Primary Outcome Measures:
- N° of no progressive disease [ Time Frame: evaluated by PSA ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- ORR,Duration of responses,TTP,OS,PSA doubling time, PK-PD,of Bay plus docetaxel,Baseline pERK concentration, phospho VEGF-R2 concentration, plasma proteomics and gene expression profiling on blood cells and tumor biopsy. [ Time Frame: Recist Criteria ] [ Designated as safety issue: Yes ]
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 .
Bay 43-9006, 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 Bay 43-9006 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 Bay 43-9006 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
Purpose
