Two doses of NGR-hTNF (N) given alone or in combination with doxorubicin (D) in soft tissue sarcomas (STS).

Abstract

10568 Background: N, a tumor-targeted antivascular agent, displays a biphasic dose response curve with activity shown at low dose (LD) or high dose (HD). Vascular effects involve at LD an early vessel stabilization that enhances intratumor D uptake followed by late vessel damage and at HD a rapid vessel disruption. Methods: STS patients (pts), stratified by prior D dose (> vs ≤ 300 mg/m2), were randomized to N alone given at LD (0.8 μg/m2) in arm A and at HD (45 μg/m2/d1/q1w) in B, or combined with D (60 mg/m2/d1/q3w/6 cycles) at LD in arm C and at HD in D. Primary aim of this 4-arm phase II trial was progression free survival (PFS) with CT scans performed q6w until progressive disease (PD). Using 2-stage design, each regimen was rejected if ≤ 2/14 and ≤ 7/24 pts were PD free at 3 months after 1st and 2nd stage, respectively (β=20%, α=10%, n=96). Secondary aims: adverse events (AEs), response rate by RECIST criteria and early metabolic response (MR), as quantified by fractional change in SUV using FDG-PET according to EORTC criteria Results: 66 pts have been enrolled and 55 were included in 1st study stage analysis: median age: 57 yrs; male: 30; PS ≥ 1: 26; leiomyosarcomas: 12; median prior lines: 3 (range, 0-7). In all, 488 weekly cycles were given (mean, 9; range, 1-45). Main grade 3/4 AEs were: neutropenia 18%, chills 7%. After first study stage, primary endpoint was met only in arm C (LD N + D), with 7/14 pts PD free at 3 months. Median PFS was 1.3 months (95% CI, 1.1-1.5) for arm A, 1.5 (1.1-1.8) for B, 4.5 (3.6-5.4) for C and 1.3 (1.1-1.5) for D (p=.01 for trend). By RECIST, there were no objective responses and 20/48 (42%) evaluable pts had stable disease (SD), including 1/12 in arm A, 6/12 in B, 9/12 in C and 4/12 in D. Median SD duration in arm C was 5.5 months (95% CI, 3.7-7.3). By FDG-PET imaging done after 3 weeks, 7/30 (23%) assessable pts had partial MR (4 SD/3 PD per RECIST), with mean change in SUV of -34% (SD, ± 12), while 18 pts (60%) had stable MR (7 SD/11 PD per RECIST), with mean change in SUV of 2% (± 11). Median PFS was 4.2 months in pts who achieved partial MR and 1.5 months in pts who did not (HR=0.67). Complete follow-up for arm C and central histology/radiology review are under way. Conclusions: LD NGR-hTNF plus D is safe, with promising activity as measured by FDG-PET. Clinical trial information: NCT00484341.