A phase II clinical trial of sorafenib in androgen-independent prostate cancer.

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Clin Cancer Res. 2008 Jan 1;14(1):209-14.
A phase II clinical trial of sorafenib in androgen-independent prostate cancer.
Dahut WL, Scripture C, Posadas E, Jain L, Gulley JL, Arlen PM, Wright JJ, Yu Y, Cao L, Steinberg SM, Aragon-Ching JB, Venitz J, Jones E, Chen CC, Figg WD.
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.

To determine if sorafenib is associated with a 4-month probability of
progression-free survival, which is consistent with 50%, as determined
by clinical, radiographic, and prostate-specific antigen (PSA) criteria
in patients with metastatic androgen-independent prostate cancer
EXPERIMENTAL DESIGN: Patients with progressive metastatic AIPC
were enrolled in an open-label, single-arm phase II study. Sorafenib
was given continuously at a dose of 400 mg orally twice daily in 28-day
cycles. Clinical assessment and PSA measurement were done every cycle
whereas radiographic measurements were carried out every two cycles.

RESULTS: Twenty-two patients were enrolled in the study to date,
completing a planned first stage of the trial. Baseline patient
characteristics included a median age of 63.9 years (range, 50-77
years), Gleason score of 9 (range, 4-9.5), and PSA concentration of
53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had
received one prior chemotherapy regimen. Of the 21 patients with
progressive disease, 13 progressed only by PSA criteria in the absence
of evidence of clinical and radiographic progression. Two patients were
found to have dramatic reduction of bone metastatic lesions as shown by
bone scan, although they met PSA progression criteria at the time when
scans were obtained. Toxicities likely related to treatment included
one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2
toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and
diarrhea. Results from in vitro studies suggested that PSA is not a
good marker of sorafenib activity. The geometric mean exposure
(AUC(0-12)) and maximum concentration (C(max)) were 9.76 h mg/L and
1.28 mg/L, respectively. The time to maximum concentration (t(max)) and
accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68
to 6.43, respectively.
CONCLUSIONS: Sorafenib is relatively well
tolerated in AIPC with two patients showing evidence of improved bony
metastatic lesions. Interpretation of this study is complicated by
discordant radiographic and PSA responses. PSA may not be an adequate
biomarker for monitoring sorafenib activity. Based on these
observations, further investigation using only clinical and
radiographic end points as progression criteria is warranted. Accrual
to the second stage of trial is ongoing.