μg/m2 (n = 4), 0.4 μg/m2 (n = 3) and 1.6 μg/m2 (n = 3). At 0.8 μg/m2, a patient had a G3 transient acute infusion reaction. This cohort was expanded up to 6 patients for safety reasons, with no DLTs registered, and up to 12 patients, for preliminary activity evaluation. At this dose level of 0.8 μg/m2, two lung cancer patients, both pre-treated with platinum, achieved a partial response (-79%) and a significant tumor shrinkage (-28%) lasting 7.2 and 6.7 months, respectively, and an additional 4 patients experienced stable disease for a median duration of 6.4 months. The median progression-free survival for all patients (n = 22), for patients enrolled at 0.8 μg/m2 (n = 12), and for patients pre-treated with platinum (n = 9) was 2.7, 4.7, and 4.3 months, respectively. Conclusions: The combination of NGR-hTNF 0.8 μg/m2 with cisplatin 80 mg/m2 shows a favourable toxicity profile and promising antitumor activity. [Table: see text]