Dovitinib(TKI258) in Patients With Castration-resistant Prostate Cancer

The aim of this study is to evaluate efficacy and safety of Dovitinib(TKI258) in patients with castration resistant prostate cancer after failure of docetaxel-based chemotherapy. Further correlative study for metabolic response using PET image and change in serum fibroblast growth factor 23(FGF23) will be conducted.

Growth factor signals are important in carcinogenesis and progression of prostate cancer, and fibroblast growth factors (FGF) have important roles in this regard. FGF ligands (FGF1, -2, -6, -8, and -17) and FGF receptors (FGFR1 and FGFR4) have all shown to be significantly overexpressed in prostate cancer1-5. And, the recent studies have demonstrated that the critical roles of the FGF family members are mediated by the signaling between epithelial and stromal compartments, thus, promoting epithelial-mesenchymal transition (EMT)6,7. Moreover, a recent study has shown that FGF-2 is a mediator of second wave angiogenesis and tumor progression in men during the formation of castration-resistant tumors. Therefore, inhibition of signaling via FGF axis might be a viable strategy for the treatment of castration-resistant prostate cancer. TKI258, an oral multitargeted receptor tyrosine kinase (RTK) inhibitor is known to potently inhibit the class III, IV, and V RTKs, showing biochemical 50 percent inhibitory concentration(IC50) values <20 nmol/L for VEGFRs (VEGFR-1, VEGFR-2, and VEGFR-3); the platelet-derived growth factor receptor-β (PDGFR-β); fibroblast growth factor receptors 1, 2, and 3 (FGFR-1,2,3); fetal liver tyrosine kinase receptor 3 (FLT-3); and KIT Ret, tyrosine kinase A (TrkA), and csf-1 RTKs. Due to the unique inhibitory activity on FGF pathways, TKI258 has shown significant activity in a variety of tumor xenograft models in athymic mice, including acute myeloid leukemia, multiple myeloma, and colon- and prostate-derived models9. Castration-resistant prostate cancers (CRPC) are one of the challenges in oncology practice. Although there have been advances in chemotherapy10, new hormonal agents11, and immunotherapeutics12, patients in this subgroup still have limited life expectancy. Therefore, there is an urgent need to identify therapeutic targets and clinical development of target agents for the treatment of CRPC. For this end, sorafenib has been tested in multiple phase II studies earlier13-17; however, the clinical efficacy was very limited. The low efficacy of sorafenib might be partly explained by the lower potency in inhibition of RTKs. Considering nanomolar concentration range of IC50 for TKI258 compared with micromolar concentration for other multi-TKIs, the efficacy of TKI258 should be evaluated in CRPC patients.

Intervention: TKI258 Investigational drug, TKI258, will be administered to all of the patients after enrollments. Treatment will initially be administered as 28-day cycles as follows: - Daily 500mg of TKI258 will be self-administered orally by the patient for 5 days, followed by 2 days of treatment off.

Investigational treatment refers to TKI258 in this study Until Progression, unacceptable toxicity, withdrawal

disease progression defined as either the appearance of new lesions or unidimensional tumor measurements increasing >20% or symptomatic progression

Overall response rate per Response Evaluation Criteria in Solid Tumors(RECIST)1.0 and Prostate-specific antigen(PSA), overall survival time, toxicity, and biological effect of TKI258 in patients via correlative study using serum and PET-CT image

Overall survival is defined as the time from date of randomization to date of death due to any cause. If the patient is not known to have died, survival will be censored at the date of the last contact. Overall survival will be analyzed at the final analysis cut-off date. The Kaplan-Meier product-limit method will be used to describe the overall survival for the study drug (median, 95% confidence intervals, and plots).

The objective of the exploratory biomarker is to identify a biomarker 'profile' of a patient population most likely to benefit from treatment with TKI258. Since this clinical trial was not designed to address specific biomarkers-related hypotheses, the analysis of this data should be viewed as exploratory and hypotheses generating.

The objective of the exploratory biomarker is to identify a biomarker 'profile' of a patient population most likely to benefit from treatment with TKI258.

Inclusion Criteria: Patients with histologically confirmed progressive metastatic androgen-independent adenocarcinoma of the prostate with radiographic evidence of disease. No more than two previous cytotoxic chemotherapy Castration level of testosterone (< 50 ng/dl) achieved by orchiectomy or gonadotropin-releasing hormone(GnRH) agonist Eastern Cooperative Oncology Group(ECOG) performance status 0 - 2 Finished any study drug or chemotherapy earlier than 4 weeks before the first administration of the study drug. Age ≥ 20 years old Patients must have the following laboratory values: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelets ≥ 75 x 109/L Hemoglobin (Hgb) > 8 g/dL Serum total bilirubin: ≤ 1.5 x ULN alanine transaminase(ALT) and aspartate aminotransferase(AST) ≤ 2.0 x upper limit of normal(ULN) with or without liver metastases Serum creatinine ≤ 1.5 x ULN or serum creatinine >1.5 - 3 x ULN or 1.5 x ULN<serum creatinine < 3 x ULN, if calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockcroft-Gault equation, see formula below: CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if patient is female multiply the above by 0.85) Patients who give a written informed consent obtained according to local guidelines Exclusion Criteria: Patients eligible for this study must not meet any of the following criteria Patients with known brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases Patients with another primary malignancy within 3 years prior to starting study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, basal or squamous cell carcinoma or non-melanomatous skin cancer

Dorkin TJ, Robinson MC, Marsh C, Bjartell A, Neal DE, Leung HY. FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene. 1999 Apr 29;18(17):2755-61. doi: 10.1038/sj.onc.1202624.

Gnanapragasam VJ, Robinson MC, Marsh C, Robson CN, Hamdy FC, Leung HY. FGF8 isoform b expression in human prostate cancer. Br J Cancer. 2003 May 6;88(9):1432-8. doi: 10.1038/sj.bjc.6600875.

Heer R, Douglas D, Mathers ME, Robson CN, Leung HY. Fibroblast growth factor 17 is over-expressed in human prostate cancer. J Pathol. 2004 Dec;204(5):578-86. doi: 10.1002/path.1668.