Ph 1 Study in Subjects With Tumors Requiring Arginine to Assess ADI-PEG 20 With Pemetrexed and Cisplatin

Weekly ADI-PEG 20 will be cohort dose escalated (18, 27 and 36 mg/m2), with pemetrexed 500
mg/m2 and cisplatin 75 mg/m2 both given every 3 weeks. Subjects may receive a maximum of 6,
3-week cycles of ADIPemCis for a total of 18 weeks of treatment. Subjects with NSCLC may
receive 4 to 6, 3-week cycles as per local institutional policy. Those subjects completing
ADIPemCis treatment may continue on ADI-PEG 20 monotherapy if they have SD or better.
Subjects with NSCLC may continue to receive pemetrexed as per local institutional policy
along with ADI-PEG 20 and/or continue on ADI-PEG 20 monotherapy after pemetrexed is also
discontinued.

Inclusion Criteria:

1. Histologically proven advanced MPM, advanced peritoneal mesothelioma (for dose
escalation cohort only) or non-squamous NSCLC (stage IIIB/IV) who have not been
treated with prior chemotherapy or immunotherapy, except that NSCLC subjects with EGFR
mutant or ALK positive must have had an EGFR tyrosine kinase inhibitor (TKI) or ALK
inhibitor and progressed or been shown to be intolerant of therapy prior to enrolling
in this trial, if such ALK inhibitor and EGFR targeted therapy are approved and
available in the country in which patients are being enrolled OR Histologically proven
metastatic uveal melanoma who have not been treated with prior chemotherapy (MTD
cohort only), OR Histologically proven HCC who have failed (PD and/or side
effects-been intolerant of) treatment with sorafenib. Failure is defined as having
progressed radiographically on, or been intolerant to prior systemic therapy.
Intolerance is defined as discontinuation due to an AE(s) on prior systemic therapy
that was unacceptable to the treating physician and / or patient, with or without dose
interruption and modification. Failure requires at least 14 days of treatment with
sorafenib, except for a subject that has had a severe allergic reaction to sorafenib
at any time, even less than 14 days of treatment with sorafenib and thus it would be
imprudent to re-challenge them with that agent. Cirrhotic status of Child-Pugh grade
A-B7 must be present. Child-Pugh status should be determined based on clinical
findings and laboratory data during the screening period (Appendix E). Subjects on
anti-coagulants are to receive 1 point for their INR status, as they are presumed to
have a <1.7 baseline PT/INR.", OR Histologically proven high-grade glioma who have
failed (PD and/or side effects) treatment with radiotherapy ± temozolomide, OR
Sarcomatoid cancer of any line.

2. ASS1 deficiency (defined as ≤50% ASS expression) demonstrated on tissue specimen
(cytospin samples are acceptable) by immunohistochemistry (IHC). For subjects
previously treated with chemotherapy, this specimen may have been obtained before that
chemotherapy. A new tissue specimen obtained after most recent chemotherapy is not
required. Thus ASS1 deficiency is required for entrance into the study. If tissue is
not available to determine ASS1 deficiency, then tissue must be obtained by biopsy to
determine ASS1 status.

3. Measurable disease as assessed by modified RECIST for MPM and by RECIST 1.1 criteria
for peritoneal mesothelioma, NSCLC, uveal melanoma, HCC, glioma and sarcomatoid
carcinoma

4. ECOG performance status of 0 - 1

5. Predicted life expectancy of at least 12 weeks.

Exclusion Criteria:

1. Radiotherapy (except for palliative reasons), targeted therapy, or immunotherapy
(except for uveal melanoma) the previous four weeks before study treatment.

2. Ongoing toxic manifestations of previous treatments.

3. Symptomatic brain or spinal cord metastases (patients must be stable for > 3 months
post radiotherapy or surgery) for subjects with mesothelioma, NSCLC, uveal melanoma
excludes subjects with HCC or glioma).

4. Major thoracic or abdominal surgery from which the patient has not yet recovered.

5. Serious infection requiring treatment with intravenous antibiotics at the time of
study entrance, or an infection requiring intravenous therapy within 7 days prior to
the first dose of study treatment.