Dose escalation of capecitabine in combination with biweekly cetuximab and hepatic arterial infusion (HAI) of oxaliplatin in patients with liver metastases of colorectal cancer: Preliminary clinical results

Abstract

e15080 Background: To determine the maximum-tolerated dose (MTD) and the doses-limiting-toxicities (DLT) of concurrent capecitabine and cetuximab plus HAI of oxaliplatin (LOHP) in patients with hepatic metastases from colorectal cancer (CCR). Methods: Successive cohorts of 3–6 patients (pts) were treated with HAI LOHP (100 mg/m2), biweekly cetuximab (500 mg/m2) and escalation doses of capecitabine (825 mg/m2 BID d1–7:DL1; 1000 mg/m2 BID d1- 7:DL2; 1250 mg/m2 BID d1–7:DL3; 1500 mg/m2 BID d1–7:DL4) recycled every 14 days. Dose-limiting-toxicities (DLT) were defined as any grade 3–4 events, excepting grade 3–4 skin rash. LOHP and cetuximab PK/PD data were prospectively collected. Results: 19 patients (median age: 60; range: 34–74; 52.9% men, 47.1% females) and ECOG performance status of 1 (range 0–2) were treated at 4 DLs (dose level) as follows: DL: 3 pts, DL2: 6 pts, DL 3: 7 pts and DL 4: 3 pts. All pts were evaluable for toxicity. With a median of follow-up of 21.23 months, ORR was 78.9%, all of them partial response, with 4 pts SD (21.1%). Initially, only 4 pts were considered potentially resectable. Among the remaining 15 pts, 4 (20.6%) could be resected after treatment. Disease progression occurred in 15 pts (78.9%; 3 pts in liver only; 4 pts with extrahepatic metastases; 8 cases with both, hepatic and extrahepatic disease). The TTP was 9.6 months. OS has not been reached. 4 pts have died during the follow-up. Grade ¾ toxicities including Hand-foot Syndrome in 3 pts (1 pt at DL1, other at DL3 and other at DL4), diarrhoea in 3 pts ( one at DL3 and 2 at DL4), anaemia in 2 pts (DL2 and DL4), asthenia in 2 pts (DL2 and DL4) and mucositis in 1 pts (DL3). DLT and MTD were established in DL4 (two pts with diarrhoea grade IV with one of them with grade III HFS) Conclusions: Combination therapy with HAI LOHP plus concurrent capecitabine and cetuximab, can be safely administered to patients with liver metastases from CCR. The MTD and DLT was established in 1500 mg/m2 BID d1 to d7 of capecitabine. The Doses-recommended (DR) has not been obtained yet. oxaliplatin PK/PD is best defined through a bicompartimental model. Mature results of PK/PD analysis will be presented at 2009 ASCO Symposium. No significant financial relationships to disclose.