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

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 ?g/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 ?g/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.

SUBMITTER: Mammoliti S

PROVIDER: S-EPMC3065876 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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

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

Annals of oncology : official journal of the European Society for Medical Oncology 20100920 4

<h4>Background</h4>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.<h4>Patients and methods</h4>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 combi ...[more]

PMID: 20855468

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Project description:LESSONS LEARNED:The NEO-CLASSIC study provided valuable insight for the clinical efficacy and tolerability profiles of perioperative chemotherapy with oxaliplatin and capecitabine, plus gastrectomy, in patients with localized resectable gastric cancer.The study was designed to explore the potential survival benefits of an eight-cycle, perioperative oxaliplatin and capecitabine (XELOX) schedule in the above-mentioned setting and to explore the feasibility of prolonging the cycles of preoperative chemotherapy. The projected endpoint was not met. BACKGROUND:This multicenter, open-label study (NEO-CLASSIC) evaluated the efficacy and safety of oxaliplatin and capecitabine (XELOX), plus D2 gastrectomy, in localized resectable gastric cancer. METHODS:Patients aged 18-75 years with histologically-confirmed gastric adenocarcinoma (stage T2-4a/N+M0) were given eight cycles of XELOX (four preoperatively, four postoperatively). Each 3-week cycle comprised capecitabine 1,000 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1. Curative D2 gastrectomy was scheduled 2-4 weeks after the last preoperative cycle. The primary objective of the study was to determine the objective response rate (ORR) of XELOX in the preoperative setting. Sample size was calculated by assuming that a minimum of 47 cases would be required to increase the ORR by 15% (from 40% to 55%). With an estimated 10% dropout rate, 55 patients would have to be recruited. RESULTS:Fifty-five patients were enrolled, and one was excluded because of screening failure. R0 resections were achieved in 45 of 54 intent-to-treat patients (83.3%), and four patients received R1 resections (Fig. 1). There were no complete responses, 27 (50.0%) partial responses, 22 cases (40.7%) of stable disease, and 4 (7.4%) of progressive disease. The objective response rate was 50.0%. Median follow-up was 52.97 months; 30 patients (55.6%) had disease progression (Table 1), and median progression-free survival was 20.10 (95% confidence interval: 4.31-35.89) months; median overall survival was 30.77 months (95% confidence interval was not yet available) (Fig. 2). Fifty-four patients completed 209 cycles of preoperative chemotherapy; 42 patients received 133 cycles of postoperative chemotherapy (Table 3). The rate of grade 3-4 adverse events was 8.5% (29/342 cycles); the most frequent events were neutropenia (9/342 cycles) and leukopenia (4/342 cycles). CONCLUSION:These findings suggest that combination therapy with capecitabine and oxaliplatin as perioperative chemotherapy, followed by D2 gastrectomy, is effective and safe in late-stage, locally advanced gastric cancer. Although enrollment exceeded the 47 patients required to identify an increase in the ORR by 15% (from 40% to 55%), results did not meet the primary endpoint.

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

Publications

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

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