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A Phase II Study of TKI258 in Patients With Castration-resistant Prostate Cancer

Phase 2
Open (Enrolling)
Hormone Refractory Prostate Cancer

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Trial Information

A Phase II Study of TKI258 in Patients With Castration-resistant Prostate Cancer

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

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

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 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

16 week progression free survival rate

Outcome Description:

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

Outcome Time Frame:

Week 16

Safety Issue:


Principal Investigator

Kyong Hwa Park, MD, phD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Korea University


Korea: Food and Drug Administration

Study ID:




Start Date:

November 2012

Completion Date:

June 2016

Related Keywords:

  • Hormone Refractory Prostate Cancer
  • castration-resistant prostate cancer
  • TKI258
  • FGF23
  • Prostatic Neoplasms