Phase I pharmacokinetic/pharmacodynamic study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) in first-line treatment of patients with metastatic colorectal cancer.
OBJECTIVE
To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC).


METHODS
Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3). Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted.


RESULTS
Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogen-activated protein kinase (MAPK) and induced p27 expression in the skin.


CONCLUSIONS
The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.
Folprecht
Gunnar
G
Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany. Gunnar.Folprecht@uniklinikum-dresden.de
Tabernero
Josep
J
Köhne
Claus-Henning
CH
Zacharchuk
Charles
C
Paz-Ares
Luis
L
Rojo
Federico
F
Quinn
Susan
S
Casado
Esther
E
Salazar
Ramon
R
Abbas
Richat
R
Lejeune
Chantal
C
Marimón
Irene
I
Andreu
Jordi
J
Ubbelohde
Ulrike
U
Cortes-Funes
Hernan
H
Baselga
Jose
J
D000328:Adult; D000368:Aged; D000634:Aminoquinolines; D000814:Aniline Compounds; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D066246:ErbB Receptors / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009930:Organic Chemicals / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects
D000634:Aminoquinolines; D000814:Aniline Compounds; D009930:Organic Chemicals; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; D000077146:Irinotecan; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D002955:Leucovorin; D005472:Fluorouracil; C413879:EKB 569; D002166:Camptothecin