A Phase II Study of Cetuximab Plus P-HDFL (Cisplatin and Weekly 24-Hour Infusion of High-Dose 5-Fluorouracil and Leucovorin) for the First-Line Treatment of Advanced Gastric Cancer
Non-resectable gastric cancer is an incurable disease. Systemic chemotherapy confers
prolongation of survival and improvement of quality of life. Regimens containing cisplatin
and 5-fluorouracil (5-FU) are widely adopted in the world. A P-HDFL regimen, based primarily
on weekly 24-hour infusion of cisplatin and high-dose 5-FU and leucovorin, is commonly used
in Taiwan for patients with advanced gastric cancer; the overall response rate is around 60%
(45%-76%, 95% C.I.), and the patients' compliance is excellent.
Expression of EGF and EGFR was detected in about 62.1% and 51.5% gastric cancer tissues,
respectively. Tumors with simultaneous expression of EGF, TGF-alpha, EGFR and p185c-erbB-2
were associated with a high BrdU labeling index, rapid tumor growth, and an unfavorable
outcome. Teramoto et al. have shown a dose-dependent growth inhibition of an anti-EGFR
monoclonal antibody (MoAb 528) on EGFR-overexpressing human gastric cancer cells, both in
vitro and in vivo. We have recently demonstrated that cetuximab is cytotoxic to human
gastric cancer cells, and cetuximab has a chemo-sensitizing effect for cisplatin and 5-FU in
human gastric cancer cells (Yeh et al, unpublished observation). We hypothesize that the
combination of cetuximab with P-HDFL will further improve the efficacy of the latter on
advanced gastric cancer.
This is a multi-center, prospective phase II trial. Patients with histologically proven
nonresectable or recurrent/metastatic gastric adenocarcinoma, with at least one measurable
lesion, no prior chemotherapy or radiotherapy, and adequate baseline organ functions will be
eligible. Cetuximab (Erbitux; Merck, Germany) 400 mg/m2 will be given as an intravenous (IV)
infusion, initially (i.e., day 1 of cycle 1); and then followed by weekly IV infusions of
cetuximab 250 mg/m2 (i.e., days 8, 15, 22 of cycle 1, and days 1, 8, 15, 22 of cycle 2 and
subsequent 28-day cycles). Cisplatin will be given as a 24-hour continuous IV infusion in a
dose of 35 mg/m2/day, admixing with 5-FU 2,000 mg/m2 and leucovorin (folinic acid) 300
mg/m2, day 1 and day 8. A 24-hour continuous IV infusion of 5-FU 2,000 mg/m2 and leucovorin
300 mg/m2 will be given on day 15. The cycles will be repeated every 28 days, and the
response evaluation will be performed every two cycles and at the end of protocol treatment.
Confirmed objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors)
will be the primary end-point. Using the Simon two-stage design for phase II study (P1 - P0
= 0.20 with the response rates of interest being P0 = 60% and P1 = 80%), a total of 35
patients are planned to be enrolled in an estimated enrollment period of 12 to 18 months.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The primary end point of the study is confirmed objective response rates (by RECIST, Response Evaluation Criteria in Solid Tumors).
Kun Huei Yeh, Ph.D.
Far Eastern Memorial Hospital
Taiwan: Department of Health