Ph 1 Study in Subjects With Tumors Requiring Arginine to Assess ADI-PEG 20 With Pemetrexed and Cisplatin
Ph 1 Study in Subjects With Tumors Requiring Arginine to Assess ADI-PEG 20 With Pemetrexed and Cisplatin
A study of ADI-PEG 20 (pegylated arginine deiminase), an arginine degrading enzyme in
 patients with histologically proven advanced malignant pleural mesothelioma (MPM), advanced
 peritoneal mesothelioma (in dose escalation cohort only), non-squamous non-small cell lung
 carcinoma stage IIIB/IV (NSCLC), metastatic uveal melanoma, hepatocellular carcinoma (HCC),
 glioma and sarcomatoid cancers
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.