A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer.
BACKGROUND
Docetaxel/estramustine was a commonly used regimen to treat metastatic hormone-refractory prostate cancer. Imatinib inhibits the platelet-derived growth factor receptor that is expressed in prostate cancer and is synergistic with taxanes in preclinical prostate cancer models.


METHODS
A phase I trial of docetaxel/estramustine/ imatinib was undertaken to determine the safety and maximum tolerated dose of this combination. Patients with progressive, metastatic, hormone-refractory prostate cancer were treated every 21 days with fixed doses of estramustine (280 mg orally 3 times a day on days 1-5), imatinib (400 mg orally daily on days 1-21), dexamethasone (8 mg orally twice daily on days 1-3), and prophylactic warfarin (2 mg orally daily on days 1-21). Cohorts of 3-6 patients were enrolled to receive escalating doses of docetaxel on day 2 from 50 mg/m2 to 60 mg/m2 to 70 mg/m2. Thirteen patients were treated.


RESULTS
On dose level 3 (docetaxel 70 mg/m2 and imatinib 400 mg daily), 2 patients experienced grade 3 elevations in prothrombin time, attributed to the interaction between imatinib and warfarin. The protocol was amended to include an intermediate dose level (docetaxel 60 mg/m2 and imatinib 300 mg daily). However, in the overall study, there were 5 unacceptable toxicities (2 cerebrovascular accidents, 1 myocardial infarction, 1 mesenteric ischemia, and 1 deep venous thrombosis) in 13 patients; 2 of those toxicities resulted in death. The study was closed early to further accrual.


CONCLUSIONS
The high incidence of thromboembolic events observed when imatinib was combined with docetaxel/estramustine precludes further exploration of this regimen.
Lin
Amy M
AM
UCSF Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA. amlin@medicine.ucsf.edu
Rini
Brian I
BI
Derynck
Mika K
MK
Weinberg
Vivian
V
Park
Margaret
M
Ryan
Charles J
CJ
Rosenberg
Jonathan E
JE
Bubley
Glenn
G
Small
Eric J
EJ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D018450:Disease Progression; D000077143:Docetaxel; D004961:Estramustine / Q000008:administration & dosage; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D000068877:Imatinib Mesylate; D017430:Prostate-Specific Antigen