Phase II Open Label Study to Evaluate the Biological Activity of ASLAN001 (ARRY 334543) in Patients With Recurrent/Metastatic Gastric, Gastro-oesophageal Junction, and Oesophageal Carcinoma Whose Tumours Are Epidermal Growth Factor Receptor-2 (HER 2) Amplified or Co-expressing Epidermal Growth Factor Receptor-1 (HER-1) and HER-2.
About 1 million new cases of gastric cancer were estimated to have occurred in 2008 (988,000
cases, 7.8% of the total), making it currently the fourth most common malignancy in the
world, behind cancers of the lung, breast, and colo-rectum. Gastric cancer is also the
second leading cause of cancer-related death in both sexes worldwide with 700,000 deaths
occurring annually. The incidence and mortality rates for gastric cancer vary widely in
different regions of the world. The incidence has dramatically declined in the United
States where it ranks seventh as a cause of cancer- related deaths. In the Asia-Pacific
region, the highest incidences of gastric cancer can be found in China, Japan, and Korea,
where the age standardized incidence rate (ASR) is greater than 20 per 100,000 populations.
Intermediate risk countries (ASR 11-19/100,000 population) include Malaysia, Singapore, and
Taiwan, while low-risk countries (ASR < 10/100,000 population) include Australia, New
Zealand, India, and Thailand.
Approximately 95% of all malignant gastric neoplasms are adenocarcinomas. One of the most
striking epidemiologic observations has been the increasing incidence of adenocarcinomas
involving the proximal stomach and distal oesophagus including the oesophagogastric
junction. These tumours are thought to have different etiologic factors; gastric body and
antral lesions are associated with low acid production and Helicobacter pylori infection,
whereas cardiac lesions are not associated with either.
The treatment for advanced and un-resectable disease has remained essentially unchanged for
the past 2 decades, with platinum and fluoro-pyridine-based combination chemotherapy being
the mainstay of therapy. The molecular biology responsible for carcinogenesis, tumour
biology, and response to therapy in gastric cancer are active areas of investigation.
Amplification and/or over-expression of epidermal growth factor receptor-2 (HER 2) have been
found to promote tumourigenesis and to be involved in the pathogenesis of gastric cancer.
Recently, data from randomised studies of trastuzumab (Herceptin®) in patients with HER 2
amplification demonstrated significant improvement in outcome in comparison to chemotherapy
alone. Studies on a number other molecularly targeted agents used alone or in combination
with chemotherapy have been undertaken, or are ongoing. Translational research, undertaken
as part of these studies, demonstrates the great molecular heterogeneity of the disease,
with multiple growth factor and survival pathways being implicated.
In view of this, successful therapeutic intervention is likely to require both the
identification of molecularly defined subsets of disease, and the evaluation of
rationally-selected combinations of targeted agents.
Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science
The percentage of patients demonstrating clear evidence of inhibition of receptor auto-phosphorylation in HER-2 amplified patients on Day 29.
Seock-Ah Im, Dr.
Seoul National University Hospital
South Korea: Korea Food and Drug Administration (KFDA)