01.12.2017 | Research article | Ausgabe 1/2017 Open Access

A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors
- Zeitschrift:
- BMC Cancer > Ausgabe 1/2017
Electronic supplementary material
Background
Methods
Patient selection
Study design and dosing
Assessments
Tolerability
Pharmacokinetics assessments
Tumor response
EGFR and KRAS mutation analyses
Statistical analysis
Results
Patient characteristics and disposition
Characteristics,
n (%)
|
Selumetinib + docetaxel (
N = 35)
|
Selumetinib + dacarbazine (
N = 25)
|
---|---|---|
Age, years; mean (SD)
|
58.9 (9.5)
|
57.1 (11.5)
|
Male
|
21 (60.0)
|
15 (60.0)
|
Female
|
14 (40.0)
|
10 (40.0)
|
Race
|
||
White
|
33 (94.3)
|
25 (100.0)
|
Black/African American
|
2 (5.7)
|
0
|
WHO performance status
|
||
0
|
14 (40.0)
|
12 (48.0)
|
1
|
21 (60.0)
|
13 (52.0)
|
Primary tumor site
|
||
Skin/soft tissue
|
11 (31.4)
|
17 (68.0)
|
Lung
|
8 (22.9)
|
3 (12.0)
|
Breast
|
3 (8.6)
|
0
|
Colorectal
|
2 (5.7)
|
0
|
Esophagus
|
2 (5.7)
|
0
|
Ovary
|
2 (5.7)
|
0
|
Head and neck
|
1 (2.9)
|
1 (4.0)
|
Uveal
|
1 (2.9)
|
1 (4.0)
|
Other
a
|
5 (14.3)
|
3 (12.0)
|
Mean prior systemic treatments
|
3.1
|
2.0
|
Prior therapy,
n (%)
|
||
Chemotherapy
|
30 (85.7)
|
18 (72.0)
|
Platinum compounds
|
24 (68.6)
|
9 (36.0)
|
Taxanes
|
18 (51.4)
|
8 (32.0)
|
Pyrimidine analogues
|
6 (17.1)
|
1 (4.0)
|
Anthracyclines
|
5 (14.3)
|
3 (12.0)
|
Radiotherapy
|
18 (51.4)
|
13 (52.0)
|
Other systemic anticancer therapy
b
|
8 (22.9)
|
8 (32.0)
|
Immuno/hormonal therapy
|
6 (17.1)
|
0
|
Hormonal therapy
|
3 (8.6)
|
0
|
Immunotherapy
|
2 (5.7)
|
10 (40.0)
|
Prior lines of chemotherapy,
n (%)
|
||
0 or 1
|
17 (48.6)
|
21 (84.0)
|
2 or 3
|
10 (28.6)
|
2 (8.0)
|
4+
|
8 (22.9)
|
2 (8.0)
|
Selumetinib in combination with docetaxel
Dose-limiting toxicities
Part
|
Selumetinib dose
|
n (evaluable for dose escalation)
|
Evaluable patients with a DLT
|
DLT information
|
|
---|---|---|---|---|---|
Selumetinib in combination with docetaxel
|
|||||
A
|
50 mg BID
|
7 (6)
|
0
|
NA
|
|
75 mg BID with ppG-CSF
|
7 (6)
|
0
|
NA
|
||
75 mg BID without ppG-CSF
|
8 (5)
|
2
|
Grade 4 neutropenia with fever (
n = 1) Grade 4 thrombocytopenia (
n = 1)
|
||
B
|
75 mg BID with ppG-CSF
|
12 (NA)
|
NA
|
NA
|
|
75 mg BID without ppG-CSF
|
1 (NA)
|
NA
|
NA
|
||
Selumetinib in combination with dacarbazine
|
|||||
A
|
50 mg BID
|
7 (6)
|
1
|
Grade 4 thrombocytopenia (
n = 1)
|
|
75 mg BID
|
6 (6)
|
0
|
NA
|
||
B
|
75 mg BID
|
12 (NA)
|
NA
|
NA
|
Exposure
Tolerability
Part A
|
Part B
|
Part A + B
|
|||
---|---|---|---|---|---|
Selumetinib 50 mg BID (
N = 7)
|
Selumetinib 75 mg BID with ppG-CSF (
N = 7)
|
Selumetinib 75 mg BID without ppG-CSF (
N = 8)
|
Selumetinib 75 mg BID
a (
N = 13)
|
Selumetinib 75 mg BID (
N = 28)
|
|
Selumetinib in combination with docetaxel AE category,
n (%)
|
|||||
Any AE
|
7 (100.0)
|
7 (100.0)
|
8 (100.0)
|
12 (92.3)
|
27 (96.4)
|
Any grade ≥3 AE
|
5 (71.4)
|
1 (14.3)
|
7 (87.5)
|
11 (84.6)
|
19 (67.9)
|
Any SAE
|
4 (57.1)
|
2 (28.6)
|
5 (62.5)
|
7 (53.8)
|
14 (50.0)
|
Any AE leading to discontinuation
|
0
|
0
|
0
|
2 (15.4)
|
2 (7.1)
|
Most frequently reported AEs (≥20% of patients receiving selumetinib 75 mg BID + docetaxel),
n (%)
|
|||||
Diarrhea
|
5 (71.4)
|
3 (42.9)
|
7 (87.5)
|
11 (84.6)
|
21 (75.0)
|
Edema peripheral
|
5 (71.4)
|
3 (42.9)
|
7 (87.5)
|
10 (76.9)
|
20 (71.4)
|
Fatigue
|
7 (100.0)
|
2 (28.6)
|
5 (62.5)
|
9 (69.2)
|
16 (57.1)
|
Nausea
|
2 (28.6)
|
3 (42.9)
|
4 (50.0)
|
8 (61.5)
|
15 (53.6)
|
Vomiting
|
4 (57.1)
|
3 (42.9)
|
4 (50.0)
|
5 (38.5)
|
12 (42.9)
|
Dermatitis acneiform
|
3 (42.9)
|
4 (57.1)
|
3 (37.5)
|
5 (38.5)
|
12 (42.9)
|
Neutropenia
|
4 (57.1)
|
1 (14.3)
|
5 (62.5)
|
5 (38.5)
|
11 (39.3)
|
Constipation
|
3 (42.9)
|
2 (28.6)
|
3 (37.5)
|
4 (30.8)
|
9 (32.1)
|
Dyspnea exertional
|
3 (42.9)
|
1 (14.3)
|
2 (25.0)
|
5 (38.5)
|
8 (28.6)
|
Epistaxis
|
3 (42.9)
|
2 (28.6)
|
2 (25.0)
|
4 (30.8)
|
8 (28.6)
|
Dysgeusia
|
2 (28.6)
|
2 (28.6)
|
1 (12.5)
|
5 (38.5)
|
8 (28.6)
|
Neuropathy peripheral
|
2 (28.6)
|
2 (28.6)
|
3 (37.5)
|
3 (23.1)
|
8 (28.6)
|
Mucosal inflammation
|
5 (71.4)
|
3 (42.9)
|
1 (12.5)
|
2 (15.4)
|
6 (21.4)
|
Nail disorder
|
1 (14.3)
|
1 (14.3)
|
3 (37.5)
|
2 (15.4)
|
6 (21.4)
|
Selumetinib in combination with dacarbazine AE category,
n (%)
|
|||||
Any AE
|
7 (100.0)
|
6 (100.0)
|
12 (100.0)
|
18 (100.0)
|
|
Any grade ≥3
|
7 (100.0)
|
2 (33.3)
|
9 (75.0)
|
11 (61.1)
|
|
Any SAE
|
4 (57.1)
|
2 (33.3)
|
4 (33.3)
|
6 (33.3)
|
|
Any AE leading to discontinuation
|
0
|
0
|
1 (8.3)
|
1 (5.6)
|
|
Most frequently reported AEs (≥30% of patients receiving selumetinib 75 mg BID + dacarbazine),
n (%)
|
|||||
Diarrhea
|
4 (57.1)
|
6 (100.0)
|
9 (75.0)
|
15 (83.3)
|
|
Nausea
|
5 (71.4)
|
5 (83.3)
|
10 (83.3)
|
15 (83.3)
|
|
Fatigue
|
2 (28.6)
|
3 (50.0)
|
11 (91.7)
|
14 (77.8)
|
|
Decreased appetite
|
1 (14.3)
|
3 (50.0)
|
8 (66.7)
|
11 (61.1)
|
|
Dizziness
|
1 (14.3)
|
2 (33.3)
|
8 (66.7)
|
10 (55.6)
|
|
Headache
|
1 (14.3)
|
4 (66.7)
|
6 (50.0)
|
10 (55.6)
|
|
Vomiting
|
1 (14.3)
|
3 (50.0)
|
7 (58.3)
|
10 (55.6)
|
|
Constipation
|
3 (42.9)
|
3 (50.0)
|
6 (50.0)
|
9 (50.0)
|
|
Dermatitis acneiform
|
1 (14.3)
|
2 (33.3)
|
7 (58.3)
|
9 (50.0)
|
|
Edema peripheral
|
3 (42.9)
|
1 (16.7)
|
8 (66.7)
|
9 (50.0)
|
|
Dyspnea exertional
|
1 (14.3)
|
2 (33.3)
|
6 (50.0)
|
8 (44.4)
|
|
Asthenia
|
0
|
2 (33.3)
|
5 (41.7)
|
7 (38.9)
|
|
Vision blurred
|
0
|
1 (16.7)
|
6 (50.0)
|
7 (38.9)
|
|
Periorbital edema
|
1 (14.3)
|
0
|
6 (50.0)
|
6 (33.3)
|
Pharmacokinetics analysis
Geometric mean (% co-efficient of variation) [
n evaluable]
|
||||||||
---|---|---|---|---|---|---|---|---|
Selumetinib + docetaxel
|
Selumetinib + dacarbazine
|
|||||||
Parameter
|
Dosed alone
|
Dosed in combination
|
Dosed alone
|
Dosed in combination
|
||||
Selumetinib 50 mg (
N = 7)
|
Selumetinib 75 mg (
N = 19)
|
Selumetinib 50 mg (
N = 7)
|
Selumetinib 75 mg (
N = 16)
|
Selumetinib 50 mg (
N = 7)
|
Selumetinib 75 mg (
N = 18)
|
Selumetinib 50 mg (
N = 7)
|
Selumetinib 75 mg (
N = 15)
|
|
Selumetinib
|
||||||||
C
max, ng/mL
|
382.5 (114.50)
|
1165 (62.27)
|
576.6 (41.39)
|
1215 (70.09) [
13]
|
933.5 (43.38)
|
1537 (45.53)
|
692.7 (56.34)
|
1343 (74.40)
|
T
max, h
a
|
4.0 (1.0–12.0)
|
1.0 (1.0–2.0)
|
1.53 (0.5–4.0)
|
1.5 (0.5–4.0) [
13]
|
1.0 (1.0–3.0)
|
1.0 (0.5–4.0)
|
1.0 (0.5–1.5)
|
1.5 (1.0–4.0)
|
AUC
(0–8), ng•h/mL
|
1144 (52.30)
|
2735 (43.05)
|
1788 (25.59)
|
3788 (57.53) [
13]
|
2351 (23.14)
|
3784 (31.17)
|
2460 (44.05)
|
4544 (45.42)
|
AUC
(0–12), ng•h/mL
|
1479 (45.02)
|
2999 (42.33)
|
2056 (30.40) [
5]
|
5239 (31.04) [
9]
|
2652 (22.38)
|
4210 (31.55)
|
2822 (42.48)
|
5317 (43.00)
|
N-desmethyl selumetinib
|
||||||||
C
max, ng/mL
|
31.79 (60.02)
|
69.63 (49.65)
|
29.41 (175.6)
|
40.91 (52.07) [
13]
|
46.99 (77.29)
|
71.21 (69.68)
|
14.89 (161.60)
|
24.94 (96.48)
|
T
max, h
a
|
4.0 (1.0–12.0)
|
1.25 (1.0–4.0)
|
2.0 (1.0–4.0)
|
1.5 (0.5–4.0) [
13]
|
1.0 (1.0–2.0)
|
1.5 (1.0–4.0)
|
1.5 (0.5–2.0)
|
2.0 (1.0–4.0)
|
AUC
(0–8), ng•h/mL
|
120.0 (33.99) [
6]
|
209.4 (37.13)
|
170.8 (49.61) [
5]
|
150.3 (35.51) [
13]
|
163.8 (70.89)
|
212.8 (48.59)
|
102.2 (94.56) [
5]
|
101.5 (72.76)
|
AUC
(0–12), ng•h/mL
|
151.2 (37.44) [
6]
|
236.5 (36.06)
|
258.5 (42.52) [
3]
|
172.7 (38.09) [
10]
|
196.0 (70.11)
|
261.3 (40.61) [
17]
|
277.9 (2.08) [
2]
|
146.4 (58.26) [
12]
|
Docetaxel
|
||||||||
C
max, ng/mL
|
2826 (44.32)
|
2109 (83.65) [
15]
|
2789 (16.66)
|
2623 (24.33) [
13]
|
||||
T
max, h
a
|
1.0 (0.5–1.0)
|
0.5 (0.5–1.5) [
15]
|
0.5 (0.5–1.0)
|
1.0 (0.5–1.5) [
13]
|
||||
AUC
(0–8), ng•h/mL
|
3396 (48.98)
|
2445 (58.67) [
15]
|
2978 (7.75)
|
2834 (22.27) [
13]
|
||||
AUC
(0–12), ng•h/mL
|
3493 (49.31)
|
2533 (55.74) [
15]
|
3049 (8.90) [
6]
|
2871 (25.19) [
9]
|
||||
Dacarbazine
|
||||||||
C
max, ng/mL
|
29.43 (49.76)
|
30.17 (20.38) [
16]
|
28.86 (34.66)
|
30.60 (17.87) [
18]
|
||||
T
max, h
a
|
1.0 (1.0–1.5)
|
1.0 (1.0–1.5)
|
1.0 (1.0–1.0)
|
1.0 (1.0–1.5)
|
||||
AUC
(0–8), ng•h/mL
|
95.92 (39.61) [
6]
|
73.73 (22.24) [
15]
|
83.20 (45.68)
|
78.82 (24.23) [
18]
|
||||
AUC
(0–12), ng•h/mL
|
144.9 (58.46) [
4]
|
101.5 (23.28) [
9]
|
132.6 (62.18) [
4]
|
107.3 (25.27) [
15]
|
||||
AIC
|
||||||||
C
max, ng/mL
|
5.151 (28.12) [
6]
|
4.431 (48.12) [
16]
|
3.570 (122.10) [
6]
|
3.298 (38.25) [
18]
|
||||
T
max, h
a
|
1.5 (1.0–1.5)
|
1.5 (1.0–3.0)
|
1.5 (1.5–3.0)
|
1.5 (1.5–3.0)
|
||||
AUC
(0–8), ng•h/mL
|
21.54 (28.01) [
5]
|
17.58 (46.87) [
15]
|
15.05 (108.10) [
6]
|
13.29 (38.39) [
18]
|
||||
AUC
(0–12), ng•h/mL
|
28.31 (19.91) [
5]
|
22.32 (43.91) [
7]
|
21.40 (90.82) [
6]
|
19.38 (28.28) [
11]
|