Two doses of NGR-hTNF in combination with capecitabine plus oxaliplatin in colorectal cancer patients failing standard therapies

S Mammoliti, V Andretta, E Bennicelli, F Caprioni, D Comandini, G Fornarini, A Guglielmi, A Pessino, S Sciallero, A F Sobrero, G Mazzola, A Lambiase, C Bordignon, S Mammoliti, V Andretta, E Bennicelli, F Caprioni, D Comandini, G Fornarini, A Guglielmi, A Pessino, S Sciallero, A F Sobrero, G Mazzola, A Lambiase, C Bordignon

Abstract

Background: asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF), an agent selectively damaging the tumour vasculature, showed a biphasic dose-response curve in preclinical models. Previous phase I trials of NGR-hTNF indicated 0.8 and 45 μg/m(2) as optimal biological and maximum-tolerated dose, respectively.

Patients and methods: Two sequential cohorts of 12 colorectal cancer (CRC) patients who had failed standard therapies received NGR-hTNF 0.8 or 45 μg/m(2) in combination with capecitabine-oxaliplatin (XELOX).

Results: Median number of prior treatment lines was 3 in the low-dose and 2 in the high-dose cohort. Overall, 21 patients had been pretreated with oxaliplatin-based regimens. No grade 3-4 NGR-hTNF-related toxicities were observed. Grade 1-2 chills were reported in 43% and 40% of cycles in the low-dose and high-dose cohorts, respectively. In the low-dose cohort, one patient achieved a partial response and five had stable disease for a median of 4.6 months. In the high-dose cohort, six patients had stable disease for a median of 3.6 months. Three-month progression-free survival (PFS) rates were 50% and 33% in the low-dose and high-dose cohort, respectively. Three patients in low-dose cohort experienced PFS longer than PFS on last prior therapy.

Conclusions: Both NGR-hTNF doses were safely combined with XELOX in pretreated CRC patients. Hint of activity was apparent only with low-dose NGR-hTNF.

© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Waterfall diagram showing maximal change in target lesions per patient by dose level.
Figure 2.
Figure 2.
PFS duration for each patient enrolled in the low-dose cohort during the current study treatment versus (A) the last prior regimen and (B) all prior metastatic regimens. PFS duration for each patient enrolled in the high-dose cohort during the current study treatment versus (C) the last prior regimen and (D) all prior metastatic regimens. Each box in the horizontal bars indicates a treatment line administered for the metastatic disease. In panel A and C, the box on the left indicate the PFS time during the last prior regimen and the box on the right indicate the PFS time during the current study treatment. In panel B and D, all metastatic treatment lines are also shown. The patients 3, 7, 10, and 12 in the low-dose cohort and the patient 10 in the high-dose cohort received also adjuvant therapy (not shown in these panels). PFS, progression-free survival; XELOX, capecitabine + oxaliplatin.

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