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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

Phase 2
18 Years
75 Years
Open (Enrolling)
Stomach Neoplasms

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Trial Information

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human gastric cancer cells (Yeh et al, unpublished observation).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.

Inclusion Criteria:

1. Age 18 to 75 years

2. Histologically proven adenocarcinoma of the stomach that is nonresectable, locally
advanced, or recurrent/metastatic

3. At least one measurable lesion (by RECIST, Response Evaluation Criteria in Solid
Tumors), and no prior radiotherapy to the target measurable lesion

4. No prior chemotherapy for gastric cancer, but post-gastrectomy adjuvant therapy with
low-dose 5-FU [e.g., 5-FU 450 mg/m2 per week] completed more than 6 months before
study enrollment is acceptable

5. World Health Organization (WHO) performance status 2

6. Adequate baseline organ functions (checked within one week before entry into this
study), defined as WBC count 3,000 cells/µL with neutrophils ≥ 1,500 cells/µL,
platelet count 100,000 cells/µL, hemoglobin 9 g/dL, serum total bilirubin level 1.5 X
UNLs (upper normal limits), serum AST and ALT 2.5 X ULNs (or serum AST and ALT 5.0 X
ULNs for patients with liver metastases), serum creatinine level 1.5 X UNLs, 24-hour
urine CCr 60 ml/min

7. Fasting serum triglyceride level > 70 mg/dL, which should be checked within one week
before entry into this study. The lower limit for fasting serum triglyceride (70
mg/dL) is set to avoid HDFL-related hyperammonemic encephalopathy, which occurs in
around 5% of Taiwanese patients.

8. Written informed consent

9. At least one month from gastrectomy, in case gastrectomy was performed; at least 2
weeks from laparotomy without resection, in case laparotomy was performed to document
nonresectable status

10. Availability of tumor sample for retrospective testing of EGFR (pharmacogenomic
mutation analysis and immunohistochemical staining).

Exclusion Criteria:

1. Concomitant anti-cancer biological agents, chemotherapy, or radiotherapy other than
indicated in this protocol

2. CNS metastasis

3. Pregnant women, breast-feeding women, and women of child-bearing potential or fertile
men without adequate contraception

4. Life expectancy less than 3 months

5. Serious concomitant illness or significant dysfunction of major organ systems which
prohibit chemotherapy, such as:

- symptomatic heart disease, including significant arrhythmias, congestive heart
failure or myocardial infarction within 12 months.

- extensive liver disease.

- major active infection.

- severe symptomatic pulmonary disease.

6. Concurrent or prior second malignancy (except curatively resected cervical carcinoma
in situ or squamous cell carcinoma of skin).

7. Known hypersensitivity reaction to any of the components of study treatments.

8. Medical or psychological conditions that would not permit the patient to complete the
study or sign informed consent

9. Significant diseases, in the investigator's opinion, which would exclude the patient
from the study.

10. Legal incapacity or limited legal capacity.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary end point of the study is confirmed objective response rates (by RECIST, Response Evaluation Criteria in Solid Tumors).

Principal Investigator

Kun Huei Yeh, Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Far Eastern Memorial Hospital


Taiwan: Department of Health

Study ID:




Start Date:

June 2006

Completion Date:

Related Keywords:

  • Stomach Neoplasms
  • Neoplasms
  • Stomach Neoplasms