A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors.
OBJECTIVE
Based on our mouse xenograft model demonstrating that intermittent high-dose gefitinib sensitizes tumors to subsequent treatment with taxanes, we initiated this phase I trial to explore docetaxel in combination with escalating doses of intermittent gefitinib (Iressa) given prior to docetaxel.


METHODS
This was a phase I study where patients with advanced cancer were treated with escalating doses of gefitinib (1,000, 1,500, 2,250, 3,000 mg) on days 1 and 2 followed by docetaxel (75 mg/m2) on day 3 of a 21 day cycle. Gefitinib pharmacokinetic data were obtained on days 1, 2, and 3 of cycles 1 and 2 at each dose level.


RESULTS
18 patients were enrolled in this study with the most frequent tumor types being non-small cell lung cancer and head and neck squamous cell cancer. The dose-limiting toxicity was neutropenia (n=1 at dose level 2, n=2 at dose level 4). Rash, diarrhea, and fatigue were the most common grade 1-2 toxicities. Pharmacokinetic data indicated no accumulation of gefitinib between cycles 1 and 2 and no clear correlation between gefitinib plasma levels and toxicity. Partial responses were observed in one patient with head and neck squamous cell carcinoma and one patient with anaplastic thyroid cancer.


CONCLUSIONS
The recommended dose for phase II studies is gefitinib 2,250 mg on days 1 and 2, followed by docetaxel 75 mg/m2 on day 3.
Fury
Matthew G
MG
Division of Solid Tumor Oncology, Head and Neck Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY 10021, USA.
Solit
David B
DB
Su
Yungpo Bernard
YB
Rosen
Neal
N
Sirotnak
F M
FM
Smith
Robert P
RP
Azzoli
Christopher G
CG
Gomez
Jorge E
JE
Miller
Vincent A
VA
Kris
Mark G
MG
Pizzo
Barbara A
BA
Henry
Roxanne
R
Pfister
David G
DG
Rizvi
Naiyer A
NA
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000077156:Gefitinib