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Ann Oncol. 2016 Dec;27(12):2210-2215. doi: 10.1093/annonc/mdw415. Epub 2016 Sep 28.

A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC).

Author information

1
Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
2
Department of Haematology-Oncology, National University Health System, Singapore.
3
Divisions of Clinical Trials and Epidemiological Sciences.
4
Oncologic Imaging, National Cancer Centre Singapore, Singapore.
5
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
6
SingHealth Duke-NUS Radiological Sciences Academic Clinical Program, Singapore.
7
Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre Singapore, Singapore.
8
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
9
Department of Medical Oncology, National Cancer Centre Singapore, Singapore choo.su.pin@singhealth.com.sg.

Abstract

BACKGROUND:

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).

METHODS:

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).

RESULTS:

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.

CONCLUSION:

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.

CLINICALTRIALSGOV IDENTIFIER:

NCT01029418.

KEYWORDS:

hepatocellular carcinoma; pharmacokinetics; selumetinib (AZD6244, ARRY-142886); sorafenib

PMID:
27681866
DOI:
10.1093/annonc/mdw415
[Indexed for MEDLINE]

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