PMID- 12409327
OWN - NLM
STAT- MEDLINE
DCOM- 20021119
LR  - 20220316
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 20
IP  - 21
DP  - 2002 Nov 1
TI  - Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective 
      oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with 
      five selected solid tumor types.
PG  - 4292-302
AB  - PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective 
      epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore 
      its pharmacokinetic and pharmacodynamic effects in patients with selected solid 
      tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of 
      oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 
      days. Patients with either advanced non-small-cell lung, ovarian, head and neck, 
      prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients 
      received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients 
      experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 
      somnolence [one patient]). The most frequent drug-related adverse events (AEs) 
      were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 
      1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile 
      was observed with prolonged administration. Pharmacokinetic analysis showed 
      steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients 
      had stable disease and received ZD1839 for >or= 3 months; seven of these patients 
      remained on study drug for >or= 6 months. Serial skin biopsies taken before 
      treatment and at approximately day 28 revealed changes indicative of inhibition 
      of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, 
      with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting 
      toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically 
      meaningful disease stabilization across a range of tumor types and doses. 
      Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was 
      predicted from the mode of action of ZD1839.
FAU - Baselga, J
AU  - Baselga J
AD  - Vall d'Hebron University Hospital, Barcelona, Spain. baselga@hg.vhebron.es
FAU - Rischin, D
AU  - Rischin D
FAU - Ranson, M
AU  - Ranson M
FAU - Calvert, H
AU  - Calvert H
FAU - Raymond, E
AU  - Raymond E
FAU - Kieback, D G
AU  - Kieback DG
FAU - Kaye, S B
AU  - Kaye SB
FAU - Gianni, L
AU  - Gianni L
FAU - Harris, A
AU  - Harris A
FAU - Bjork, T
AU  - Bjork T
FAU - Averbuch, S D
AU  - Averbuch SD
FAU - Feyereislova, A
AU  - Feyereislova A
FAU - Swaisland, H
AU  - Swaisland H
FAU - Rojo, F
AU  - Rojo F
FAU - Albanell, J
AU  - Albanell J
LA  - eng
PT  - Clinical Trial
PT  - Clinical Trial, Phase I
PT  - Journal Article
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinazolines)
RN  - S65743JHBS (Gefitinib)
SB  - IM
CIN - J Clin Oncol. 2002 Nov 1;20(21):4276-8. PMID: 12409324
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/*adverse effects/pharmacokinetics/pharmacology
MH  - Biopsy
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/pathology
MH  - Colorectal Neoplasms/*drug therapy/pathology
MH  - Diarrhea/chemically induced
MH  - Disease Progression
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gefitinib
MH  - Head and Neck Neoplasms/*drug therapy/pathology
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/pathology
MH  - Male
MH  - Middle Aged
MH  - Ovarian Neoplasms/*drug therapy/pathology
MH  - Prostatic Neoplasms/*drug therapy/pathology
MH  - Quinazolines/*adverse effects/pharmacokinetics/pharmacology
MH  - Skin/pathology
MH  - Treatment Outcome
EDAT- 2002/11/01 04:00
MHDA- 2002/11/26 04:00
CRDT- 2002/11/01 04:00
PHST- 2002/11/01 04:00 [pubmed]
PHST- 2002/11/26 04:00 [medline]
PHST- 2002/11/01 04:00 [entrez]
AID - 10.1200/JCO.2002.03.100 [doi]
PST - ppublish
SO  - J Clin Oncol. 2002 Nov 1;20(21):4292-302. doi: 10.1200/JCO.2002.03.100.