Phase I/II and Pharmacodynamic Study of Dovitinib (TKI258), an Inhibitor of Fibroblast Growth Factor Receptors and VEGF Receptors, in Patients with Advanced Melanoma

DOI: 10.1158/1078-0432.CCR-11-1747 Published December 2011

Article Figures & Data

Download figure
Open in new tab
Download powerpoint
Figure 1.
Effect of dovitinib on plasma biomarkers: A, FGF23; B, PLGF; C, sVEGFR2; and D, VEGF. Longitudinal plots of the model-estimated fold change from baseline on days 15 and 26 of the first dosing cycle are shown. Thin line, 200 to 300 mg/d dose; bold line, 400 mg/d dose; dashed line, 500 mg/d dose; bars, SE. Mean levels at baseline were as follows: FGF23, 42.34 pg/mL; PLGF, 31.05 pg/mL; sVEGFR2, 172.99 pg/mL; and VEGF, 197.91 pg/mL.
Download figure
Open in new tab
Download powerpoint
Figure 2.
Dovitinib inhibits FGFR3 phosphorylation and pErk phosphorylation. A, a pair of tumor biopsy samples stained with anti-pFGFR3 antibody before and after treatment (day 15 of cycle 1, 400 mg/d). B, plasma FGF23 levels from the same patient receiving dovitinib (400 mg/d) on days 1, 15, and 26 of cycle 1 (C1D1, C1D15, and C1D26). C, paired tumor biopsy samples from the same patient stained with anti-pErk antibody before and after treatment (day 15 of cycle 1, 400 mg/d).
Download figure
Open in new tab
Download powerpoint
Figure 3.
Dovitinib exposure correlates with a change in K^trans in liver metastases at an early time point (day 2 of cycle 1) measured by DCE-MRI.

Table 1.

Baseline demographics and patient characteristics

Characteristic	200–300 mg	400 mg	500 mg	Total
	(n = 4)	(n = 36)	(n = 7)	(N = 47)
Age (y)
Median	48.5	57.0	62.0	57.0
Range	46–65	26–80	33–71	26–80
Sex, n (%)
Female	2 (50)	17 (47)	3 (43)	22 (47)
Male	2 (50)	19 (53)	4 (57)	25 (53)
ECOG performance status, n (%)
0	1 (25)	19 (53)	2 (29)	22 (47)
1	3 (75)	17 (47)	5 (71)	25 (53)
Primary site of cancer, n (%)
Cutaneous	2 (50.0)	23 (63.9)	4 (57.1)	29 (61.7)
Mucosal	0	2 (5.6)	0	2 (4.3)
Ocular	1 (25.0)	6 (16.7)	1 (14.3)	8 (17.0)
Unknown	1 (25.0)	3 (8.3)	0	4 (8.5)
Other	0	2 (5.6)	2 (28.6)	4 (8.5)
Melanoma subtype, n (%)
Acral-lentiginous	0	2 (5.6)	0	2 (4.3)
Desmoplastic	0	1 (2.8)	0	1 (2.1)
Mucosal	0	3 (8.3)	1 (14.3)	4 (8.5)
Nodular	1 (25)	4 (11.1)	1 (14.3)	6 (12.8)
Other	1 (25)	0	1 (14.3)	2 (4.3)
Superficial spreading	1 (25)	9 (25.0)	1 (14.3)	11 (23.4)
Unknown	1 (25)	13 (36.1)	3 (42.9)	17 (36.2)
Uveal	0	4 (11.1)	0	4 (8.5)

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

Table 2.

AEs occurring in 10% or more of patients, regardless of the study drug relationship

Table 3.

Model-adjusted average ratios from baseline observed in plasma levels of biomarkers with false discovery rate–adjusted P values for days 15 and 28

Biomarker	Dose group (mg)	Day 15 fold change	Day 15 P	Day 28 fold change	Day 28 P
bFGF	200–300	1.23	0.77	1.34	0.71
	400	0.66	0.15	1.00	1.00
	500	1.83	0.30	2.55	0.10
c-KIT	200–300	1.06	0.74	1.11	0.59
	400	0.94	0.38	0.93	0.38
	500	0.75	0.04	0.88	0.35
FGF23	200–300	1.66	0.23	1.03	0.96
	400	1.68	0.00	1.94	0.00
	500	1.46	0.25	1.13	0.71
PLGF	200–300	1.37	0.41	2.03	0.05
	400	1.93	0.00	2.18	0.00
	500	1.84	0.04	2.12	0.01
sVEGFR1	200–300	0.93	0.89	1.11	0.83
	400	0.67	0.04	0.91	0.70
	500	0.85	0.70	1.19	0.69
sVEGFR2	200–300	0.81	0.22	0.84	0.30
	400	0.76	0.00	0.82	0.00
	500	0.73	0.01	0.76	0.03
VEGF	200–300	1.29	0.59	1.54	0.30
	400	1.23	0.22	1.51	0.04
	500	1.73	0.09	3.03	0.00

Supplementary Data

Files in this Data Supplement:

Supplementary Table 1 - PDF file - 131K, Abbreviations: AUC0-t, area under the concentration-time curve from time zero to t; Cmax, maximum concentration; CV%, coefficient of variation; PK, pharmacokinetic; SD, standard deviation; T1/2, half-life.