RECRUITING: ATOMIC-meso, a Global Randomised Trial of Triplet Drug Therapy for Malignant Mesothelioma
ADI-PEG20 continues to show promise
Several ongoing trials, led by Dr Peter Szlosarek at the CRUK Barts Centre, continue to investigate the clinical efficacy of “arginine starvation” using ADI-PEG20 in difficult-to-treat tumours that lack the enzyme ASS1.
For patients with mesothelioma – a rare and aggressive cancer affecting the lining of the internal organs – this new targeted anti-metabolite strategy represents the first therapy of its kind since the development of antifolates 14 years ago.
Since opening in July 2017, the latest trial; ATOMIC-meso, is recruiting patients with ASS1-deficient non-epithelioid (biphasic and sarcomatoid) malignant pleural mesothelioma and follows the success of two earlier trials of the arginine-depleting drug (ADI-PEG20, Polaris Pharma), ADAM and TRAP.
The Phase 2/3 ATOMIC-meso trial is the largest randomised trial to investigate triplet drug combination therapy with ADI-PEG20 for non-epithelioid mesothelioma with low ASS1.
Having already established the safety of the combination of ADI-PEG20, Cisplatin and Pemetrexed, the trial hopes to recruit 386 patients to assess response rate, progression free and overall survival.
We invite anyone affected by these cancers, or looking for information for family or friends, to contact our Trial Co-ordinators by e-mail:
- Catherine Norman - Catherine.email@example.com
- Marina Baccarini - Marina.firstname.lastname@example.org
Previous trials: ADAM and TRAP
ADAM was the world’s first randomised trial to assess the safety and efficacy of ADI-PEG20 in patients with ASS1 negative mesothelioma, reporting an improvement in the average time of survival without disease progression, compared to standard chemotherapy (Szlosarek et al, Jama Onc, 2017)
Encouraging results from both the clinic and lab inspired the TRAP study to investigate the benefits of ADI-PEG20 in combination with standard chemotherapy – Pemetrexed and Cisplatin – drugs that target rapidly dividing cancer cells.
In the first phase of the TRAP trial (now completed), the combination reported significantly improved tumour shrinkage in patients with mesothelioma that had spread to other parts of the body (metastatic), with no additional side effects when compared with Cisplatin and Pemetrexed alone.
A major benefit of the combination was attributed to the ability of ADI-PEG20 to reduce the action of another protein in the body that would otherwise block the efficiency of the drug Pemetrexed.
Part 2 of the TRAP study is ongoing and continues to recruit patients with a variety of sarcomatoid cancers (excluding mesothelioma). Studies in uveal melanoma, glioma and lung cancer have now completed.
Targeting arginine addiction
We know that cancer cells rely on a variety of means to ‘fuel’ their own growth. Arginine is a key amino acid, identified as an essential requirement for the growth and metabolism of many aggressive tumours, particularly those with a poor clinical outcome.
Dr Szlosarek’s team have identified that unlike normal healthy cells, tumour cells – due to the loss of the arginine producing protein argininosuccinate synthetase ASS1 – are unable to produce their own internal supply of arginine. Tumour cells therefore rely on its availability in the bloodstream.
Since ADI-PEG20 depletes the arginine supply found in the blood, it provides an efficient way of targeting a specific metabolic vulnerability of cancer cells, without affecting normal healthy cells.
Figure 1: Arginine “starvation” using ADI-PEG20. Arginine is an amino acid produced by the argininosuccinate synthetase ASS1 protein. (A) Normal cells are able to produce their own supply of arginine to use for growth and metabolism. (B) Several aggressive tumours inactivate ASS1 thereby promoting tumorigenesis but this also leads to a dependence on an exogenous supply of arginine from the bloodstream (or “arginine auxotrophy”). (C) Arginine dependence leaves these tumours vulnerable to starvation approaches. ADI-PEG20 or pegylated arginine deiminase targets this unique vulnerability by depleting the levels of arginine in the blood, leaving nothing for the tumour cells to feed on. Starved of arginine, tumour cells are no longer able to grow and soon die. Normal healthy cells continue to produce arginine and remain insensitive to arginine depletion with ADI-PEG20.