Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for advanced esophagogastric cancer: dose-finding study for the prospective multicenter, randomized, phase II/III REAL-3 trial.
OBJECTIVE
Epirubicin, oxaliplatin, and capecitabine (EOC) is a standard treatment in advanced esophagogastric cancer. Panitumumab (P) is a fully human, immunoglobulin G2 monoclonal antibody targeting epidermal growth factor receptor. Randomized Trial of EOC +/- Panitumumab for Advanced and Locally Advanced Esophagogastric Cancer (REAL-3) will evaluate whether the addition of P to EOC improves survival in patients with advanced esophagogastric adenocarcinoma and undifferentiated carcinoma.


METHODS
The original design of REAL-3 added P 9 mg/kg to the standard dose of EOC (dose level [DL] + 1). Due to toxicity, a dose de-escalation was made to EOC + P DL-1 (epirubicin 50 mg/m(2), oxaliplatin130 mg/m(2), capecitabine 1,000 mg/m(2)/d + P 9 mg/kg every 3 weeks). After additional toxicity was observed, the study was amended to include two additional EOC + P dose levels. Using a 3 + 3 design, dose-limiting toxicities (DLTs) were assessed weekly during cycle 1. Patients were randomly assigned 1:1 to EOC +/- P.


RESULTS
Between July 2008 and October 2009, 29 patients were randomly selected for standard-dose EOC (n = 13) or EOC + P (n = 16). Five patients were treated at DL + 1, with grade 3 diarrhea in four of five patients by cycle 4. At DL-1, one patient had grade 3 diarrhea and grade 5 infection. Three patients were treated at DL-3, and then six were treated at DL-2, without DLTs.


CONCLUSIONS
The recommended dose for EOC + P is epirubicin 50 mg/m(2), oxaliplatin 100 mg/m(2), capecitabine 1,000 mg/m(2)/d, and P 9 mg/kg every 3 weeks. This dose has been selected for the ongoing phase II/III REAL-3 study.
Okines
Alicia F C
AF
Royal Marsden Hospital, London, UK.
Ashley
Sue E
SE
Cunningham
David
D
Oates
Jacqueline
J
Turner
Andrea
A
Webb
Janine
J
Saffery
Claire
C
Chua
Yu Jo
YJ
Chau
Ian
I
D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D000077544:Panitumumab; D013274:Stomach Neoplasms / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D015251:Epirubicin; D000069287:Capecitabine; D000077544:Panitumumab; D005472:Fluorouracil