A phase II study of TKI258 in patients with castration-resistant prostate cancer (KCSG-GU11-05)

Background

FGF signals are important in carcinogenesis and progression of prostate cancer. TKI258 (dovitinib) is an oral, pan-class VEGFR, PDGFR, and FGFR inhibitor. Preclinical data demonstrated a significant activity of TKI258 in mouse xenograft models. We evaluated the efficacy and toxicity of TKI258 in men with metastatic CRPC.

Methods

This study was a single-arm, phase II, open-label, multicenter trial of TKI258 (500mg orally according to a 5-days-on and 2-days-off schedule). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), toxicity and PSA response rate. Biomarker analyses for serum FGFR, FGF-23 and VEGFR using multiplex ELISA were performed. This study is registered with ClinicalTrials.gov, number NCT01741116.

Results

Forty-four men were accrued from 11 hospitals: 80% post-docetaxel; median PSA was 100 ng/dl, median age was 69, 82% had bone metastases, 23% had liver metastases. Median cycles of TKI258 was 2 (range 0-33). Median PFS was 3.67 months (95% CI: 1.36-5.98) and median OS was 13.7 months (95% CI: 0-27.41). Chemotherapy-naïve patients had longer PFS (17.9 months, 95% CI, 9.23-28.57) compared with docetaxel-treated patients (2.07 months, 95% CI, 1.73-2.41, p = 0.001) and the patients with high serum VEGFR2 level over median level (7800 pg/ml) showed longer PFS compared with others. (6.03 [95% CI, 4.26-7.80] vs 1.97 [95% CI, 1.79-2.15] months, p = 0.023). The PSA decline was observed in 32.3% and 12.9% of patients achieved a > 50% decline. Four objective responses were observed with ORR of 12.5% (95% CI: 5.0-28.1%). Grade 3 related AEs were seen in 40.9% of patients with 7.0% stopping TKI258 due to toxicity. The most common related AEs included grade 1-2 nausea, diarrhea, fatigue, anorexia and all grade thrombocytopenia (29.5%).

Conclusions

TKI258 showed modest antitumor activity with manageable toxicities in men with mCRPC. Especially, patients who were chemo-naïve or with high levels of serum VEGFR2 had the benefit from TKI258.

Clinical trial identification

ClinicalTrials.gov NCT01741116

Legal entity responsible for the study

KCSG (Korean Cancer Study Group)

Funding

KCSG (Korean Cancer Study Group)

Disclosure

All authors have declared no conflicts of interest.