Phase II Study of Sorafenib (Bay 43-9006) and Docetaxel in Metastatic Prostate Cancer
Background Prostate cancer is the most common malignancy in men and the second leading cause
of cancer death among males in the Western World. When tumors become refractory to androgen
withdrawal therapy, chemotherapy represent a palliative treatment with an improvement on
quality of life, particularly the combination of mitoxantrone and prednisone . This
observation has led to numerous studies evaluating the potential use of new chemotherapeutic
agents as Docetaxel in patients with metastatic androgen independent prostate cancer.
Recently Docetaxel based regimens have shown an improvement in survival when compared with
mitoxantrone in a phase III trial .
However the prognosis of these patients remains very poor and new effective tolerated
approaches are needed to improve the results of chemotherapy.
Rationale In a recent study a Raf kinase inhibitor protein (RKIP) encoded by a suppressor
gene was found to be responsible of the metastatic process; in fact the decreased RKIP
expression was associated with increased invasive capability of prostate cancer cells,
presumably though the activation of MEK and ERK by phosphorilation .
Sorafenib, a novel signal transduction inhibitor, prevents tumor cell proliferation and
angiogenesis blocking Raf/Mek/Erk pathway at the level of Raf kinase and tyrosine kinase
receptors VEGFR-2 and PDGFR.
In a phase I study the combination of docetaxel and Sorafenib was evaluated in prostate and
other tumors . The treatment was well tolerated and one partial response (4%) and 12 stable
disease (50%) were reported.
According to these data we designed a phase II study to evaluate the association of
Sorafenib and Docetaxel in metastatic prostate cancer
Simon's Optimal two-stage design for phase II clinical trial will be applied to calculate
the sample size that minimizes the expected number of patients to be accrued. The sample
size will be calculated on the following assumptions: alpha error =0.05, beta error =0.20;
PD (clinically uninteresting true no progressive disease rate) and P1 (sufficiently
promising true no progressive disease rate) will be set at 60% and 80%. 11 patients will be
enrolled in the first stage: if no progressive diseases are < 7 the accrual will be stopped
and the drug's combination rejected. In the case of >= 7 no progressive diseases 32 more
patients will be accrued at the second stage. The treatment will be accepted if >= 30 no
progressive diseases out of 43 patients will be observed
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
N° of no progressive disease
Italy: Ethics Committee