Inclusion Criteria:

1. Males and Females aged 18 years and older. (There is no upper age limit)
2. Histopathological evidence of ASS-negative MPM. All biopsies will be reviewed for ASS expression using immunohistochemistry. Central lab confirmation is required before randomization
3. Performance status ECOG ≤ 1. Life expectancy should be greater than 3 months
4. Chemo-naive patients OR, Patients who have been previously treated with platinum-based combination chemotherapy with progressive disease at entry. In the event of a baseline diagnostic ASS-positive test, a repeat biopsy confirming loss of ASS expression will be required post platinum-based combination chemotherapy, with at least a 4 week interval from the last treatment episode.
5. CT evaluable disease by modified RECIST criteria

6. Adequate bone marrow function, or supported through treatment:

   • Haemoglobin 10g/dl or greater.
   • White cell count 2 x 109/L or greater, neutrophil count 1.5 x 109/L or greater
   • Platelets 75 x 109 /L or greater.
7. Adequate hepatic function (AST and ALT < 3 x upper limit of normal; bilirubin < 1.5 x upper limit of normal)
8. Creatinine clearance >30ml/min
9. Able to give written informed consent to participate

Exclusion Criteria:

1. Participation in another clinical trial using an investigational agent
2. Patients with surgically resectable disease
3. Recurrent pleural effusion (not pleurodesed)
4. Receipt of extensive radiation (hemi-thorax) therapy within 6 weeks before enrollment. Radiation to chest port sites following thoracotomy is permitted
5. A history of prior malignant tumour, unless the patient has been without evidence of disease for at least three years, or the tumour was a non-melanoma skin tumour or in-situ cervix carcinoma
6. Symptomatic or known brain or leptomeningeal metastases
7. Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment
8. New York Heart Association (NYHA) Class III or IV heart failure (Attachment 10, NYHA Classification of Cardiac Disease), uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis
9. Serious medical (e.g. uncontrolled diabetes, hepatic disease, infection, uncontrolled gout) or psychiatric illness likely to interfere with participation in this clinical study
10. History of seizures
11. Patients of child-bearing age must not become pregnant. Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for protocol therapy. All patients enrolled on the study must agree to use acceptable birth control measures whilst on the study; using both barrier and hormonal methods. Patients that are surgically sterile are also eligible to participate in this study
12. Females must not be breastfeeding
13. Prior exposure to ADI-PEG 20
14. Preplanned surgery or procedures that would interfere with the study protocol
15. Allergy to pegylated products
16. Exposure to another investigational drug within 4 weeks prior to start of study treatment