Genesis of a Clinical Trial: VADER

A considerable amount of effort, time and collaboration across multidisciplinary teams is required to successfully obtain funding to establish and perform an academic clinical trial

Follow the genesis of the VADER study – originating as an idea at the inaugural Idea Generation Workshop in 2019, the VADER trial will test the effectiveness of a drug called sodium valproate in first-line treatment of patients with colorectal cancer. Sodium valproate is not a new drug, rather is a drug which has been used to treat epilepsy and mood disorders for several decades. Professors Niall Tebbutt and John Mariadason are leading this study, and hope to build on recent research that suggests sodium valproate may help inhibit tumour growth. Thanks to community support through the Innovation Grant last year and a Medical Research Future Fund grant this year, this trial is now funded and opened to Australian patients in 2023.

Professor Niall Tebbutt

 

Step 1. Identification of a gap in research

Led by Convenors Professor Martin Stockler and Professor Mustafa Khasraw, ten embryonic research ideas were presented and discussed at the 2019 Idea Generation Workshop. The purpose of this workshop was to determine the best direction for future research in GI cancer, with ideas covering the topic of treatments for rare cancers, including pancreatic cancer, gastric cancer and hepatocellular carcinoma. There were also ideas for quality-of-life studies, such as those that addressed symptoms relating to skin toxicity associated with colorectal cancer treatment and chemotherapy-induced peripheral neuropathy. The ideas that progressed to research concepts were developed with the support of the Upper and Lower GI Working Parties.

The VADER study will “re-purpose” a drug called sodium valproate to treat patients with advanced colon cancer. Laboratory findings have shown that this drug also has anti-cancer activity.

“Over 5000 Australians die from colorectal cancer each year including an increasing number of younger people. This trial will investigate a potential new treatment which is urgently needed for these patients” says Professor Mariadason.

Step 2. Literature review

Advanced bowel cancer is a major health problem in Australia, and concerningly there is an increasing incidence of bowel cancer in younger adults. Bowel cancer that has spread to other organs (metastatic) is a generally considered an incurable disease with limited survival times, typically measured in months. Therefore, it is imperative that new treatments are developed, particularly as bowel cancer is largely resistant to immunotherapy which is showing promise in many  other cancer types.

Step 3. Pre-clinical research

This study tests a novel combination of drugs which have shown promise in several laboratory studies. Specifically, it tests the combination a drug (an antibody protein called cetuximab) which inhibits one of the cancer cell’s growth pathways (called the MAPK pathway) with another drug (sodium valproate) which amongst other effects can act to inhibit molecules termed histone de-acetylases inhibitor (HDAC inhibitors). Laboratory studies have shown that many different combinations of MAPK pathway inhibitors and HDAC inhibitors are effective in damaging cancer cells, and that this combination is more effective at causing cell death.

Step 4. Pilot study

This is a signal seeking study. If positive, this study will form the basis of a larger phase III GI Cancer Trials-led study which could define a new treatment option for patients with advanced bowel cancer.

Step 5. Application to GI Cancer Trials Innovation Grant

Professors Tebbutt and Mariadason prepared a grant application for the 2020 GI Cancer Trials Innovation Grant and was awarded a $200,000 grant. The application scored highly for scientific merit, feasibility, and alignment with GI Cancer Trials research priorities. The Innovation Grant is made possible by the generosity of donors.

Step 6. Application to the MRFF Medical Research Future Fund Efficient Use of Existing Medicines

Leveraging on the successful Innovation Grant, the study team applied for additional funding through the MRFF scheme and was awarded funds to support more sites and patients.

Step 7. A clinical trial is started

The phase II clinical trial opened for enrolment in Q1 2023 at Austin Health, Victoria. The study is set to open at 15 sites and enrol 90 patients.