A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC).
Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC).



Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).



Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes.



The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation.



NCT01029418.
Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
W M
WM
Tai
Department of Haematology-Oncology, National University Health System, Singapore.
W P
WP
Yong
Divisions of Clinical Trials and Epidemiological Sciences.
C
C
Lim
Divisions of Clinical Trials and Epidemiological Sciences.
L S
LS
Low
Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
C K
CK
Tham
Oncologic Imaging, National Cancer Centre Singapore, Singapore.
T S
TS
Koh
Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
Q S
QS
Ng
Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
W W
WW
Wang
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
L Z
LZ
Wang
SingHealth Duke-NUS Radiological Sciences Academic Clinical Program, Singapore.
S
S
Hartano
Oncologic Imaging, National Cancer Centre Singapore, Singapore.
C H
CH
Thng
Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre Singapore, Singapore.
H
H
Huynh
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
K T
KT
Lim
Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
H C
HC
Toh
Department of Haematology-Oncology, National University Health System, Singapore.
B C
BC
Goh
Department of Medical Oncology, National Cancer Centre Singapore, Singapore choo.su.pin@singhealth.com.sg.
S P
SP
Choo
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000077157:Sorafenib
C517975:AZD 6244; D001562:Benzimidazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib
hepatocellular carcinoma; pharmacokinetics; selumetinib (AZD6244, ARRY-142886); sorafenib