Table 3.

Descriptive statistics of AMG 232 plasma PK parameter estimates after oral administration of AMG 232 for 6 days at steady-state levels on cycle 1, day 7, without trametinib (and dabrafenib for Arm 1) and cycle 2, day 7, with trametinib (and dabrafenib for Arm 1) in subjects with metastatic melanoma

Arm	Cohort	AMG 232 dose (mg)	tmax (hr)	Cmax (ng/mL)	AUC24hr (hr•ng/mL)	t1/2,z (hr)	CL/F (L/hr)
Cycle 1, Day 7 (AMG 232 monotherapy; prior to co-administration with T + D [Arm 1] or T alone [Arm 2)
Arm 1: AMG 232 + T + D	1	120	2.0 (1.0–4.0) n = 4	491 (59.4%) n = 4	5140 (59.4%) n = 4	7.04 (NR) n = 1	23.4 (53.6%) n = 4
	2	180	2.0 (1.0–4.0) n = 6	847 (51.3%) n = 6	5890 (34.6%) n = 5	7.79 (0.718) n = 4	30.6 (37.5%) n = 5
Arm 2: AMG 232 + T	1	120	2.0 (2.0–4.0) n = 6	914 (37.4%) n = 6	9810 (61.4%) n = 6	8.32 (NR) n = 2	12.2 (69.7%) n = 6
	2	180	2.0 (0.0–4.0) n = 7	1250 (62.2%) n = 7	10600 (71.7%) n = 7	7.54 (NR) n = 2	16.9 (115.6%) n = 7
	3	240	2.0 (2.0–2.0) n = 4	3300 (46.5%) n = 4	21100 (28.3%) n = 3	8.12 n = 1	11.4 (24.7%) n = 3
Cycle 2, Day 7 (AMG 232 with co-administration of T + D [Arm 1] or T alone [Arm 2])
Arm 1: AMG 232 + T + D	1	120	2.0 (2.0–4.0) n = 4	392 (43.3%)a n = 4	3140 (31.4%)a n = 4	5.86 (NR) n = 2	38.2 (32.5%) n = 4
	2	180	3.0 (1.0–6.0) n = 6	647 (44.3%)a n = 6	4750 (38.7%)a n = 4	6.93 (NR) n = 2	37.9 (38.2%) n = 4
Arm 2: AMG 232 + T	1	120	3.0 (2.0–6.0) n = 4	630 (77.2%)a n = 4	6740 (62.9%)a n = 4	ND n = 0	17.8 (101.2%) n = 4
	2	180	1.0 (1.0–6.0) n = 5	1010 (52.0%)a n = 5	9410 (107.0%)a n = 5	ND n = 0	19.1 (99.6%) n = 5
	3	240	1.5 (1.0–2.0) n = 2	953 (NR)b n = 2	6280 (NR)b n = 2	5.30 (NR) n = 2	38.2 (NR) n = 2

Data are presented as geometric mean (CV%) except for t_max and t_1/2,z, which were presented as median (minimum-maximum) and mean (SD), respectively. Number of subjects (n) are presented for each parameter

AUC_24h area under the concentration-time curve from time 0 to 24 hrs post-dose, CL/F apparent drug clearance after extravascular administration, C_max maximum observed plasma concentration, CV% percent coefficient of variation, D dabrafenib (150 mg twice daily dosing), hr hour, ND no data, NR not reported, SD standard deviation, T trametinib (2 mg once daily dosing), t_1/2,z terminal half-life, t_max time to reach C_max

^a p>0.05 comparing AMG 232 C_max and AUC_24h values for subjects following cycle 1, day 7 (AMG 232 monotherapy), and cycle 2, day 7 (AMG 232 in combination with trametinib and dabrafenib or trametinib alone, Wilcoxon matched-pairs signed῏rank test)

^b Wilcoxon test not performed (insufficient subjects to conduct test)