Clinical trial NCT02709512
Conditions: Mesothelioma
Keywords: Malignant Pleural Mesothelioma
Sponsor: Polaris Group
Start date: 2017-08-01; Completion date: 2022-08-15
Enrollment: 249 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of ADI-PEG 20 (pegylated arginine deiminase), an arginine degrading enzyme versus placebo in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma have been found to require arginine, an amino acid. Thus the hypothesis is that by restricting arginine with ADI-PEG 20, the malignant pleural mesothelioma cells will starve and die.

Detailed description:

Arms: arm 1: Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) Duration : Course of Study

In Combination With:

Pemetrexed Dose: 500 mg/m2 every 3 weeks Route of Administration: Intravenous Cisplatin Dose: 75 mg/m2 every 3 weeks Route of Administration: Intravenous Carboplatin Dose: AUC 5 mg/mL/min every 3 weeks Route of Administration: Intravenous

ADI-PEG 20 plus Pem Platinum: Investigational Drug in combination approved standard of care treatment for this indication arm 2: Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) Duration : Course of Study

In Combination With:

Pemetrexed Dose: 500 mg/m2 every 3 weeks Route of Administration: Intravenous Cisplatin Dose: 75 mg/m2 every 3 weeks Carboplatin Dose: AUC 5 mg/mL/min every 3 weeks Route of Administration: Intravenous

Placebo plus Pem Platinum: Placebo in combination approved standard of care treatment for this indication
Interventions: intervention 1: ADI-PEG 20 plus Pem Platinum intervention 2: Placebo plus Pem Platinum
Intervention descriptions: intervention 1: Investigational Drug in combination approved standard of care treatment for this indication intervention 2: Placebo in combination approved standard of care treatment for this indication

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
ADI-PEG 20 
POLARIS2015-003 RANDOMIZED, DOUBLE-BLIND, PHASE 2/3 STUDY IN 
SUBJECTS WITH MALIGNANT PLEURAL MESOTHELIOMA TO ASSESS ADI-PEG 
20 WITH PEMETREXED AND CISPLATIN (ATOMIC-MESO PHASE 2/3 STUDY) 
(NCT02709512) 
 
This supplement contains the following items: 
 
1. Protocol version 6 (21Sept2021). 
2.  Statistical analysis plan version 4 (04Jan2022). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document and the information contained herein or attached hereto ("Confidential Material") is confidential and proprietary to Polaris Group 
(Polaris). The Confidential Material should only be viewed by those individuals or companies that have been given prior authorization to do so by 
Polaris ("Authorized Users"). The Confidential Material should not be made available in any form to any person or company, other than the 
Authorized User and their respective employees or associates on a need-to-know basis, without the prior written consent from Polaris. This trial 
was conducted in accordance with the ethical principles of Good Clinical Practice, according to the ICH Harmonized Tripartite Guideline. 


Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 1 of 87 
 
 
 
Polaris Group 
 
 
 
Randomized, Double-Blind, Phase 2/3 Study in Subjects with Malignant Pleural 
Mesothelioma to Assess ADI-PEG 20 with Pemetrexed and Cisplatin (ATOMIC-Meso 
Phase 2/3 Study) 
 
 
 
Protocol Number:  
POLARIS2015-003 
 
 
EudraCT Number:  
2015-004281-28 
 
 
Date:    
 
21 September 2021 
 
 
Version:  
 
01 (Original): 10 December 2015  
                                    Version 2: 26 February 2016 
 
 
 
Version 3: 25 August 2016 
 
 
 
Version 4:  05 December 2016 
 
 
 
Version 5:  12 November 2019 
 
 
 
Version 6:  21 September 2021 
 
 
Sponsor:  
 
Polaris Group 
 
  
 
10675 Sorrento Valley Road, Suite 200 
San Diego, CA  92121 USA 
Phone: (858) 452-6688 
 
 
 
 
Confidentiality Statement 
 
This document and the information contained herein or attached hereto ("Confidential Material") is 
confidential and proprietary to Polaris Group (Polaris). The Confidential Material should only be viewed by 
those individuals or companies that have been given prior authorization to do so by Polaris ("Authorized 
Users"). The Confidential Material should not be made available in any form to any person or company, 
other than the Authorized User and their respective employees or associates on a need-to-know basis, 
without the prior written consent from Polaris.


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 2 of 87 
 
 
1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS .........................................................................................2 
 
Study Administrative Structure ....................................................................6 
 
Signature Page .............................................................................................7 
 
Synopsis .......................................................................................................8 
 
Schedule of Assessments and Procedures ..................................................12 
1.4.1 
Screening and Schedule of Assessments and Procedures ..........................12 
1.4.2 
Study Assessments and Procedures ...........................................................15 
1.4.3 
Follow-up Period .......................................................................................17 
 
List of Abbreviations .................................................................................18 
2 
INTRODUCTION AND BACKGROUND ..........................................................21 
 
Introduction ................................................................................................21 
2.1.1 
Mesothelioma .............................................................................................21 
2.1.2 
Amino Acid Deprivation Therapy .............................................................25 
2.1.3 
Arginine Auxotrophy in Cancer Cells .......................................................25 
2.1.4 
Development of ADI-PEG 20 ....................................................................26 
2.1.5 
Current ADI-PEG 20 Clinical Trials .........................................................27 
2.1.6 
Cisplatin .....................................................................................................27 
2.1.7 
Pemetrexed .................................................................................................27 
2.1.8 
Phase 2 Study of ADI-PEG 20 Monotherapy in ASS1-deficient 
MPM in the United Kingdom (ADAM Study) ..........................................28 
2.1.9 
Phase 1 Study of ADI-PEG 20 Plus Pemetrexed and Cisplatin in 
MPM and Non-squamous Non-Small Cell Lung Cancer (NSCLC) 
(TRAP Study) ............................................................................................29 
2.1.10 
Rationale for Combining ADI-PEG 20 with Pemetrexed and 
Cisplatin .....................................................................................................30 
 
Description of Investigational Product ......................................................31 
 
Summary of Findings to Date ....................................................................32 
2.3.1 
Clinical Experience with Hepatocellular Carcinoma .................................32 
2.3.2 
Clinical Experience with Metastatic Melanoma ........................................32 
2.3.3 
Clinical Experience in MPM .....................................................................32 
2.3.4 
Adverse Events ..........................................................................................32 
 
Study Rationale ..........................................................................................32 
3 
STUDY OBJECTIVES ..........................................................................................33 
 
Primary Objectives .....................................................................................33 
 
Secondary Objectives .................................................................................33 
4 
STUDY DESIGN ....................................................................................................34 
 
Design Summary ........................................................................................34 
4.1.1 
Continued Treatment after 6 Weeks of Treatment of ADIPemCis ............34 
4.1.2 
Blinded and Open-Label Extension at Study End .....................................34 
4.1.3 
Anticipated Number of Subjects and Target Accrual ................................35 
 
Criteria for Study Termination ...................................................................35 
5 
STUDY POPULATION .........................................................................................36 
 
Inclusion Criteria .......................................................................................36 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 3 of 87 
 
 
 
Exclusion Criteria ......................................................................................37 
 
Criteria for Subject Withdrawal .................................................................38 
 
Withdrawal Procedures ..............................................................................38 
6 
STUDY PROCEDURES ........................................................................................39 
 
Screening Procedures .................................................................................39 
6.1.1 
ASS1 Expression Screening ......................................................................39 
6.1.2 
Study Screening .........................................................................................39 
 
Clinic Visits ...............................................................................................40 
6.2.1 
End of Treatment .......................................................................................40 
6.2.2 
Follow-up Period .......................................................................................40 
7 
STUDY DRUGS .....................................................................................................41 
 
Identity of Investigational Product and Standard, Background 
Chemotherapies ..........................................................................................41 
7.1.1 
Drug Name(s) .............................................................................................41 
7.1.2 
Storage Conditions .....................................................................................41 
 
Blinding of Investigational Product ...........................................................41 
 
Study Treatment .........................................................................................42 
7.3.1 
Dose and Administration ...........................................................................42 
7.3.2 
Rationale and Dose Selection ....................................................................42 
7.3.3 
Dose Adjustments ......................................................................................43 
7.3.4 
Switching from Cisplatin to Carboplatin ...................................................45 
7.3.5 
Missed Doses .............................................................................................45 
7.3.6 
Subject Replacement ..................................................................................45 
7.3.7 
Optional Single Agent Treatment ..............................................................46 
7.3.8 
Data Safety and Monitoring Board (DSMB) .............................................46 
7.3.9 
Duration of the Study .................................................................................46 
7.3.10 
Estimated Study Drug Requirements .........................................................46 
7.3.11 
Study Drug Dispensing ..............................................................................47 
7.3.12 
Packaging and Labeling .............................................................................47 
7.3.13 
Study Drug Handling .................................................................................47 
7.3.14 
Study Drug Storage ....................................................................................48 
7.3.15 
Study Drug Accountability and Return......................................................48 
7.3.16 
Cross-Over .................................................................................................48 
7.3.17 
Compliance ................................................................................................48 
 
Prior and Concomitant Therapy .................................................................49 
7.4.1 
Non-Permitted Concomitant Therapies .....................................................49 
7.4.2 
Permitted Concomitant Therapies ..............................................................49 
8 
EFFICACY ASSESSMENTS ................................................................................50 
 
Efficacy Parameters ...................................................................................50 
8.1.1 
Timing and Methods of Efficacy Assessments ..........................................50 
 
Appropriateness of Efficacy Assessments .................................................51 
9 
SAFETY ASSESSMENTS ....................................................................................51 
 
Vital Signs ..................................................................................................51 
 
Laboratory Tests ........................................................................................51 
 
ECG............................................................................................................53 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 4 of 87 
 
 
 
Physical Examination.................................................................................53 
 
Adverse Events ..........................................................................................53 
9.5.1 
Assessment of Adverse Events – Relationship to Study Drug ..................53 
9.5.2 
Recording of Adverse Events ....................................................................54 
9.5.3 
Following Adverse Events .........................................................................55 
9.5.4 
Discontinuation due to Adverse Events .....................................................55 
9.5.5 
Pregnancy ...................................................................................................55 
9.5.6 
Post-treatment Adverse Events ..................................................................56 
9.5.7 
Serious Adverse Events .............................................................................56 
9.5.8 
Reporting Serious Adverse Events ............................................................57 
 
Appropriateness of Safety Assessments ....................................................58 
10 PHARMACODYNAMIC, PHARMACOKINETIC,IMMUNOGENICITY AND 
OTHER ASSESSMENTS ......................................................................................58 
 
Pharmacodynamic Parameters ...................................................................58 
 
Immunogenicity Parameters ......................................................................58 
 
Pharmacokinetics .......................................................................................58 
 
Exploratory Research .................................................................................58 
11 STATISTICAL CONSIDERATIONS ..................................................................59 
 
Statistics and Sample Size Considerations ................................................59 
 
Analysis Populations ..................................................................................59 
 
Demographics and Baseline Characteristics ..............................................60 
 
Safety Analysis ..........................................................................................60 
11.4.1 
Adverse Events ..........................................................................................60 
 
Efficacy Analysis .......................................................................................61 
11.5.1 
Primary Efficacy Endpoints .......................................................................61 
11.5.2 
Key Secondary Efficacy Endpoints ...........................................................61 
 
Multiplicity Adjustment .............................................................................61 
 
Interim Analysis .........................................................................................61 
 
Pharmacodynamics ....................................................................................62 
 
Immunogenicity .........................................................................................62 
 
Pharmacokinetics .......................................................................................62 
12 ETHICS 62 
 
Institutional Review Board / Independent Ethics Committee ....................62 
 
Ethical Conduct of the Study .....................................................................63 
 
Informed Consent.......................................................................................63 
 
Changes to Protocol ...................................................................................63 
13 STUDY MONITORING ........................................................................................63 
 
Data Reporting and Electronic Case Report Forms ...................................63 
13.1.1 
Pre-Study Requirements ............................................................................64 
13.1.2 
Study Master Files .....................................................................................64 
13.1.3 
Study Records ............................................................................................64 
13.1.4 
Electronic Case Report Forms (eCRFs) .....................................................64 
 
Access to Source Data/Documents ............................................................65 
 
Confidentiality ...........................................................................................65 
 
Retention of Data .......................................................................................65 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
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Quality Control and Quality Assurance .....................................................65 
14 ADMINISTRATIVE INFORMATION ...............................................................65 
 
Financing and Insurance ............................................................................65 
 
Publication Policy ......................................................................................66 
 
Protocol Amendments ................................................................................66 
 
Premature Trial Termination ......................................................................66 
 
Language ....................................................................................................66 
15 REFERENCES .......................................................................................................67 
16 APPENDIX A: MODIFIED RECIST CRITERIA FOR MALIGNANT 
PLEURAL MESOTHELIOMA ............................................................................77 
17 APPENDIX B: RECIST 1.1 CRITERIA .............................................................78 
18 APPENDIX C: PERFORMANCE STATUS PERFORMANCE SCALES 
(KARNOFSKY, ECOG-WHO-ZUBROD) ..........................................................87 
 
 
 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 6 of 87 
 
 
 
Study Administrative Structure 
 
Randomized, Double-Blind Phase 2/3 Study in Subjects with Malignant Pleural Mesothelioma to 
Assess ADI-PEG 20 with Pemetrexed and Cisplatin (ATOMIC-Meso Phase 2/3 Study) 
 
Sponsor: 
Polaris Group 
Sponsor’s Responsible Medical Officer: 
John S. Bomalaski, MD 
Sponsor’s Contact: 
John S. Bomalaski, MD 
Lead Investigator and Lead Clinical Study 
Center: 
Peter Szlosarek, MD PhD 
Centre for Experimental Cancer Medicine 
(CECM) 
Barts Cancer Institute (BCI) 
Queen Mary University of London 
Lower Ground Floor 
Old Anatomy Building 
Charterhouse Square 
London, EC1M 6BQ, UK 
Tel: 020 7882  3559 
Fax: 020 7882 8490 
Email: p.w.szlosarek@qmul.ac.uk 
Study Monitoring: 
Polaris Group and its representatives 
Clinical Laboratory: 
Central Laboratory 
Pharmacodynamic and Pharmacokinetic 
Analytical Laboratory: 
Central Laboratory 
Immunogenicity Analytical Laboratory: 
Central Laboratory 
Diagnostic Imaging Review:  
Blinded Independent Central Review  


Polaris Group 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 7 of 87 
 
Signature Page 
Polaris Group Approval: 
 
John S. Bomalaski, MD 
Date 
Executive Vice-President, Medical Affairs 
21 September 2021


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 8 of 87 
 
 
 
Synopsis 
 
Protocol Title: 
Randomized, Double-Blind Phase 2/3 Study in Subjects with Malignant 
Pleural Mesothelioma to Assess ADI-PEG 20 with Pemetrexed and 
Cisplatin (ATOMIC-Meso Phase 2/3 Study) 
Sponsor: 
Polaris Group 
Study Phase: 
Phase 2/3 
Indication: 
Unresectable malignant pleural mesothelioma (MPM) 
Rationale:  
In a previous randomized phase 2 study of ADI-PEG 20 monotherapy in 
MPM tumors with low argininosuccinate synthetase (ASS1) expression 
(ASS1-deficient) (ADAM Study), ADI-PEG 20 treatment resulted in 
significantly prolonged progression free survival (PFS) compared to best 
supportive care. In an ongoing phase 1 study of ADI-PEG 20 with 
pemetrexed and cisplatin (ADIPemCis) in MPM or non-squamous 
non-small cell lung carcinoma (NSCLC) subjects with ASS1-deficient 
tumors (TRAP study), this combination has resulted in a significant 
number of objective responses. Interestingly, most of the subjects have a 
non-epithelioid histology, and known poorest prognosis of the MPM 
histologies. Apparent prolonged PFS and OS have also been observed in 
these MPM treated subjects. This phase 2/3 study will treat only MPM 
using the same three drug regimen. In addition, it will enroll only 
biphasic and sarcomatoid histologies.  
Objectives: 
The primary objective of this study is: 
• Determine efficacy as determined by the objective response rate 
(RR), measured by modified RECIST for local pleural disease and 
RECIST 1.1 criteria for metastatic lesions (phase 2 portion), and OS 
(phase 3 portion) 
The key secondary objective of the phase 2 portion is: 
• Determine the duration of response (DOR) 
The key secondary objective of the phase 3 portion is: 
• Assess progression free survival (PFS) 
Other secondary objectives of this study include: 
• Assessment of safety and tolerability of ADI-PEG 20 in combination 
with pemetrexed and cisplatin   
• Determine the pharmacodynamics of ADI-PEG 20 in combination 
with pemetrexed and cisplatin  
• Determine the immunogenicity of ADI-PEG 20 in combination with 
pemetrexed and cisplatin  
• Determine the pharmacokinetics of ADI-PEG 20 in combination 
with pemetrexed and cisplatin 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 9 of 87 
 
 
The goal of the phase 2 portion of the trial is to provide data to support 
accelerated approval by the United States Food & Drug Administration, 
and the goal of the phase 3 portion of the trial is to provide a 
confirmatory study that would be ongoing at the time of the marketing 
application. 
Number of Sites: 
Global – to be determined 
Study Design: 
This is a phase 2/3, randomized, double-blind trial. Weekly 
ADI-PEG 20 at 36 mg/m2 (or placebo) will be combined with 
pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 both given every 3 
weeks as first-line chemotherapy to non-epithelioid (biphasic and 
sarcomatoid) MPM.  Eligible subjects will be randomized in a 1:1 ratio 
to ADIPemCis or PlaceboPemCis.  The randomization will be stratified 
by histology (biphasic or sarcomatoid).  Subjects may receive a 
maximum of 6, 3-week cycles of ADIPemCis or PlaceboPemCis for a 
total of 18 weeks of treatment. Those subjects completing ADIPemCis 
or PlaceboPemCis treatment may continue on ADI-PEG 20 or Placebo 
monotherapy if they have SD or better. Subjects who do not or who 
would not tolerate cisplatin may be switched to carboplatin. 
Planned Sample 
Size: 
Approximately 176 subjects (88 per arm) will be enrolled in the phase 2 
portion of the trial (phase 2 primary outcome measure = RR) and 386 
subjects (193 per arm) in the whole phase 2/3 trial (phase 3 primary 
outcome measure = OS).  
Sample size justification: The sample size calculation for the first 
efficacy endpoint (RR) assumed that the objective response rate in the 
PlaceboPemCis arm was 15%.  A total sample size of 176 subjects (88 
per arm) in the phase 2 portion of the study will provide approximately 
87% power to detect an improvement in the RR from 15% to 35% at the 
interim analysis. 
The sample size calculation for the OS assumed that the median OS was 
6 months in the PlaceboPemCis arm. Assuming a median OS of 8.4 
months in the ADIPemCis arm (corresponding to a 40% improvement in 
survival and a hazard ratio [HR] of 0.714), 338 OS events will provide 
power of approximately 87% for the OS analysis.  Assuming uniform 
accrual over a 24-month period and a total study duration of 36 months, 
the planned total sample size in the study was 386 subjects.  
Subject Selection 
Criteria: 
 
 
 
 
 
 
 
Selection Inclusion Criteria Summary: 
• Histologically proven unresectable MPM of biphasic or sarcomatoid 
histology 
• Naïve to chemotherapy or immunotherapy 
• ECOG PS 0-1 
• Expected survival of at least 3 months 
• Age 18 years or over (there is no upper age limit) 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 10 of 87 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Measurable disease by modified RECIST criteria for MPM for local 
pleural disease and RECIST 1.1 criteria for metastatic lesions  
• Written (signed and dated) informed consent and must be capable of 
co-operating with treatment and follow up 
• Adequate hematologic, hepatic, and renal function 
Selection Exclusion Criteria Summary: 
• Radiotherapy (except for palliative reasons) in the previous two 
weeks before study treatment 
• History of unstable cardiac disease  
• Ongoing toxic manifestations of previous treatments   
• Symptomatic brain or spinal cord metastases (patients must be stable 
for > 1 month post radiotherapy or surgery) 
• 
Major thoracic or abdominal surgery from which the patient has not 
yet recovered. 
Study Drug: 
ADI-PEG 20 
Dose and Route of 
Administration: 
ADI-PEG 20 (or Placebo) 
Dose:  36 mg/m2 (or Placebo) given weekly 
Route of Administration: Intramuscular (IM) 
Pemetrexed 
Dose: 500 mg/m2 every 3 weeks 
Route of Administration: Intravenous  
Cisplatin 
Dose: 75 mg/m2 every 3 weeks 
Route of Administration: Intravenous 
Carboplatin 
Dose: area under the plasma concentration–time curve (AUC) 5 
mg/ml/m2 every 3 weeks 
Route of Administration: Intravenous 
Safety Monitoring: 
Response Criteria: 
Performed by the sponsor and its representatives 
Safety: Adverse events (AEs), laboratory tests, ECGs and physical 
examinations 
Efficacy: RR, DOR, PFS, and OS; RR and DOR will be based on the 
tumor response assessments by blinded independent central review 
(BICR) for phase 2 and PFS will be derived based on the tumor 
response assessments by the investigator for phase 3. BICR results will 
be used for decisions on continued treatment in the phase 2 portion.   
Statistical Analysis: 
Analysis Populations: All efficacy analyses will be completed in the 
intent-to-treat (ITT) population and additional analyses will be 
performed in the per-protocol (PP) population.  The safety population 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 11 of 87 
 
 
(all treated subjects) will be used for all safety summaries and analyses.  
Efficacy Analyses: The analysis of RR will be performed at the first 
interim analysis at the end of the phase 2 portion.  The treatment groups 
will be compared using the Cochran-Mantel-Haenszel (CMH) test, 
stratified by tumor histology (biphasic versus sarcomatoid). The 
significance level and coverage probability to be used in the RR analysis 
will be based on α=0.05 (two-sided). The RR will only be tested once at 
the end of the phase 2 regardless of its significance.    
The primary analysis of OS will be performed at the final analysis.  The 
treatment effect on OS will be evaluated using the stratified log-rank test 
(stratified by tumor histology). The significance level to be used in the 
OS analysis at the final analysis will be based on α=0.05 (two-sided). 
There will be an interim analysis of OS once 50% of the planned OS 
events for phase 3 have occurred and will be used to determine whether 
to terminate the study for futility or for possible sample size re-
estimation for the phase 3 portion of the trial as described in the 
Statistical Analyses Plan (SAP). 
Safety Analyses: Safety will be assessed by comparing adverse events, 
vital signs, laboratory results, and physical examination results. 
Pharmacodynamics: Pharmacodynamics (peripheral blood arginine 
and citrulline levels) will be summarized for all subjects by time point 
for the observed value and by duration of arginine depletion and 
citrulline increase.  
Immunogenicity: Immunogenicity (antibodies to ADI-PEG 20) will be 
summarized for all subjects from the ADIPemCis arm by time point for 
the observed value as well as for the change from baseline value. 
Pharmacokinetics: Pharmacokinetics (peripheral blood ADI-PEG 20 
levels) will be summarized for all subjects from the ADIPemCis arm.  
 
 
 
 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 12 of 87 
 
 
 
Schedule of Assessments and Procedures 
 
1.4.1 Screening and Schedule of Assessments and Procedures   
 
Table 1.4.1 Study Assessments and Procedures: Pre-study (Screening) and Cycles 1 to 4o 
 
Screening Assessments 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
 
 
 
Day of Cycle (Week of Treatment) 
Study Procedure 
Within 4 
weeks 
(Day -28 to 0) 
Within 1 
week (Day  
-7 to 0) 
1 
(1) 
8 
(2) 
15 
(3) 
1 
(4) 
8 
(5) 
15 
(6) 
1 
 (7) 
8 
(8) 
15 
 (9) 
1 
(10) 
8 
(11) 
15 
(12) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Inclusion 
and Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
X (update) 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
X 
Xm 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital Signsc 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/ Body Surface 
Area (BSA) 
 
X 
Xm 
 
 
X 
 
 
X 
 
 
X 
 
 
Performance Status 
(ECOG) 
 
X 
Xm 
 
 
 
 
 
 
 
 
 
 
 
AE Assessmentd 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Concomitant 
Medications 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Radiological Tumor 
Disease Assessment 
(CT, MRI)e 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum Pregnancy Testf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
Xn 
 
 
 
 
 
 
 
Xn 
Clinical Laboratory 
Testsg 
 
   Hematology 
 
X 
Xm 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 


Polaris Group 
 
Protocol Number: POLARIS2015-003, Phase 2/3 MPM ADI-PEG 20 + Pemetrexed + Cisplatin  
 
Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
Page 13 of 87 
 
 
 
Screening Assessments 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Study Procedure 
Within 4 
weeks (Day 
-28 to 0) 
Within 1 
week 
(Day -7 to 0) 
1 
(1) 
8 
(2) 
15 
(3) 
1 
(4) 
8 
(5) 
15 
(6) 
1 
(7) 
8 
(8) 
15 
(9) 
1 
(10) 
8 
(11) 
15 
(12) 
   Chemistry 
 
X 
Xm 
 
 
X 
 
 
X 
 
 
X 
 
X 
   Creatinine Clearanceh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Special Blood 
Samplingi 
 
   Arginine + Citrulline 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
   Anti-ADI-PEG 20 Abs  
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
   ADI-PEG 20 Levels 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
ADI-PEG 20 or Placebo 
Administrationj 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pemetrexed 
Administrationk 
 
 
Xl 
 
 
X 
 
 
X 
 
 
X 
 
 
Cisplatin 
Administrationk, p 
 
 
Xl 
 
 
X 
 
 
X 
 
 
X 
 
 
Note: Visits may occur ± 3 days of the planned date except for PemCis administration on cycle 1 
Day 3. All study evaluations and related procedures may occur 3 days prior to dosing except for 
CT or MRI which may occur ± 7 days of the planned date.  See Appendices for more on modified 
RECIST response criteria for MPM local pleural disease (Appendix A), RECIST 1.1 response 
criteria for metastatic lesions (Appendix B) and performance status (Appendix C). 
a. The informed consent window is extended to -42 days without requiring a reconsent. 
b. Physical examination is to be performed on Day 1 of each cycle and is symptom directed as 
clinically indicated.  
c. Vital signs to be obtained before and 1 hour ± 15 minutes after ADI-PEG 20 or placebo 
treatment. 
d. Subjects will be assessed for AEs on Day 1 of each cycle and weekly thereafter or as clinically 
indicated. 
Adverse events, including serious adverse events and toxicities –These will be recorded after 
the first administration of study treatment until 30 days after last study drug administration.  
Adverse events related to ADI-PEG 20 that were still ongoing at End-of-Treatment (EOT) 
visit should be followed up until resolution or stabilization.  Any medical sign or symptom a 
subject may experience post signing of ICF and before first administration of study treatment 
should be recorded as part of medical history.  If any toxicity or medical sign or symptom a 
subject may experience post signing of ICF meets the definition of Serious Adverse Event 
(SAE) per Section 9.5.7 they must be reported as an SAE per Section 9.5.8.  
e. Baseline CT with contrast or MRI of the involved organs is to be conducted within 28 days 
prior to subject receiving the first ADI-PEG 20 or placebo dose (this may be conducted prior 
to signing informed consent if part of standard of care).  Scans are to be performed every 6 
weeks (preferably in the week after 2 cycles of ADIPemCis or PlaceboPemCis dosing) and 
after every 8th weekly dose of ADI-PEG 20 or placebo during ADI-PEG 20 or placebo only 
treatment.  Tumor measurements must be noted.  CT with contrast must be used unless the 
subject is allergic to intravenous contrast despite use of diphenhydramine and corticosteroids, 


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in this case CT without contrast (if borders are distinct) is the second choice and MRI a third 
choice if borders are not well-defined on CT. The same imaging modality is to be used 
throughout the study. Details are provided in the Imaging Manual. For subjects with tumor 
responses (complete response and partial response), scans will continue according to the 
regular schedule.  Imaging should follow calendar days; do not adjust for changes in dosing 
schedule.  Subjects withdrawn from treatment for reasons other than PD may continue to 
receive regular scans until PD. 
f. Female subjects only, serum HCG. 
g. Blood samples to be collected before ADI-PEG 20 or placebo administration.  Hematology 
and Chemistry sampling from Cycle X/Day 1 should follow the chemotherapy administration 
day in case of a chemotherapy dosing delay.  Local blood samples may be collected as part of 
standard of care on chemotherapy days and the results used for dosing decisions without 
waiting on central results provided central samples are also collected at the same time and sent 
in for testing.  Clinically significant local laboratory findings that directly inform a dosing 
decision will be recorded as an adverse event.  See Section 9.2 for specific studies.   
h. Creatinine clearance ≥ 45 mL/min (estimated, using Cockcroft and Gault formula). 
i. 
Blood samples to be collected before ADI-PEG 20 or placebo administration for arginine and 
citrulline (pharmacodynamics), antibody to ADI-PEG 20 (immunogenicity), and ADI-PEG 20 
levels (pharmacokinetics). Special blood sampling should follow calendar days; do not adjust 
for changes in dosing schedule.  See Section 10 for specific studies.   
j. 
ADI-PEG 20 or placebo is to be administered before pemetrexed and cisplatin on days when 
all three drugs are given, except during cycle 1 where the chemotherapy is administered on 
Day 3.  Pemetrexed and cisplatin administration is to begin at least 60 minutes after ADI-PEG 
20 or placebo administration on the same day.  
k. Supportive and pre-medications to include the following or as per local policy (see Section 
7.4.2.2 for further details): 
• Folic acid 400 mcg daily, oral 
• Hydroxycobalamin 1000 mcg i.m. injection  
• Dexamethasone 4 mg bd (3 doses) preceding hospital visit by 24 hours. Dexamethasone 
may also be administered i.v. and at a dose per local policy.  
• Anti-emetic e.g. 5HT3 antagonist, domperidone and dexamethasone 8 mg 
• Furosemide 40 mg oral once 
l. 
PemCis to be administered on Day 3 of cycle 1 
m. These assessments at week 1 may be omitted if performed within 72 hours of the first dose. 
n. ECG to be performed 1 hour ± 15 minutes after ADI-PEG 20 or placebo treatment.  This 
assessment should include the QT/QTc interval using Fridericia’s correction: QTc = 
QT/RR0.33 
o. During the chemotherapy treatment period (Cycles 1-6), a cycle is 3 weeks.  During the Single 
Agent period, beginning on Week 19, a cycle is defined as every 4 weeks. 
p. Cisplatin is the recommended chemotherapy for use in the initial and subsequent cycles. 
However, subjects who do not tolerate cisplatin or who would not be expected to tolerate 
cisplatin may have carboplatin substituted for cisplatin at any cycle including the initial cycle 
at the discretion of the investigator. 
 
 


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1.4.2 Study Assessments and Procedures 
 
Table 1.4.2 Study Assessments and Procedures: Weeks 13 to 18, ADI-PEG 20 or Placebo Single Agent 
Treatment, End of Treatment, and Follow up 
 
Cycle 5j 
Cycle 6j 
Cycles 7 and Beyond 
 
Study Procedure 
1 
(13) 
8 
(14) 
15 
(15) 
1 
(16) 
8 
(17) 
15 
(18) 
Single Agent ADI-PEG 20/Placebok  
EOTa 
19 
20 
21 
22 
23 
24 
25 
26j 
 
Physical Examinationb 
X 
 
 
X 
 
 
As clinically indicated 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/ Body Surface Area 
(BSA) 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
AE Assessmentd 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Concomitant Medications 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Radiological Tumor Disease 
Assessment (CT, MRI)e 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
ECG 
 
 
 
As clinically indicated 
 
Clinical Laboratory Testsf 
 
   Hematology 
X 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
   Chemistry 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Special Blood Samplingg 
 
   Arginine + Citrulline 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
   Anti-ADI-PEG 20 Abs  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
   ADI-PEG 20 Levels 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ADI-PEG 20 or Placebo  
Administrationh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pemetrexed Administrationi 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cisplatin Administrationi,l 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Note: Visits may occur ± 3 days of the planned date. All study evaluations and related procedures may occur 
3 days prior to dosing except for CT or MRI which may occur + 7 days of the planned date, but preferably after 
every two (2) cycles of ADIPemCis or PlaceboPemCis and after every 8th weekly dose of ADI-PEG 20 or 
placebo during ADI-PEG 20 or placebo only treatment.   
See Appendices for more on modified RECIST response criteria for local pleural disease (Appendix A), 
RECIST 1.1 response criteria for metastatic lesions (Appendix B) and performance status (Appendix C). 
a. EOT visit to occur 7-30 days (preferably 30 days) after last dose of treatment. 
b. Physical examination is to be performed on Day 1 of each cycle and is symptom directed as clinically 
indicated. 
c. Vital signs to be obtained before and 1 hour ± 15 minutes after ADI-PEG 20 or placebo treatment. 
d. Subjects will be assessed for AEs on Day 1 of each cycle and weekly thereafter or as clinically indicated. 
Adverse events, including serious adverse events and toxicities – Baseline toxicities/symptoms will be 
recorded starting with the signing of the informed consent form (ICF).  These will be recorded until 30 days 
after last study drug administration.  Adverse events related to ADI-PEG 20 or placebo that were still 
ongoing at EOT visit should be followed up until resolution or stabilization.  Any medical sign or symptom 
a subject may experience post signing of ICF and before first administration of study treatment should be 
recorded as part of medical history.  If any toxicity or medical sign or symptom a subject may experience 
post signing of ICF meets the definition of SAE per Section 9.5.7 they must be reported as an SAE per 
Section 9.5.8.  


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e. Scans are to be performed every 6 weeks (preferably in the week after 2 cycles of ADIPemCis or 
PlaceboPemCis dosing) and after every 8th weekly dose of ADI-PEG 20 or placebo during ADI-PEG 20 or 
placebo only treatment.  Tumor measurements must be noted.  The same imaging modality is to be used 
throughout the study. For subjects with tumor responses (complete response and partial response), scans 
will continue according to the regular schedule.   Imaging should follow calendar days; do not adjust for 
changes in dosing schedule.  Subjects withdrawn from treatment for reasons other than PD may continue to 
receive regular scans until PD. 
f. Blood samples to be collected before ADI-PEG 20 or placebo administration. Hematology and Chemistry 
sampling from Cycle X/Day 1 should follow the chemotherapy administration day in case of a 
chemotherapy dosing delay.  Local blood samples may be collected as part of standard of care on 
chemotherapy days and results used for dosing decisions without waiting on central results provided central 
samples are also collected at the same time and sent in for testing.  Clinically significant local laboratory 
findings that directly inform a dosing decision will be recorded as an adverse event.   See Section 9.2 for 
specific studies. 
g. Blood samples to be collected before ADI-PEG 20 or placebo administration for arginine and citrulline 
(pharmacodynamics), antibody to ADI-PEG 20 (immunogenicity), and ADI-PEG 20 levels 
(pharmacokinetics). Special blood sampling should follow calendar days; do not adjust for changes in 
dosing schedule.  See Section 10 for specific studies.  Special blood sampling is not required during ADI-
PEG 20 or placebo only treatment after 25 weeks. 
h. ADI-PEG 20 or placebo is to be administered before pemetrexed and cisplatin on days when all three drugs 
are given.  Pemetrexed and cisplatin administration is to begin at least 60 minutes after ADI-PEG 20 or 
placebo administration on the same day.  
i. Supportive and pre-medications to include the following or as per local policy (see Section 7.4.2.2 for 
further details): 
• Folic acid 400 mcg daily, oral 
• Hydroxycobalamin 1000 mcg i.m. injection  
• Dexamethasone 4 mg bd (3 doses) preceding hospital visit by 24 hours. Dexamethasone may also be 
administered i.v. and at a dose per local policy. 
• Anti-emetic e.g. 5HT3 antagonist, domperidone and dexamethasone 8 mg  
• Furosemide 40 mg oral once 
j. Subjects who remain on treatment after 26 weeks and up to 2 years of study treatment will continue to 
follow the schedule in Table 1.4.2.  For example, week 27 will follow visit assessments for week 19; week 
28 will follow week 20 and so on.  Therefore, CT scans will be obtained every 8 weeks for those still on 
treatment. 
k. During the chemotherapy treatment period (Cycles 1-6), a cycle is 3 weeks.  During the Single Agent 
period, beginning on Week 19, a cycle is defined as every 4 weeks. 
l. Cisplatin is the recommended chemotherapy for use in the initial and subsequent cycles. However, subjects 
who do not tolerate cisplatin or who would not be expected to tolerate cisplatin may have carboplatin 
substituted for cisplatin at any cycle including the initial cycle at the discretion of the investigator. 
 
 
 


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1.4.3 Follow-up Period 
 
Table 1.4.3  Study Assessments and Procedures: Follow-up* begins 30 days ± 7 days 
After End of Treatment Visit  
Study Procedure 
Every 3 Months (± 1 week) until end of study 
Survival status 
X 
*Via telephone, email or clinic visit 
 
 


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List of Abbreviations 
 
Abbreviation 
Definition 
ADI 
Arginine deiminase 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALL 
Acute lymphocytic leukemia 
ALT 
Alanine transaminase (also known as SGPT) 
ALP 
Alkaline phosphatase 
ANC 
Absolute neutrophil count 
ASL 
Argininosuccinate lyase 
ASS1 
Argininosuccinate synthetase (also known as ASS) 
AST 
Aspartate transaminase (also known as SGOT) 
BSA 
Body surface area 
BSC 
Best supportive care 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CPO 
Conditional Power for OS 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTC 
Common toxicity criteria 
CTCAE 
Common terminology criteria for adverse events 
DCR 
Disease Control Rate 
DesigneRx 
DesigneRx Pharmaceuticals, Inc. 
DHFR 
Dihydrofolate reductase 
DLT 
Dose Limiting Toxicity 
 
 


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Abbreviation 
Definition (Continued) 
DOR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EOT 
End-of-treatment 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HCC 
Hepatocellular carcinoma 
HCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IRB 
Institutional Review Board 
ITT 
Intent- to-treat 
MPM 
Malignant pleural mesothelioma  
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NSCLC 
Non-small cell lung carcinoma 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PE 
Physical examination 
PFS 
Progression free survival 
PR 
Partial response 
PS 
Performance status 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 


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Abbreviation 
Definition (Continued) 
QTcF 
Fridericia’s correction formula 
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
R2PD 
Recommended phase 2 dose 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
TBD 
To be determined 
TTP 
Time to progression 
TYMS 
Thymidylate synthase (also known as TS) 
SOP 
Standard operating procedures 
TEAE 
Treatment-emergent adverse event  
TMF 
Trial Master File 
USA 
United States of America 
WBC 
White blood cell count 
 
 


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2 
INTRODUCTION AND BACKGROUND 
 
 
Introduction 
 
The following background information is being provided in addition to the information provided in 
the Investigator’s Brochure. 
 
2.1.1 Mesothelioma  
 
Mesotheliomas are neoplasms arising from mesothelial cells lining the pleura, peritoneum, tunica 
vaginalis testis and pericardium (Kao 2010, Mirarabshahii 2012).  Approximately 80-85% are 
malignant pleural mesothelioma (MPM), 15-20% are peritoneal, and vaginal and pericardial occur 
rarely (Moolgavkar 2009, Kao 2010, McDonald 2010, Turner 2012).  MPM is an aggressive 
thoracic malignancy associated with exposure to asbestos, and its worldwide incidence is 
anticipated to increase during the first half of this century (Fennell 2008).   
 
2.1.1.1 Mesothelioma: Histologic Subtypes Predict Prognosis 
 
Malignant mesothelioma has three histologic subtypes, epithelioid, sarcomatoid and biphasic. Most 
patients present with advanced disease; the median age at diagnosis is 72 years and the median OS 
is approximately 1 year (Ettinger 2016). The majority of cases are epithelioid, which has the best 
prognosis. Sarcomatoid has the worst while biphasic (mixed epithelioid with sarcomatoid) has 
intermediate prognosis, with predominantly sarcomatoid biphasic having a worse prognosis than 
predominantly epithelioid biphasic (Bueno 2016). This has been confirmed by recently published 
epidemiology studies in the US (Surveillance, Epidemiology, and End Results [SEER] database 
from 2004-2010, Meyerhoff 2015), Australia (cases of malignant mesothelioma between 2002 and 
2009 from the New South Wales Dust Diseases Board, Linton 2014), UK-Scotland (data from 
2002-2012 from the National Health Service Grampian pathology database in the northeast of 
Scotland, Marshall 2015), UK-Wales+England (data from 2008-2012 from the National Lung 
Cancer Audit, Beckett 2015, Canada (data from 1991-2012 from Ottawa Hospital, Saint-Pierre 
2015), and France (data from 1998-2016 from the French MESOBANK, Galateau Salle 2018). The 
statistics from these publications are summarized below and show the OS in months (m):  
 
Reference  
Number Years 
Epithelioid Sarcomatoid Biphasic 
Non-epithelioid 
US SEER  
1183 
2004-2010 69% 
19% 
12% 
 
Australian  
   Median OS 
910 
2002-2009 60% 
   13.3 m 
17% 
   5.4 m 
 13% 
   7.2 m 
 
   6.2 m 
UK-Scotland 
   Median OS 
114 
2002-2012 56% 
   13.5 m 
12% 
   4.1 m 
16% 
   11.0 m 
 
UK-England 
+Wales 
   Median OS 
8740* 
2008-2012 
 
 
75% 
 
   13.1 m 
14% 
 
   4 m 
11% 
 
   8.4 m 
 
Canada 
   Median OS 
245 
1991-2012 
 
63% 
   12.5 m 
14% 
   4.5 m 
11% 
   8.1 m 
 
France 
   Median OS 
5726 
1998-2016 91% 
   14 m 
8% 
   4 m 
1% 
   8 m 
 


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*histology % noted only for specified types (N=3319) 
 
Thus, these recent studies confirm further the poorer prognosis of nonepithelioid MPM ranging 
from 4.0 to 5.4 months for sarcomatoid and from 7.2 to 11.0 months for biphasic and are consistent 
with the 6.2 months for non-epithelioid histology noted in the Australian study (Linton 2014). The 
poor prognosis of sarcomatoid MPM has recently been reviewed (Galetta 2016).  
 
Indeed, poor outcome of patients with non-epithelioid histologies has led to their exclusion from 
recent clinical trials (e.g., the anti-mesothelin [amatuximab] study: A Randomized, Double-blind, 
Placebo-controlled Study of the Safety and Efficacy of Amatuximab in Combination With 
Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma, 
NCT02357147) (Amatuximab 2015). This underscores further the urgent need for development of 
effective therapy for non-epithelioid MPM.  
 
The reason(s) for this poor prognosis for sarcomatoid histology has been attributed to expression of 
B7 homolog 1 (B7-H1; also known as programmed death ligand 1 [PD-L1]) which is expressed 
more frequently in sarcomatoid than epithelioid histologies (Mansfield & Roden 2014). Also, 
sarcomatoid and biphasic more frequently are deficient in expression of ASS1, the rate limiting 
enzyme in the urea cycle to form arginine. ASS1-deficiency is also associated with a poor prognosis 
in MPM and a variety of other cancers (Szlosarek 2006 & 2016, Delage 2008). The reason for this 
is not entirely clear, but appears due to rapidly expanding cancer cells preferentially using aspartate 
from the urea cycle to form nucleic acids and not arginine (Rabinovich 2015). ASS1 deficiency 
typically occurs through epigenetic modification (Phillips 2013).  
 
2.1.1.2 Mesothelioma: Chemotherapy for MPM 
 
The recommended treatment is dependent on both stage and histology. It is recommended that 
patients with operable clinical stage I-III epithelioid or mixed histology disease undergo 
multimodality therapy including surgery (Ettinger 2016). Current National Comprehensive Cancer 
Network (NCCN) guidelines (Mesothelioma NCCN 2015) recommend chemotherapy alone for all 
patients who have sarcomatoid histology, as well as for inoperable or clinical stage IV patients. 
Similar recommendations come from the European Society of Medical Oncology (ESMO) 
(Baas 2015). This underscores further the poor prognosis for sarcomatoid patients. 
 
In MPM, both RR and PFS correlate with OS (Francart 2009, Blayney 2012, Hasan 2014). Thus RR 
and PFS serve as surrogate endpoints for OS in MPM. 
 
Pemetrexed + Cisplatin/Carboplatin 
 
The standard first-line chemotherapy treatment for MPM and advanced peritoneal mesothelioma is 
pemetrexed + cisplatin (Fennell 2008, Mirarabshahii 2012, Turner 2012, Kotova 2015).  This is 
based on a phase 3 study for MPM comparing pemetrexed + cisplatin to cisplatin only 
(Vogelzang 2003) and open access data for peritoneal mesothelioma (Mirarabshahii 2012, 
Turner 2012).  For MPM, median OS in the pemetrexed + cisplatin arm was 12.1 months 
(confidence interval [CI]: 10.0 to 14.4) vs. 9.3 in the control cisplatin arm, thus there was a 
2.8 months survival advantage.  Median time to progression (TTP) was 5.7 months in the study arm 


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vs. 3.9 months in the control arm. Response rates, determined by investigator assessment, were 
41.3% (95% CI: 34.8 to 48.1) in the pemetrexed+cisplatin arm versus 16.7% in the control arm. The 
1-year survival rate was 50.3% for pemetrexed + cisplatin arm. Change in disease was assessed by 
measuring the thickness of up to three involved areas of pleural rind at each of three separate levels 
at least 2 cm apart on computed tomography scan, at baseline, and every other cycle (at least one 
measurement was > 1.5 cm). Although the overall RR (ORR) was 41.3%, it was only 4/18 (22.2%) 
for sarcomatoid (Mansfield & Symanowski 2014), and this result was not noted in the primary 
publication (Vogelzang 2003). Indeed, in that summary review on MPM clinical trials focusing on 
sarcomatoid, the ORR for all subjects in the 30 studies that recorded data on survival and ORR in 
sarcomatoid, the ORR for all MPM was 21.9% in 1475 patients and only 19/137 (13.9%) in those 
with sarcomatoid disease (9.3% of total). As such, these results for sarcomatoid ORR to platinum 
based therapy may be an over estimate.  
 
Further data on pemetrexed + cisplatin comes from expanded access programs that occurred after 
enrollment of the pivotal trial. In an expanded access program in the USA before regulatory 
approval (2002 to 2004), 728 chemotherapy naïve patients with MPM were enrolled and treated 
with pemetrexed + cisplatin (Obasaju 2007). The inclusion criteria were similar to the phase 3 study 
except that measurable lesions were not required, and RR could be assessed using RECIST, 
Southwest Oncology Group or World Health Organization criteria. Response data was available on 
615 patients. Histologic subtype data was not reported. The ORR was 20.8% (95% CI: 17.7-24.3), 
the median survival was 10.9 (95% CI: 9.8-12.3) months, and the one year survival was 45.9%. 
Likewise, an expanded access program was initiated internationally (Santoro 2008). A total of 1704 
chemo naïve patients were enrolled from 2002 to 2006, 843 received pemetrexed + cisplatin and 
861 received pemetrexed + carboplatin (AUC of 5). The inclusion criteria were similar to the phase 
3 study except that measurable lesions were not required, and the three different response criteria 
for assessment were allowed. The histologic breakdown for the pemetrexed + cisplatin group was as 
follows: epithelial 67.0%, sarcomatoid 6.3%, mixed 9.1%, and others 17.6%. Similar histologic 
breakdown occurred for the pemetrexed + carboplatin cohort. The ORR in 745 patients evaluable 
for response in the pemetrexed + cisplatin group was 26.3% (95% CI: 23.2-29.6), and was 21.7% 
(95% CI: 18.1-24.8) in the pemetrexed + carboplatin group. The median TTP was 7.0 months in the 
cisplatin cohort and 6.9 in the carboplatin cohort. The median survival was not estimated due to the 
high censoring rate. The 1-year survival rate was 63.1% in the cisplatin arm and 64% in the 
carboplatin arm. More grade 3/4 toxicity was noted in the carboplatin arm, as were more deaths. 
 
The results of two phase 2 trials of pemetrexed + carboplatin in 178 patients from 11 Italian centers 
treated between 2002 and 2005 also were reported (Ceresoli 2008). Epithelioid represented 77%, 
mixed biphasic 12% and sarcomatoid 5%. The ORR was 23.8% (95% CI: 16.8-32.1). Therefore, 
these ORR results with pemetrexed + carboplatin in a heavily epithelioid population are similar to 
those observed in the international expanded access program with pemetrexed + cisplatin 
(Santoro 2008). 
 
Thus the ORR in the expanded access programs with pemetrexed + cisplatin (Obasaju 2007, 
Santoro 2008) were approximately half of that observed in the phase 3 study of pemetrexed + 
cisplatin (20.8% and 26.3% vs. 41.3%) although measureable lesions were not required in the 
expanded access programs. Median TTP and median OS were only available for one expanded 


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access program, but these were similar to the phase 3 trial. The 1-year survival rates were 45.9 and 
63.1% versus 50.3% in the phase 3 trial. 
 
More recently, a randomized phase 2 study compared pemetrexed + cisplatin to that combination 
plus CBP501 in chemo naïve MPM (Krug 2014). Of the 23 in the pemetrexed + cisplatin arm, the 
histology was 70% epithelioid, 22% sarcomatoid and 9% mixed. For pemetrexed + cisplatin, the 
ORR, by modified RECIST (Byrne 2004), was 4/20 (20%) by investigator assessment and 2/20 
(10%) by independent radiology assessment. For the doublet, the median PFS was 4.6 months by 
investigator and 3.4 by independent assessment, and the median OS was 12.8 (95% CI: 6.5-16.1) 
months by independent assessment.  
 
In Japan, a retrospective analysis compared the results of 17 patients treated with pemetrexed + 
cisplatin to 13 with gemcitabine + cisplatin in MPM (Shukuya 2014). Overall, epithelioid accounted 
for 70%, sarcomatoid for 20% and not otherwise specified for 10%. The RR were 35% vs. 15%, the 
PFS were 215.5 days vs. 142.5 days and median OS was 597.5 days vs. 306.5 days, respectively, 
favoring the pemetrexed group.  Hematologic AEs were more common in the gemcitabine group.  
 
A French consortium (French Group of Onco-Pneumology) reported their data collected from 
medical files between 2005 and 2008 (Raynaud 2015). There were 406 patients from 37 sites, and 
75% of patients received chemotherapy, primarily platinum + pemetrexed (91%). The ORR was 
17.2%. 
 
More recently, a French consortium of 73 hospitals added the anti-vascular endothelial growth 
factor (VEGF) bevacizumab to first-line pemetrexed + cisplatin in a randomized, open-label, phase 
3 trial that enrolled 448 subjects aged 18-75 years (Zalcman 2016). Epithelioid accounted for 81% 
and sarcomatoid or mixed for 19%. ORR was not reported. The primary outcome measure was OS 
with an anticipated improvement of 33% (hazard ratio [HR] 0.75). The trial did not meet its primary 
outcome measure with HR = 0.77; the trial was stopped early by the independent data monitoring 
committee after assessment at 342 of the planned 397 deaths. Median OS for the doublet was 16.1 
(95% CI: 14.1-17.9) months. Furthermore, the predictive analysis based on VEGF assessed as a 
continuous variable showed that the VEGF interaction between treatment group and VEGF 
concentration was not significant with bevacizumab treatment and OS or PFS. In addition, there 
were more serious cardiovascular adverse events as well as study discontinuation associated with 
the triplet therapy. Survival related to specific histologic subtypes was not shown. Another concern 
with the study was the exclusion of potential subjects older than 75 years, as they account for a 
significant percentage of MPM patients (Zauderer 2016). Indeed, in a review of 9014 patients with 
MPM from Belgium, the Netherlands and England collected between 2007 and 2011, 59% were 
70 years or older (Damhuis 2015). Thus patients older than 75 years comprise a significant portion 
of MPM patients. 
 
Cediranib or placebo was combined with cisplatin and pemetrexed in a randomized, phase 2 trial 
(Tsao 2019). The triplet did not improve OS. There were 12 patients with biphasic or sarcomatoid 
histology randomized to the placebo plus cisplatin and pemetrexed arm. Their median OS on 
cisplatin plus pemetrexed was 6.3 months. The ORR for these 12 was 8.3% (1/12) by both RECIST 
1.1 and mRECIST criteria.  
 


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Other Chemotherapies 
 
Similar data were obtained in MPM with another antifolate, raltirexed in combination with cisplatin 
vs. cisplatin monotherapy (Van Meerbeeck 2005). Among 213 patients with measurable disease 
(125 for combination vs. 122 for cisplatin), ORR by RECIST by investigator assessment was 23.6% 
(95% CI: 15.7-31.6) vs. 13.6%, PFS was 5.3 vs. 4.0 months, and median OS was 11.4 (95% CI: 
11.1-15.0) vs. 8.8 months, respectively. For the combination arm, the histologies were: epithelioid 
75%, mixed 14% and sarcomatoid 4%. A double-blind, phase 2 study compared gemcitabine + 
cisplatin with or without bevacizumab (Kindler 2012). Epithelioid accounted for 70.4% and non-
epithelioid for 20.6%. The ORR was 24.5% in 53 patients treated with the 3 drug regimen vs. 
21.8% in 55 treated with the two drug regimen. The median PFS was 6.9 vs. 6.0 months, and the 
median OS were 15.6 and 14.7 (95% CI: 10.3-20.0) months, respectively.  
 
Summary 
 
The prognosis for MPM is poor, with an overall median OS of ~ 1 year. The OS for epithelioid 
MPM is best followed by biphasic and then sarcomatoid. For the non-epithelioid, the median 
survival appears to be ~ 6 months. Regarding ORR, a variety of studies enriched for the epithelial 
subset, with best survival and response rate, more consistently show a rate of ~20-25% by 
investigator assessment in contrast to the 41% observed in the registration study, which also used 
investigator assessment (Vogelzang 2003). Thus it is also reasonable to believe the ORR assessed 
by BICR would be even lower, as was shown in a recent, albeit small study, where the ORR by 
BICR was half that compared to investigator assessment (Krug 2014). 
 
It is generally considered that conventional cytotoxic chemotherapy has reached a therapeutic 
plateau and novel approaches are urgently needed (Fennell 2008, Mirarabshahii 2012, Turner 2012, 
Kotova 2015). 
 
2.1.2 Amino Acid Deprivation Therapy 
 
One established method for treating some malignancies is amino acid deprivation 
(Holcenberg 1977).  This is based on the observation that some tumors are auxotrophic for 
otherwise non-essential amino acids.  The best known example is the use of asparaginase (in the 
form of a polyethylene glycol conjugate, peg-asparaginase) in acute lymphoblastic leukemia (ALL) 
(Pasut 2008).  Since most normal cells are able to synthesize asparagine, while the leukemia cells 
cannot due to lack of the enzyme asparagine synthetase, there is a selective effect on the growth of 
leukemia cells.  Depletion of asparagine is relatively well tolerated and peg-asparaginase is part of 
standard therapeutic regimens for ALL (Zeidan 2009, van den Berg 2011). 
 
2.1.3 Arginine Auxotrophy in Cancer Cells 
 
Arginine is a non-essential amino acid that is, by definition, not required for the growth of most 
cells.  The biochemical basis for this is synthesis of arginine from citrulline via the urea cycle 
(Husson 2003, Haines 2011).  The ASS1 enzyme catalyzes the conversion of citrulline and aspartic 
acid into argininosuccinate, which is then converted into arginine and fumaric acid by 
argininosuccinate lyase (ASL).  It has long been known that some tumor cells are auxotrophic for 


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arginine, based on the observation that normal cells derived from liver, kidney and testes could 
grow in medium depleted of arginine but supplemented with citrulline, while tumor cells from these 
organs could not (Tytell 1960).  This implies that certain tumor cells could not re-synthesize 
arginine from citrulline.  Other investigators also reported that certain tumor cell lines could not be 
maintained in medium contaminated with Mycoplasma species and that the killing of tumor cells 
under these conditions was associated with arginine depletion (Kenny 1963, Kraemer 1963 and 
1964).  Further studies showed that the depletion of arginine by Mycoplasma was due to the activity 
of the enzyme arginine deiminase (ADI), which is not present in mammalian cells (Schimke 1966).  
Thus, the understanding at that point was that some tumors were killed by arginine depletion 
mediated by Mycoplasma-produced ADI. 
 
Depletion of available arginine however, should not lead to cell death in the presence of the ASS1 
and ASL enzymes, which would replete arginine through conversion of citrulline. It was therefore 
hypothesized that cells auxotrophic for arginine might lack one of these enzymes and subsequently 
shown that certain cancer cell lines and human cancer tissue specimens lack significant expression 
of ASS1 (Sugimura 1992, Ensor 2002, Dillon 2004).  The activity of ADI as an arginine-degrading 
drug is only apparent in cells that lack the ability to compensate by synthesizing endogenous 
arginine from citrulline.  
 
In particular, methylation-dependent silencing of the ASS1 promoter has been identified as a 
mechanism of gene repression in a subset of ASS1-deficient arginine auxotrophic solid and 
hematological tumors, including MPM (Szlosarek 2006, Nicholson 2009, Delage 2012).  
ASS1-deficiency is associated with a poor prognosis in MPM (Delage 2008) and a variety of other 
cancers including osteosarcoma (Kobayashi 2010), myxofibrosarcoma (Huang 2013), glioblastoma 
(Syed 2013), bladder cancer (Allen 2014), breast cancer (Qiu 2014) and pancreatic cancer 
(Liu 2014). The reason for this is not entirely clear, but may due to rapidly expanding cancer cells 
preferentially using aspartate from the urea cycle to form nucleic acids and not arginine 
(Rabinovich 2015). This ASS1 deficiency redirects aspartate to pyrimidine synthesis. In contrast, 
expressing ASS1 decreases cell proliferation by decreasing nucleotide synthesis, resulting in a less 
malignant phenotype. Therefore, the urea cycle enzymes are metabolically linked to pyrimidine 
synthesis and regulation of neoplastic growth. Another group has also shown that ASS1 is a tumor 
suppressor in renal cell carcinoma by modulating both the urea cycle and glycolytic flux 
(Simon 2015). Furthermore, they showed that re-expression of ASS1 retarded proliferation both in 
vitro and in vivo xenograft models. 
 
2.1.4 Development of ADI-PEG 20 
 
As a result of the above observations regarding the potential anti-cancer activity of arginine 
depletion, interest was focused on the development of ADI as a drug.  The enzyme was cloned from 
Mycoplasma hominis, expressed in E. coli and subsequently conjugated to polyethylene glycol 
(PEG) (Takaku 1992 and 1993, Holtsberg 2002).  The PEG conjugates were prepared to enhance in 
vivo stability, to increase the circulating half-life and decrease the immunogenicity of the 
recombinant Mycoplasma enzyme.  It was determined that synthesis of ADI-PEG with PEG of 
20,000 mw via a succinimidyl succinate linker (ADI-PEG 20) provided the optimal combination of 
enhanced half-life and diminished immunogenicity, as well as ease and yield of manufacture 
(Holtsberg 2002).  Results of phase 1 and 2 ADI-PEG 20 treatment of subjects with HCC in the 


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USA, Italy and Taiwan have been reported (Curley 2003, Izzo 2004 and 2007, Yang 2010, 
Glazer 2010), as have similar phase 1 and 2 studies in metastatic melanoma (Ascierto 2005, 
Savaraj 2007, Feun 2008, 2012, Ott 2013).  These studies demonstrated medical benefit. 
 
2.1.5 Current ADI-PEG 20 Clinical Trials 
 
The therapeutic applicability of targeting arginine deprivation therapy with ADI-PEG 20 in 
combination with systemic chemotherapy is only now being studied in the clinic.  Recent preclinical 
studies have revealed that arginine deprivation may be combined successfully with cisplatin, 
docetaxel, gemcitabine, chloroquine and PI3K inhibitors to enhance the pro-apoptotic effect of 
ADI-PEG 20 in various arginine-dependent cancer xenograft models, including prostate cancer, 
pancreatic cancer, osteosarcoma and melanoma (Cheng 2007, Kim 2009, Daylami 2014, 
Tsai 2012).  Clinically, the first combination phase 1 trial to assess the role of docetaxel with 
ADI-PEG 20 commenced in the US in 2011 (ClinicalTrials.gov Identifier: NCT01497925) and a 
second phase 1 is underway with cisplatin at the MD Anderson Cancer Center (Texas, US) 
(ClinicalTrials.gov Identifier: NCT01665183).  Preliminary results show that the 
ADI-PEG 20-doublet chemotherapy regimens are well tolerated and have resulted in objective 
responses (Polaris-data on file).  ADI-PEG 20 is currently being investigated in multiple clinical 
trials. Further information is available on these trials at ClinicalTrials.gov. 
 
2.1.6 Cisplatin 
 
Cisplatin is a heavy metal compound containing platinum (Rozencweig 1977, Prestayko 1979).  Its 
mechanism of action involves covalent binding to purine DNA bases, this leads to cellular apoptosis 
(Kelland 2007).  Side effects of cisplatin include nephrotoxicity, ototoxicity, gastrointestinal upset 
(including nausea and vomiting), neurotoxicity (especially peripheral neuropathy), electrolyte 
disturbances (hypomagnesaemia, hypokalemia and hypocalcaemia) and myelosuppression 
(Cisplatin 1999).  The latter, depending on dosage regimen, typically has an onset of about 10 days 
with a nadir of about 14-23 days, with recovery by 39 days.  Fever and infection may occur in those 
with neutropenia.  Deaths due to infection, secondary to myelosuppression, may also occur. 
Myelosuppression appears to occur less frequently with lower doses (Rozencweig 1977).  
 
2.1.7 Pemetrexed 
 
Pemetrexed is a folate analog metabolic inhibitor (Pemetrexed 2013).  In clinical trials, the most 
common adverse reactions (incidence ≥ 20%) during therapy as a single agent were fatigue, nausea, 
and anorexia.  Additional common adverse reactions (incidence ≥ 20%) during therapy when used 
in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, 
stomatitis/pharyngitis, thrombocytopenia, and constipation. 
 
2.1.7.1 ADI-PEG 20 plus Cisplatin in Melanoma: Preclinical Studies 
 
Arginine is the substrate for nitric oxide (NO) synthase (Husson 2003, Haines 2011).  Depletion of 
NO inhibited melanoma proliferation, and enhanced cisplatin-induced apoptosis in melanoma cells 
in tissue culture (Tang 2004, Sikora 2010).  In addition, NO inhibition with the selective antagonist 
N6-(1-iminoethyl) – L lysine dihydrochloride (L-NIL) synergized with cisplatin in xenograft models 


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without added toxicity (Sikora 2010).  Interestingly, although the mice only received 3 doses of 
cisplatin every 3 days, continued dosing of L-NIL was sufficient to suppress tumor growth 
(Sikora 2010).  These findings suggest that combination of NO inhibition with ADI-PEG 20 and 
cisplatin would be a reasonable approach to inhibiting melanoma, as ADI-PEG 20 has been shown 
to inhibit NO both in tissue culture, animals and humans with either melanoma or HCC 
(Thomas 2002, Dillon 2002, Ascierto 2005, Izzo 2007). 
 
More recently, in vitro data has confirmed enhanced melanoma cell apoptosis with the combination 
of ADI-PEG20 and cisplatin and with the combination in xenograft models (Savaraj 2015).  
Treatment with ADI-PEG 20 and cisplatin combination showed significantly enhanced activity 
compared to either agent alone. The underlying mechanism is complex, but increased DNA damage 
upon arginine deprivation appears due to decreased DNA repair proteins which blunt the cancer 
cells’ ability to respond to cisplatin induced DNA damage.  
 
Thus both laboratory and xenograft data show that the combination of ADI-PEG 20 and cisplatin 
results in enhanced anti-tumor activity in ASS1-deficient melanoma cells, even when the cisplatin 
was administered over a limited period of time. 
 
2.1.7.2 ADI-PEG 20 plus Cisplatin in Melanoma: Clinical Study 
 
As noted, a phase 1 is underway with cisplatin at the MD Anderson Cancer Center (Texas, US) 
(ClinicalTrials.gov Identifier: NCT01665183).  Preliminary results show that this doublet 
chemotherapy regimen (cisplatin 35 mg/m2 weekly x weeks 1 - 3 of every 4 weeks [105 mg/m2 
every 4 weeks] and ADI-PEG 20 36 mg/m2 weekly) is well tolerated and has resulted in objective 
responses (Fu 2014).  This dose of ADI-PEG 20 is the same as that planned in this study, and the 
dose of cisplatin planned in this study (75 mg/m2 every 3 weeks or 300 mg/m2 planned for every 
12 weeks [4 months]) is slightly less than that (315 mg/m2 every 12 weeks) in the ongoing 
melanoma study. 
 
2.1.8 Phase 2 Study of ADI-PEG 20 Monotherapy in ASS1-deficient MPM in the United 
Kingdom (ADAM Study) 
The benefit of ADI-PEG 20 treatment in ASS1-deficient mesothelioma is supported strongly by a 
Phase 2 randomized study in ASS1-deficient MPM at 8 cancer centers in the United Kingdom (A 
Clinical Trial of ADI-PEG 20 in Patients with Malignant Pleural Mesothelioma [ADAM Study] 
[NCT01279967]), led by the principal investigator of the current study. This study compared 
ADI-PEG 20 monotherapy with best supportive care (BSC) (Szlosarek 2013, 2016). When this trial 
started, pemetrexed and cisplatin were not the approved first-line chemotherapy in the UK. Potential 
subjects had to have inoperable MPM, an ECOG performance status of 0-1, measurable disease by 
CT scan, and ASS1 deficiency (defined as ≤ 50% tumor cells with moderate and/or strong 
expression by IHC). ASS1 deficiency was found in 98 out of 214 subjects screened (46%). Sixty 
eight (68) patients were randomized 2:1 to ADI-PEG 20 (36 mg/m2) + BSC (N=44) or BSC (N=24). 
CT scan was performed every 8 weeks. The primary endpoint was PFS, and the secondary 
endpoints were response rate, OS and toxicity. The study was powered for PFS with a target hazard 
ratio of 0.60. The study enrolled between March 2011 and May 2013. Epithelioid accounted for 
96% of the enrolled subjects. Approximately half of the subjects were previously treated with a 


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platinum doublet. For ADI-PEG 20 + BSC, 17/44 (39%) were chemonaïve and 27/44 (61%) had 
been treated with prior chemotherapy.  
 
ADI-PEG 20 + BSC prolonged PFS (3.2 months) compared with BSC alone (2.0 months) 
(hazard ratio 0.56, 95% CI [0.33-0.96], p=0.03).  
 
Furthermore, although the study was not powered for OS, there was also a trend to improvement in 
OS with ADI-PEG 20 treatment. A test for proportional hazards produced p=0.02 for OS. Thus OS 
violated the proportional hazards assumption, so the restricted mean survival time, a measure of life 
expectancy, was also estimated. The restricted mean survival times (life expectancy) for OS are 
15.7 (ADI-PEG 20) vs. 12.1 (BSC) months, a difference of 3.6 months (95% CI -1.0 to 8.1, p=0.13) 
 
Note that the restricted mean survival of ADI-PEG 20 monotherapy treated subjects of 15.7 months 
compares favorably with the 12.1 months OS observed with the pemetrexed + cisplatin doublet 
(Vogelzang 2003). 
 
There was no objective response on CT scan using modified RECIST criteria for MPM, although 
18/39 (46%) of ADI-PEG 20 treated patients had a PR by FDG-PET. 
 
ADI-PEG 20 was well tolerated as monotherapy in MPM patients, with no new adverse events 
compared with other ADI-PEG 20 monotherapy studies. 
 
Given that PFS is a well-established surrogate for OS in MPM, the extended median PFS supports 
further exploration of the role of ADI-PEG 20 treatment in providing survival benefit.  
 
ADI-PEG 20 was generally well tolerated and showed evidence of clinically significant activity in 
patients selected for arginine-dependent MPM (Szlosarek 2016).  Thus arginine deprivation with 
ADI-PEG 20 may have a role in the future management of MPM either alone or in combination 
with selected therapies.  One of the metabolically responding patients has already been reported 
(Szlosarek 2013).  Furthermore, another patient with a prolonged response was on coexistent folate 
inhibition with methotrexate used to treat their rheumatoid arthritis.  This suggests further that 
combination treatment with ADI-PEG 20 may be beneficial in MPM (see below). 
 
2.1.9 Phase 1 Study of ADI-PEG 20 Plus Pemetrexed and Cisplatin in MPM and Non-
squamous Non-Small Cell Lung Cancer (NSCLC) (TRAP Study) 
 
Based on the success of ADAM study, a phase 1 study in ASS1-deficient patients with MPM or 
nonsquamous non-small cell lung carcinoma (NSCLC-nonsquamous) was undertaken (Phase 1 
Study in Subjects with Tumors Requiring Arginine to Assess ADI-PEG 20 With Pemetrexed and 
Cisplatin [ADIPemCis] [TRAP Study];  NCT02029690). The TRAP study examines the standard 
regimen of pemetrexed + cisplatin (500 mg/m2 and 75 mg/m2 respectively, both given every 
3 weeks) with escalating doses of ADI-PEG 20 (18, 27 and 36 mg/m2).  Subjects may receive a 
maximum of 6, 3-week cycles of three-drug treatment for a total of 18 weeks of treatment.  Those 
subjects completing the three-drug regimen may continue on ADI-PEG 20 monotherapy if they 
have SD or better. Subjects must be chemotherapy naïve except for those with NSCLC and EGFR 
mutant or ALK positive disease, who must have had an EGFR tyrosine kinase inhibitor (TKI) or 


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ALK inhibitor (if available). Following the dose escalation portion, maximum tolerated dose 
(MTD) cohorts of up to 30 subjects each for MPM and NSCLC will be enrolled. 
 
As of 20 March 2019, 36 MPM patients (12 epithelioid; 12 biphasic; and 12 sarcomatoid) were 
enrolled in the dose-escalation and dose expansion study at the MTD. The overall response rate was 
as follows: 15/36 (41.6%) PR and 19/36 (52.8%) SD for a DCR of 34/36 (94.4%);  the PR rate in 
non-epithelioid disease was 8/24 (33.3%). Notably, the overall median OS in the expansion cohort 
was 10.1 months and 8.2 months in the non-epithelioid patient population, comparing favorably 
with the 22.2% of the pemetrexed + cisplatin phase 3 benchmark trial (Vogelzang 2003-quoted in 
Mansfield & Symanowski 2014) and known poorest prognosis of the MPM histologies 
(Mansfield & Symanowski 2014, Galetta 2016). The reason(s) for the higher than anticipated non-
epithelioid enrollment are not clear, but appear due, at least in part, to enhanced referral of such 
patients to the lead investigator as this trial does not exclude such patients (see above) 
(Peter Szlosarek-personal communication).  
 
Thus, for MPM with a high percentage of non-epithelioid, the ORR achieved with 
ADI-PEG 20 + pemetrexed + cisplatin is significantly higher than would be expected for the 
standard pemetrexed + cisplatin doublet. 
 
In view of the poorer outcome for non-epithelioid MPM, it is remarkable that the median PFS for 
the sarcomatoid and biphasic subjects in the dose expansion TRAP study (20/31 enrolled) was 5.0 
months, approaching the level of 5.7 months in a population containing 68% epithelioid in the 
pemetrexed + cisplatin treated group (Vogelzang 2003). 
 
Note that response rate in the TRAP trial was determined using the modified RECIST criteria 
(Byrne 2004, Tsao 2011). Modified RECIST takes into account disease only in the thorax. In 
contrast, RECIST 1.1 takes into account disease in the thorax as well as in other body areas, 
although it does not assess pleural disease as well as modified RECIST does (Eisenhauer 2009, 
Tsao 2011). In the TRAP trial, tumor measurements using modified RECIST or RECIST 1.1 
resulted in the same ORR (Peter Szlosarek, personal communication). However, as non-epithelioid 
tumors, especially sarcomatoid more frequently have more aggressive disease that may extend 
beyond the thorax (Klebe 2010, Galetta 2016), we will use modified RECIST response criteria for 
MPM for intra-thoracic disease (Appendix A) and RECIST 1.1 response criteria for extra-thoracic 
disease (Appendix B) for this current trial.  
 
2.1.10 Rationale for Combining ADI-PEG 20 with Pemetrexed and Cisplatin 
 
2.1.10.1 Rationale for Combining ADI-PEG 20 with Pemetrexed 
 
ADI-PEG 20 inhibits intracellular levels of thymidine, and pemetrexed potentiates the anti-tumor 
activity of ADI-PEG 20. Treatment with ADI-PEG 20 was lethal in ASS1 negative bladder cancer 
cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, 
due to suppression of both uptake and de novo synthesis (Allen 2014). Inhibition of de novo 
thymidine synthesis was linked to decreased expression of folate-dependent nucleotide synthesizing 
enzymes thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis 
was associated with potentiation of ADI-PEG 20’s anti-tumor activity by the antifolate drug 


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pemetrexed in a xenograft model. Similar data on thymidine salvage and de novo synthesis 
pathways were obtained in a panel of ADI-PEG 20 treated ASS1-negative mesothelioma cell lines. 
Taken together, these findings argue that arginine deprivation combined with antifolates warrants 
clinical investigation in cancers such as MPM and nonsquamous NSCLC where pemetrexed + 
cisplatin are first-line chemotherapy. 
 
As noted above, there is a biochemical rationale for combining ADI-PEG 20 with pemetrexed in 
those tumors where standard treatment includes pemetrexed. Furthermore, there are biochemical 
rationales for combining ADI-PEG 20 with cisplatin, too.  
 
2.1.10.2 Rationale for Combining ADI-PEG 20 with Cisplatin 
 
Inhibition of nitric oxide synthesis by arginine depletion is enhanced by cisplatin, and ADI-PEG 20 
inhibits synthesis of DNA repair enzymes required to repair cisplatin induced DNA damage.  
Arginine is the substrate for nitric oxide (NO) synthase (Husson 2003, Haines 2011).  Depletion of 
NO inhibited melanoma proliferation, and enhanced cisplatin-induced apoptosis in melanoma cells 
in tissue culture (Sikora 2010).  In addition, NO inhibition with the selective antagonist N6 
(1 iminoethyl) – L lysine dihydrochloride (L NIL) synergized with cisplatin in xenograft models 
without added toxicity (Sikora 2010).  These findings suggest that combination of ADI-PEG 20 and 
cisplatin would be a reasonable approach to inhibiting melanoma, as ADI-PEG 20 has been shown 
to inhibit NO in tissue culture, animal models and humans with either melanoma or HCC (see 
Investigator’s Brochure). 
 
Pre-clinical data have also been obtained with combination of cisplatin and ADI PEG 20 in treating 
melanoma (Savaraj 2015).  Compared with either agent alone, treatment of ADI-PEG 20 + cisplatin 
caused significantly more growth inhibition as well as an increase in apoptosis in ASS1-negative 
melanoma cells.  Tissue culture data shows that arginine deprivation with ADI-PEG 20 potentiates 
cisplatin sensitivity in ASS1-deficient tumor cells, and this effect is mediated by increased DNA 
damage and increased apoptosis, partly due to decreased DNA repair proteins. Thus tumor cells 
have increased difficulty in attempting to repair DNA damage caused by cisplatin in the presence of 
ADI-PEG 20. In addition, treatment with ADI-PEG 20 and cisplatin combination showed 
significantly enhanced anti-tumor activity compared with either agent alone in a xenograft model. 
 
ADI-PEG 20 has also been tested in combination with cisplatin in a phase 1 trial (NCT01665183) 
(Fu 2014). The combination has been shown to be well-tolerated with no added toxicity with 
ADI-PEG 20 compared with those reported for cisplatin alone, except for injection site reactions 
that are consistent with the intramuscular injection mode of administration for ADI-PEG 20. In 
addition, objective responses have been observed.  
 
 
Description of Investigational Product 
 
Arginine deiminase (ADI) is a recombinant protein cloned from M. hominis, produced in E. coli, 
and conjugated with PEG of 20,000 mw using a succinimidyl succinate linker.  Thus ADI-PEG 20 
is an arginine degrading enzyme, ADI, coupled to PEG. 
 


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Summary of Findings to Date 
 
2.3.1 Clinical Experience with Hepatocellular Carcinoma 
 
ADI-PEG 20 has been found to be well tolerated and to result in apparent medical benefit in phase 1 
and phase 2 studies. Some patients have been on ADI-PEG 20 weekly therapy for over 3 years.  A 
global phase 3 trial has finished enrolling.  For further information, see the Investigator’s Brochure. 
 
2.3.2 Clinical Experience with Metastatic Melanoma 
 
ADI-PEG 20 has been found to be well tolerated and to result in apparent medical benefit in phase 1 
and phase 2 studies (Phillips 2013).  In particular, patients with metastatic uveal melanoma 
appeared to benefit with a significant prolongation of progression-free survival (Ott 2013). For 
further information, see the Investigator’s Brochure. 
 
2.3.3 Clinical Experience in MPM 
 
The results of the phase 2 and phase 1 studies have been noted above. 
 
2.3.4 Adverse Events 
 
The toxicities expected from the use of ADI-PEG 20 are relatively mild based on the clinical 
experience to date detailed above.  The most frequently reported physical symptom was mild, 
temporary tenderness at the injection site beginning 24 hours after the injection and lasting a total of 
1 to 2 days.  However, allergic reactions, including anaphylaxis have occurred.  The most common 
laboratory toxicities, even at doses higher than those proposed here, were mild (Grade 1 to 2) and 
asymptomatic elevations of various serum chemistry values. Neutropenia also has been observed 
and has responded to growth factor support. 
 
 
Study Rationale 
 
The above background information provides the biochemical rationale for the use of ADI-PEG 20 
in oncology studies. Tissue for ASS1 testing was initially required for study entry to support an 
adaptive biomarker-driven trial design. However, this design was amended prior to the interim 
analysis following objective responses in other clinical studies of ADI-PEG 20 combined with 
chemotherapeutic agents (FOLFOX and gemcitabine plus nab-paclitaxel; Harding 2018 and Lowery 
2017) that did not correlate with ASS1 deficiency and were seen in both subjects with and without 
ASS deficiency. Pemetrexed and cisplatin are the first line chemotherapy in advanced MPM. Taken 
together, our preclinical and clinical data suggest that such a treatment combined with ADI-PEG 20 
would be even more efficacious than standard pemetrexed plus cisplatin only.  
 
In MPM, both RR and PFS correlate with OS (Francart 2009, Blayney 2012, Hasan 2014). Thus RR 
and PFS serve as surrogate endpoints for OS in MPM. 
 
 
 


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Clinical Experience 
 
As noted above, a phase 1 combination study of ADI-PEG 20 plus pemetrexed and cisplatin is 
currently enrolling. The combination has been safe and well tolerated, with no more toxicity than 
with pemetrexed and cisplatin alone, except for injection site reactions consistent with the IM 
method of ADI-PEG 20 administration.  
 
3 
STUDY OBJECTIVES 
 
 
Primary Objectives 
 
The primary objective of this study is: 
• Determine efficacy as determined by RR, measured by modified RECIST criteria for 
unresectable MPM and RECIST 1.1 criteria (phase 2 portion) and OS (phase 3 portion) 
 
 
Secondary Objectives 
 
The key secondary objective of the phase 2 portion is: 
• Determine the duration of response (DOR) 
 
The key secondary objective of the phase 3 portion is: 
• Assess progression free survival (PFS) 
 
Other secondary objectives of this study are:  
 
• Assess safety and tolerability of ADI-PEG 20 in combination with pemetrexed and cisplatin  
• Determine the pharmacodynamics of ADI-PEG 20 in combination with pemetrexed and 
cisplatin  
• Determine the immunogenicity of ADI-PEG 20 in combination with pemetrexed and cisplatin  
• Determine the pharmacokinetics of ADI-PEG 20 in combination with pemetrexed and cisplatin 
 
Objectives will be assessed according to the overall MPM population and according to each of the 
MPM subtypes. 
 
The goal of the phase 2 portion of the trial is to provide data to support accelerated approval by the 
United States Food & Drug Administration, and the goal of the phase 3 portion of the trial is to 
provide a confirmatory study that would be ongoing at the time of the marketing application. 
 


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4 
STUDY DESIGN 
 
 
Design Summary 
 
This is a randomized, double-blind, multi-center, phase 2/3 trial of ADI-PEG 20 in combination 
with pemetrexed and cisplatin in subjects with unresectable MPM of sarcomatoid or biphasic 
histologies.  
 
The starting dose represents 100% of the recommended dose of cisplatin and pemetrexed and 
ADI-PEG 20 as determined in the phase 1 trial. 
 
4.1.1 Continued Treatment after 6 Weeks of Treatment of ADIPemCis 
 
Tumor assessment imaging will be performed at baseline (during screening) and at the end of week 
6 for tumor response using modified RECIST for MPM for local pleural disease (Byrne 2004, Tsao 
2011) and RECIST 1.1 for metastatic lesions (Eisenhauer 2009). The same imaging modality is to 
be used throughout the triplet treatment duration.  
 
In the event of disease progression, the triplet chemotherapy will be stopped and the patient offered 
an alternative treatment plan.   
 
In the absence of disease progression requiring other therapeutic interventions, patients may receive 
additional cycles of ADIPemCis or PlaceboPemCis treatment following the same procedures and 
schedule as week 7 and onward for up to 18 weeks.   
 
Subjects may continue to receive treatments unless, one of the following occurs at any time during 
the course of therapy: (1) unacceptable AEs, or (2) death, or (3) progressive disease, or (4) 
significant noncompliance on the part of the subject, or (5) refusal of the subject to continue 
treatment or observations, or (6) decision by the Investigator that termination is in the subject’s best 
medical interest, or (7) unrelated medical illness or complication, or (8) lost to follow-up.  Any 
patient with tumor and stable disease or partial response should continue treatment until 
progression, unless Investigator thinks a better option is available.  Thus, subjects completing 
ADIPemCis or PlaceboPemCis may continue to receive ADI-PEG 20 or placebo treatment.  Any 
patient with a complete response may receive 4 more weekly treatments of ADI-PEG 20 or placebo.  
The maximum number of cycles of pemetrexed + cisplatin is 6 (18 weeks at every 3 weeks cycle).  
 
4.1.2 Blinded and Open-Label Extension at Study End 
 
Subjects ongoing at study end (once the required number of events have been observed for the final 
analysis) may continue to receive weekly treatment on ADIPemCis or PlaceboPemCis (or 
ADI-PEG 20/placebo alone), depending on where the subjects are in the treatment schedule, until 
the study is unblinded. Once the study treatment assignments are known, the subjects receiving 
ADI-PEG 20 may continue to receive ADIPemCis (or ADI-PEG 20 alone) until 1 of the following 
occurs: (1) unacceptable AEs, or (2) death, (3) PD or (4) decision by the Sponsor. Subjects 
receiving placebo should be consulted regarding alternative treatment options.  A local laboratory 
may be used instead of a central laboratory for the extension phase of the study. 


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Subjects wishing to continue study treatment will follow the Schedule of Assessments in 
Table 4.1.2.1 
 
Blinded and Open-Label Extension Schedule of Assessments and Procedures 
 
 Table 4.1.2.1 Study Assessments and Procedures  
 
Study Week 
Study Procedure 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
E
O
T 
Vital Signsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE assessmentb 
X 
 
 
X 
 
 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Concomitant medications  
X 
 
 
X 
 
 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Study drug administrationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Note: All study evaluations and related procedures may occur ± 3 days of the planned date.  
Subjects who remain on treatment after 18 weeks will continue following the schedule in Table 4.1.2.1.  For example, week 
19 would follow the schedule for week 1, week 20 would follow the schedule for week 2 and so on.  
a. 
Vital signs to be obtained before and 1 hour ± 15 minutes after ADI-PEG 20 or placebo treatment. 
b. Adverse events, including serious adverse events will be assessed at each of the indicated visits.  Ongoing adverse 
events will be followed until resolution or stabilization.  New AEs will be recorded until 30 days after last drug 
administration. Adverse events will be reported to Polaris monthly. SAEs will be reported within 24 hours of 
awareness to Polaris or designee.  
c. 
During blinded extension, visits will be registered in IWRS. During Open-Label Extension, Polaris will provide a list 
of vial numbers to be pulled from inventory and given to subjects at each visit.  ADI-PEG 20 will be administered 
weekly.  Cisplatin and pemetrexed will be administered every 3 weeks up to the planned 18 weeks duration of these 
agents. 
 
Note:  CT/MRI scans during the extension will be standard of care in the opinion of the 
investigator. 
 
4.1.3 Anticipated Number of Subjects and Target Accrual 
 
See Section 11.  
 
 
Criteria for Study Termination 
 
The study may be terminated at any time by Sponsor for the following reasons: 1) the Investigator 
does not adhere to the protocol, i.e. commits significant protocol violations, 2) in Sponsor’s 
judgment, there are no further benefits to be achieved from the study, or 3) the clinical development 
of the investigational product in this study is discontinued.  If this study is discontinued, Sponsor 
will inform all study investigators/institutions, the IRB/IEC and regulatory authorities. 
 
The Investigator and Sponsor have the right to close a study, at any time; however, this should 
occur only after consultation between the parties.  If the study is closed, the IRB/IEC must be 


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informed.  If the study is closed prematurely, all study materials, except documentation that has to 
remain stored at the center site, must be returned to Sponsor.  The Investigator will retain all other 
documents until notification given by the Sponsor for destruction.  Events that may trigger 
premature termination of a study or closure of a center include, but are not limited to: 
 
• New toxicity finding 
• Non-compliance with the protocol 
• Change in development plans for the drug 
• Slow recruitment 
• Poor quality data 
• Regulatory authority mandate 
 
5 
STUDY POPULATION 
 
 
Inclusion Criteria 
 
A subject will be eligible for study participation if they meet the following criteria prior to the first 
dose:  
 
1. Histologically proven unresectable MPM of biphasic or sarcomatoid histology. Biphasic 
MPM is defined using the World Health Organization’s international histological 
classification of tumors as containing an epithelial and a sarcomatoid component with each 
component comprising at least 10% of the tumor (Corson 2004, Allen 2005). 
2. Naïve to prior chemotherapy or immunotherapy (i.e., this is a first-line systemic therapy 
study). 
3. Measurable disease as assessed by modified RECIST for MPM local pleural disease 
(Appendix A) and RECIST 1.1 for metastatic lesions (Appendix B).  
4. ECOG performance status of 0 – 1 (Appendix C). 
5. Predicted life expectancy of at least 12 weeks. 
6. Age ≥ 18 years (there is no upper age limit).  
7. Fully recovered from any prior surgery and no major surgery within 4 weeks. Surgery for 
placement of vascular access devices is acceptable. 
8. Subjects and their partners must be asked to use appropriate contraception.  They must agree 
to use two forms of contraception or agree to refrain from intercourse for the duration of the 
study and for 35 days after last dose of ADI-PEG 20 or for at least six months after treatment 
with pemetrexed and cisplatin whichever is the longer duration. Females must not be 
pregnant at the start of the study, and a serum human chorionic gonadotropin (HCG) 
pregnancy test must be negative before entry into the study. If positive HCG pregnancy test, 
further evaluation to rule out pregnancy must be performed according to GCP before this 
patient is claimed eligible. 
9. Informed consent must be obtained prior to study initiation. 
10. Hemoglobin (HB) > 9.0 g/dL. 
11. Absolute neutrophil count (ANC) > 1,500/µL.  


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12. Platelets > 75,000/µL. 
13. Either: (i)  serum bilirubin ≤ 1.5 x upper limit of normal (ULN) or 
(ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or alkaline 
phosphatase (ALP) ≤ 3 x (ULN) unless raised due to tumor in which case up to 5 x ULN is 
permissible 
14. Serum uric acid ≤ 10 mg/dL (595 µmol/L) (with or without medication control).  
15. Creatinine clearance ≥ 45 mL/min (estimated, using Cockcroft and Gault formula). Cisplatin 
dose adjustment is recommended for subjects with a creatinine clearance between 45 and 59 
mL/min (Bennis 2014) as follows: reduce cisplatin dose by 25% for clearance between 
50-59.9 mL/min and by 50% for clearance between 45 – 49.9 mL/min. 
 
 
Exclusion Criteria  
 
A subject will not be eligible for study participation if s/he meets any of the exclusion criteria 
before first dose: 
1. Radiotherapy (except for palliative reasons) the previous two weeks before.  
2. Ongoing toxic manifestations of previous treatments.  
3. Symptomatic brain or spinal cord metastases (patients must be stable for > 1 month post 
radiotherapy or surgery).  
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. 
6. Known to be serologically positive for human immunodeficiency virus (HIV). Testing to 
determine possible infection status is not required. 
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure (New York Heart Association Class III or IV), 
symptomatic cardiac arrhythmia, previous history of myocardial infarction (unless stable and 
good ejection fraction on echocardiogram) or psychiatric illness and social situations that 
would limit compliance with study requirements. 
8. Is a participant of, or plans to participate in, another interventional clinical study whilst 
taking part in this study.  Participation in an observational or biomarker study would be 
acceptable, with prior Sponsor approval. 
9. Subjects with history of another primary cancer, including co-existent second malignancy, 
with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated 
cervical carcinoma in situ; or c) other primary malignancy with no known active disease 
present in the opinion of the Investigator will not affect patient outcome.   
10. Allergy to cisplatin or other platinum-containing compounds.  
11. Pregnancy or lactation. 
12. Expected non-compliance. 
13. Subjects who had been treated with ADI-PEG 20 previously. 
14. History of uncontrolled seizure disorder not related to underlying cancer. 
15. ECOG performance status > 2. 


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16. Allergy to pegylated compounds.  
17. Allergy to E. coli drug products (such as GMCSF). 
18. Allergy to pemetrexed or to any other ingredient used in the formulation. 
 
 
Criteria for Subject Withdrawal 
 
Subjects are free to discontinue the study treatment at any time, for any reason, and without 
prejudice to further treatment.   
 
A subject experiencing any of the following will be withdrawn from the study treatment: 
1. 
Significant noncompliance on the part of the subject. 
2. 
Refusal of the subject to continue treatment or observations. 
3. 
Adverse Event. Laboratory abnormalities that can be corrected with interventions (e.g., 
hyperuricemia with allopurinol and/or urate oxidase, and neutropenia with growth factor 
support) do not require subject withdrawal.  
4. 
Decision by the Investigator that termination is in the subject’s best medical interest. 
5. 
Unrelated medical illness or complication. 
6. 
Death. 
7. 
Lost to follow-up. 
8. 
Progressive Disease according to modified RECIST or RECIST1.1 as appropriate for the 
disease under study, or clinical progression in the opinion of the Investigator. BICR results 
will be used for decisions on the discontinuation of or continued treatment during the phase 2 
portion.   
 
 
Withdrawal Procedures 
 
In the event of a subject’s withdrawal, the investigator will promptly notify the study monitor and 
will make every effort to complete the EOT assessments (see Table 1.4.2).  
 
Subjects withdrawn from treatment for reasons other than PD may continue to receive scans every 8 
weeks until PD. 
 
After discontinuation/withdrawal from treatment, a subject must be entered into the follow-up 
period, and contacted regularly (every 3 months) for survival status until study closure.  If a subject 
decides not to continue to receive study drug, they will be removed from the study treatment portion 
and the investigator will request the subject to provide follow up information on the study.  If a 
subject withdraws from the study treatment, every effort will be made to complete EOT, Follow-Up 
Visit, and End of Study eCRFs. 
 
If a subject should die during treatment or within 30 days of stopping treatment, the investigator 
will inform Sponsor’s representative.  The cause of death should be reported in detail, within 24 
hours, on an SAE form and reported to Sponsor’s representative/designee (see Section 9). 
 


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Subjects that have signed informed consent for treatment, and undergo at least some of the 
screening procedures, but fail to meet eligibility criteria will be considered screening failures. The 
reason for failure will be recorded on the screening log provided by Polaris.  A record of such 
subjects will be maintained in the Trial Master File (TMF) at the study site and will be retained for 
the required period of time in compliance with the Code of Federal Regulations (CFR) 21, 
Sec.312.57, part (c) and Good Clinical Practice (GCP). Subjects that are “screen failures” may be 
rescreened at the discretion of the investigator.   
 
All withdrawn subjects will be followed until resolution of any ADI-PEG 20 related AEs, or until 
these unresolved AEs are judged by the investigator to have stabilized. 
 
6 
STUDY PROCEDURES 
 
The procedures for each visit are listed in Section 1.4 SCHEDULE OF ASSESSMENTS AND 
PROCEDURES. 
 
Results of all assessments will be recorded on the appropriate eCRF. 
 
 
Screening Procedures  
 
The investigator will inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject prior to performing any study-
related procedures and prior to the administration of study drug.   
 
The results of the screening evaluation must meet the inclusion/exclusion criteria for the subject to 
be entered into the study.  Thus the investigator must review the results of histology determination, 
diagnostic testing (CT scan or MRI, serum pregnancy test [if appropriate], and clinical laboratory 
tests), and the results of that screening testing must meet the inclusion/exclusion criteria for the 
subject to be enrolled into the study. BICR results will be used for eligibility determination in the 
phase 2 portion. 
 
Study Informed Consent Form 
 
There will be one main consent form for this study.   
 
6.1.1 ASS1 Expression Screening 
 
ASS1 expression testing was initially required but the protocol was amended to remove this 
requirement. 
 
6.1.2 Study Screening  
 
6.1.2.1 Screening Procedures within 4 weeks (28 days) of Start of Treatment 
 
The following must be performed/ obtained within the four weeks before the patient receives the 
first dose of ADI-PEG 20:  


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• Upon determination that a patient has a biphasic or sarcomatoid tumor, the patient will then 
undergo further screening procedures, as follows  
• Demographic details  
• Medical History including prior diagnosis, prior treatment, concomitant diseases, 
concomitant treatment and baseline signs and symptoms  
• Disease Assessments: Radiological measurements (chest, abdominal and pelvis 
computerized tomography (CT) scan, as appropriate), ideally within 2 weeks of study drug 
administration but 28 days is acceptable. 
 
6.1.2.2 Screening Procedures within 1 week (7 days) of Start of Treatment  
 
The following must be performed within one week before the patient receiving the first dose of 
ADI-PEG 20: 
• 
ECOG performance status 
• 
Complete physical examination  
• 
Height, weight, temperature, blood pressure (BP), respiratory rate and heart rate  
• Laboratory Tests: Samples to be obtained for clinical laboratory tests as outlined in 
Table 9.2.  Serum human chorionic gonadotropin (HCG) test to rule out pregnancy at study 
entry; results must be obtained and reviewed before the first dose of ADI-PEG 20 is 
administered, if applicable (i.e., females). 
• 
Creatinine clearance ≥ 45 mL/min (estimated, using Cockcroft and Gault formula). 
Creatinine clearance = {(l 40–age[yr]) x weight[kg])/(72xSerum creatinine[mg/dL])}x 0.85 
(if female).  
• 
12 lead electrocardiogram (ECG) 
 
 
Clinic Visits 
 
There are no fasting or food restrictions for the clinic visits.  The visit frequency is described in 
Section 1.4 SCHEDULE OF ASSESSMENTS AND PROCEDURES.  Selected weekly clinic visits 
may be conducted in the home setting by home cancer care staff rather than in the clinic. If home 
care is to be used the process must be documented and approved by the Sponsor. 
 
6.2.1 End of Treatment 
 
At the time of discontinuation of treatment for any reason, subjects will be asked to report to the 
study site for EOT assessments. This assessment is to be completed 7-30 days after last dose 
administered (preferably 30 days after last dose administration but may be performed earlier if 
necessary). 
 
6.2.2 Follow-up Period 
 


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The subject will be contacted every 3 months post EOT assessment until study closure to determine 
survival status. In addition, a current survival status is required prior to the interim and final 
analysis.  Any ongoing AEs related to ADI-PEG 20 when subject stops the study treatment will be 
followed by the Investigator until the event resolves, stabilizes, or returns to baseline status (see 
Follow-up Period Table, Table 1.4.3). 
 
7 
STUDY DRUGS 
 
 
Identity of Investigational Product and Standard, Background Chemotherapies 
 
7.1.1 Drug Name(s) 
 
7.1.1.1 ADI-PEG 20 - Investigational Product 
 
For further information, see the Investigator’s Brochure. Arginine deiminase (ADI) is a 
recombinant protein cloned from M. hominis, produced in E. coli, and conjugated with polyethylene 
glycol (PEG) of 20,000 mw.  Thus, ADI-PEG 20 is an arginine degrading enzyme, ADI, coupled to 
PEG. ADI-PEG 20 is the investigational product in the study. 
 
7.1.1.2 Pemetrexed – Standard, Background Chemotherapy 
 
This is an approved medication that is considered in the study as background therapy to be provided 
through the local pharmacy. The brand name Alimta® (Lilly-name used in the USA) should be used 
for this study unless use of an alternative generic version has been approved in advance by the 
Sponsor. 
 
7.1.1.3 Cisplatin – Standard, Background Chemotherapy 
 
This is an approved medication that is considered in the study as background therapy to be provided 
through the local pharmacy. 
 
7.1.2 Storage Conditions 
 
The investigator will ensure that all the study drugs are stored and dispensed in accordance with US 
Food and Drug Administration (FDA) regulations and other country specific health authority 
regulations concerning the storage and administration of investigational drugs. 
 
ADI-PEG 20 and placebo will be stored frozen at the temperature indicated on the product label.  
The drug product is stable for 24 hours once it is thawed after taking it out from frozen storage. 
 
Pemetrexed and cisplatin are to be stored per institutional standards.  
 
 
Blinding of Investigational Product 
 
Subjects will be randomly assigned to receive ADI-PEG 20 drug product or matching placebo in a 
double-blind fashion. Thus, neither the investigator, nor the subject will know which study 


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treatment is being administered. The randomization number will be assigned based on information 
obtained from an IWRS. ADI-PEG 20 drug product and placebo will be identical in appearance in 
order to preserve the blinding. In order to maintain this blind, study medication (ADI-PEG 20 or 
placebo) will be labeled with a unique “medication number”, which will be assigned to a subject by 
an IWRS. Note that SAS programming may occur as study data accumulate in order to have 
analysis programs ready at the time the study finishes. In such an event, arbitrary treatment group 
assignments must be randomly linked to subjects, effectively rendering any output of programs 
meaningless. The complete random lists will be archived with the IWRS. Should a medical 
emergency arise that requires identification of the study medication administered, in order to 
manage the acute situation of the subject, the blind can be broken. The investigator should treat the 
subject as if the subject were on the active drug product. The study medication can be unblinded by 
the investigator via the IWRS if needed.  
 
Unblinding may occur for emergency purposes only. Investigators should note that the occurrence 
of an SAE should not routinely precipitate the immediate unblinding of the label. If unblinding is 
necessary for the treatment of a subject for an SAE, the investigator should promptly document and 
explain any unblinding to Polaris, or their designee within 24 hours of unblinding. The medical 
monitor must also be promptly notified that the blind has been broken. If unblinding occurs, the 
study medication (ADI-PEG 20 or placebo) must be discontinued. Subjects that have discontinued 
study drug/placebo may not re-start treatment.  
 
 
Study Treatment 
 
7.3.1 Dose and Administration 
 
ADI-PEG 20 or placebo will be administered by intramuscular (IM) injection to subjects once 
weekly.  Subjects will remain in the treatment area for 1 hour ± 15 minutes after the injection.  At 
the end of this post injection period, subjects will be assessed for safety and tolerability, including 
obtaining vital signs.  ADI-PEG 20 or placebo is to be administered before pemetrexed + cisplatin. 
Pemetrexed + cisplatin administration is to begin at least 60 minutes after ADI-PEG 20 or placebo 
administration on the same day, except during cycle 1 when the chemotherapy is administered on 
Day 3.   
 
Pemetrexed + cisplatin are to be administered per institutional standards (this may include capping 
of BSA for dosing, banding, rounding, prefilled products, or logistical requirements for 
prehydration, etc.). 
 
7.3.2 Rationale and Dose Selection 
 
7.3.2.1 ADI-PEG 20 
 
ADI-PEG 20 (at dose of 36 mg/m2) or placebo is to be given via the IM route of administration. 
This is the dose that has been used successfully in the current phase 1 study of ADI-PEG 20 plus 
pemetrexed plus cisplatin in MPM and NSCLC. Subjects will receive one injection of ADI-PEG 20 
or placebo intramuscularly into the deltoid, gluteal or quadriceps muscles (Note: this will total 
approximately 6 mL for a larger subject, if this volume is a problem from an institutional nursing 


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perspective, it may be given as 2 injections in different body locations) weekly.  To limit the 
volume administered for a larger subject there will be dose capping at 74.8 mg which is the 
equivalent of 6.5 mL.  The injections may be given ± 3 days from the scheduled weekly dosing, 
except for the first dose, which is fixed.  Subjects will be observed in the clinic for 1 hour ± 15 
minutes following each ADI-PEG 20 or placebo injection.  ADI-PEG 20 or placebo is to be 
administered before pemetrexed and cisplatin. Pemetrexed and cisplatin administration is to begin at 
least 60 minutes after ADI-PEG 20 or placebo administration on the same day, except for the first 
cycle where the doublet chemotherapy will be administered on day 3.  Treatments shall not be 
interrupted due to either scheduling for CT (or MRI) scans or delays in the assessment of scan 
results. 
 
7.3.2.2 Pemetrexed and Cisplatin 
 
Treatment with pemetrexed and cisplatin is as per institutional guidelines, including infusion 
protocols. 
 
The dosages of pemetrexed and cisplatin are those used to treat unresectable MPM.  The dose of 
pemetrexed is 500 mg/m2 every 3 weeks given by IV.  The dose of cisplatin is 75 mg/m2 every 3 
weeks given by IV. 
 
7.3.3 Dose Adjustments 
 
Treatment may be withheld for up to 2 weeks in any subject that demonstrates Grade 3 
non-hematologic toxicity or hematologic toxicity, as defined by the NCI Common Terminology 
Criteria for Adverse Events (CTCAE version 4.03, or approved version).  If the toxicity is no longer 
Grade 3, treatment may be resumed; treatment does not have to wait for the next scheduled dose 
visit.  Use of hematopoietic growth factors is allowed to treat hematologic toxicity at the discretion 
of the investigator. Grade 3 or 4 laboratory abnormalities (e.g., hyperuricemia) that can be corrected 
with interventions do not require cessation of therapy.  If treatment is withheld for more than 2 
weeks (or more than 2 missed doses of ADI-PEG 20/placebo), the subject should be discontinued 
from treatment, unless it is approved by Polaris in certain situations for the subject to continue.   
 
ADI-PEG 20 or Placebo 
 
ADI-PEG 20 or placebo will be given on days 1 (week 1), 8 (week 2), and 15 (week 3) of a cycle.  
Toxicity which is attributable to either cisplatin or pemetrexed will not mandate withholding the 
dose of ADI-PEG 20 or placebo for that cycle.  Dose reduction of ADI-PEG 20 or placebo is not 
allowed. 
 
Investigators retain the discretion to withhold ADI-PEG 20 or placebo dose on the grounds of 
patient safety. 
 
For patients to receive Day 15 ADI-PEG 20 or placebo the following parameter is required during 
the chemotherapy treatment period (Cycles 1-6): 
1. Platelets ≥ 50 x 109/L – on day 8 
 


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Patients who do not meet this criterion should have the dose of ADI-PEG 20 or placebo withheld.  
Specific toxicity resulting from ADI-PEG 20 or placebo administration should be managed as 
follows: 
• 
Local injection site reactions to date have been self-limiting and typically resolve within 
48 hrs. 
• 
Anaphylaxis should be managed in line with local policy for anaphylaxis.  In the event of 
Grade 2 or lower anaphylaxis re-challenge with ADI-PEG 20 or placebo may be considered 
and pre-medication with hydrocortisone and cholorpheniramine may be used.  Grade 3 or 
greater anaphylaxis will result in the patient being withdrawn from study treatment. 
• 
Hyperuricemia is to be monitored. Any clinically relevant elevation should be treated with 
allopurinol or urate oxidase, or sites may choose appropriate substitutions according to local 
policy.  
• 
Epilepsy/fits should be managed according to local policy and with benzodiazepines as 
necessary.  Once stabilized and dependent on the type and severity of reaction re-challenge 
with ADI-PEG 20 or placebo may be considered.  If further seizures occur, despite 
prophylactic measures, the patient should be withdrawn from study treatment. 
 
Pemetrexed and Cisplatin: 
 
Cisplatin dose adjustment is recommended for subjects with a creatinine clearance between 45 and 
59 mL/min (e.g., Bennis 2015).  
 
Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or 
maximum non-hematologic toxicity from the preceding cycle of therapy.  Treatment may be 
delayed to allow sufficient time for recovery.  Upon recovery, patients should be re-treated using 
the guidelines in Table 7.3.3: 
 
Table 7.3.3: Management of Drug Related Toxicity 
 
Cisplatin  
Pemetrexed 
Hematological: 
Nadir ANC <500/mm3 & nadir platelets 
≥50,000/mm3 
75% previous dose 
75% previous dose 
Nadir platelets <50,000/mm3 regardless of 
nadir ANC 
75% previous dose 
75% previous dose 
Nadir platelets <50,000/mm3 with bleeding 
regardless of nadir ANC 
50% previous dose 
50% previous dose 
Non-Haematological: 
Any Grade 3 or 4 toxicities except mucositis 
75% previous dose 
75% previous dose 
Any diarrhea requiring hospitalisation 
(irrespective of grade) or Grade 3 or 4 
diarrhoea 
75% previous dose 
75% previous dose 
Grade 3 or 4 mucositis 
100% previous dose 
50% previous dose 


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Cisplatin  
Pemetrexed 
Neurotoxicity Grade 1 
100% previous dose 
100% previous dose 
Neurotoxicity Grade 2 
50% previous dose 
100% previous dose 
Creatinine clearance 50-59.9 mL/min 
75% previous dose 
Not applicable 
Creatinine clearance 45-49.9 mL/min 
50% previous dose 
Not applicable 
 
If a subject develops non-hematologic toxicities ≥ Grade 3 (excluding neurotoxicity), pemetrexed 
should be withheld until resolution to less than or equal to the subject's pre-therapy value.  
Treatment should be resumed according to the guidelines in Table 7.3.3.   
 
Treatment with pemetrexed and cisplatin should be discontinued if a patient experiences any 
hematologic or non-hematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if 
Grade 3 or 4 neurotoxicity is observed. 
 
The first occurrence of toxicity which leads to a dose reduction of pemetrexed and / or cisplatin will 
not mandate a dose reduction in ADI-PEG 20 or placebo so long as the toxicity is attributable to the 
cytotoxic agent(s). 
 
Either pemetrexed and / or cisplatin may be discontinued due to toxicity, and the continued single 
chemotherapy agent may be given with ADI-PEG 20 or placebo.  
 
7.3.4 Switching from Cisplatin to Carboplatin  
 
Cisplatin is the recommended chemotherapy for use in the initial and subsequent cycles. However, 
subjects who do not tolerate cisplatin or who would not be expected to tolerate cisplatin may have 
carboplatin substituted for cisplatin at any cycle including the initial cycle at the discretion of the 
investigator.  The dose of carboplatin is area under the plasma concentration–time curve (AUC) 5 
mg per ml per minute. This may be modified at investigator discretion.  
 
7.3.5 Missed Doses 
 
An ADI-PEG 20 or placebo dose that is administered within the +3 days from the projected day will 
be considered delayed but not a deviation.  Beyond the +3 days, the dose would be considered 
missed for that week.  Missed doses of ADI-PEG 20 or placebo will not be made up. 
 
A pemetrexed and/or cisplatin/carboplatin (or carboplatin) dose that is not administered on Cycle 
X/Day 1 will be considered delayed if given within 2 weeks of that cycle.  Subsequent dosing 
schedule would need to be adjusted so that the chemotherapy is given in 3 weeks’ time.  Beyond 
this, the doses would be considered missed.    
 
7.3.6 Subject Replacement 
 
Only screening failure subjects will be replaced. All patients who receive any dose of study drug 
will be evaluable for safety. 


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7.3.7 Optional Single Agent Treatment 
 
Subjects that have completed 18 weekly treatments (ADI-PEG 20 or placebo plus pemetrexed and 
cisplatin/carboplatin) may continue ADI-PEG 20 or placebo if they have stable disease or better for 
up to 2 years.  
 
7.3.8 Data Safety and Monitoring Board (DSMB) 
 
A DSMB will be instituted for this study to ensure the safety of the subjects. Recommendations for 
continuation of the study will be guided by safety evaluations at safety data reviews. The committee 
will include two (2) independent oncologists with experience in thoracic oncology and an 
independent statistician. Safety meetings will be held as per the DSMB charter, approximately 
every 6 months and more often if deemed necessary. Decisions on study termination, amendment, 
or cessation of subject recruitment, based on safety or outcome findings, will be made after 
recommendations from the DSMB have been assessed by Polaris. The DSMB will not be expected 
to conduct the key efficacy analyses at the interim or final analysis.  
 
7.3.9 Duration of the Study  
 
Anticipated Duration of Treatment: 18 weeks - with possible extension for responding or stable 
disease, and stopping for progressive disease 
 
Anticipated Enrollment Period: Approximately 24 months 
 
Anticipated Follow-up Period: Approximately 12 months. Thus the study is anticipated to take 
36 months to complete. 
 
7.3.10 Estimated Study Drug Requirements 
 
Study drug is as follows: ADI-PEG 20, in the histidine-buffered formulation, will be provided as a 
sterile solution in single-dose glass vials.  
 
Placebo is as follows: Placebo will be provided as a sterile solution in single-dose glass vials. Each 
vial delivers 3.5 mL of solution containing low viscosity sodium carboxymethylcellulose, PEG 
3350, propylene glycol, and Tween 80. The placebo will not contain ADI, PEG 20 or succinimidyl 
linker. 
 
It is assumed that each subject will be treated with approximately 18 doses of either study drug or 
placebo. Some subjects will be treated for shorter duration and some for longer duration. 
 
Thus the approximate number of vials required for the phase 2 portion of the study is: 88 subjects 
per study arm x 2 vials per week x 18 weeks = 3168 vials of ADI-PEG 20 and an equivalent number 
of vials of placebo.  
 


Polaris Group 
 
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7.3.11 Study Drug Dispensing 
 
To prepare the test article for intramuscular use, first allow the frozen vial to warm to room 
temperature and then gently swirl the solution. Remove flip-off cap and using clean technique, 
withdraw an appropriate volume of solution into a syringe. Vials are designed for single-use only. 
Any test material remaining in an opened vial must not be used. 
 
Clinical trial material Preparation 
Administration 
Test Article 
Once the agent has been thawed and 
warmed to room temperature, the 
appropriate amount of agent for the 
individual subject is to be drawn into a 
syringe and injected intramuscularly. 
 
Inject 
intramuscularly 
 
7.3.12 Packaging and Labeling 
 
Label text will be approved according to Polaris or their designee’s procedures. The drug product 
and placebo labels will comply with local legal and regulatory requirements and will be 
multi-language where appropriate. The proper storage conditions of the study drug and placebo will 
also be described on the medication labels. 
 
The following clinical trial materials (CTM) will be used: 
• ADI-PEG 20 for IM injection 
• Placebo for IM injection 
 
ADI-PEG 20 is produced by DesigneRx Pharmaceuticals, Inc. (DesigneRx), a subsidiary of Polaris. 
Placebo will be identical in appearance to the active study drug. Placebo will also be supplied by 
DesigneRx. The CTM is blinded. 
 
Pemetrexed, cisplatin, and carboplatin are available through the study site pharmacy. 
 
7.3.13 Study Drug Handling 
 
Participating countries and sites will be provided with the CTM according to the number of patients 
assigned, and labeled according to local law. Once the CTM has been received, it should be kept in 
a safe place as directed on label. Study drug supplies must be used only for the investigation 
specified in this protocol, and study drug supplies must be accessible only to authorized staff. The 
investigator, or responsible person or pharmacist, as appropriate at each site must confirm the 
receipt of the drug supplies by signing the order form. Study drug supplies may only be 
administered by the investigator or the investigator’s designate. Study drug accountability must be 
performed every day study drug is dispensed. Used or partially used vials should be retained until 
use has been verified by Polaris or their designee. Documented destruction of partially used drugs 
and disposal of drug containers must be performed by each site. One copy of the destruction 
certificate must be kept by the investigator, or responsible person or pharmacist, as appropriate at 
each site, and the other copy must be sent to the Polaris representative. 
 


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7.3.14 Study Drug Storage 
 
CTM will be stored until use at conditions described on the label. 
 
7.3.15 Study Drug Accountability and Return 
 
The investigator must ensure that all drug supplies are kept in a secure locked area with access 
limited to those authorized by the investigator.  The investigators or appropriate designee will 
maintain a record of all study medications received and dispensed.  Records must include but not be 
limited to the date received, lot number, expiration date, amount received, and the disposition of all 
study drug.  Current dispensing records will also be maintained including the date and amount of 
drug dispensed and the subject receiving the drug.  All remaining drug not required by regulations 
to be held by the clinical facility must be returned to Sponsor or its representative immediately after 
the study is completed.  Study drug shipments will be addressed to the Investigator’s authorized 
designee, preferably, the site’s pharmacy.  The recipient will verify the amount and condition of the 
drug and will return a signed Acknowledgment of Receipt and the temperature profile from the 
temperature monitor to the Sponsor.  A drug dispensing log (inventory) will be kept by the study 
site, containing at least the following: 
 
• The subject’s identification (subject number and initials) 
• Date and quantity of drug dispensed 
• Date and quantity of drug returned to the investigator/pharmacy (if applicable) 
• Date and quantity of accidental loss of drug (if any) 
 
These inventories must be made available for inspection by the study monitor.  The Investigator 
should have access to the study drug dispensing record.  At the end of the study, the study monitor 
will also collect the original study drug dispensing records. 
 
At the end of the study or as directed by Sponsor, all used and unused supplies, including partially 
used or empty containers, will be disposed of or transferred as instructed by Polaris, and in 
accordance with local written procedures, if applicable.  Any disposal or transfer of investigational 
agent shall be noted on the investigational drug disposition log and signed-off by a second person.  
At the end of the study, the monitor will collect the original drug disposition logs. 
 
7.3.16 Cross-Over 
 
No crossover will be permitted.  
 
7.3.17 Compliance 
 
This study will be conducted in accordance with the provisions of the Declaration of Helsinki, the 
FDA Code of Federal Regulations, the ICH Guidelines on GCP, and local regulations as applicable. 
Before initiating the trial, the Investigator/institution should have written and dated approval from 
the Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) for the trial protocol, 
written informed consent documents, and any written information to be provided to subjects.  The 


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investigator or appropriate designee will maintain a record of all study medications received and 
dispensed and also source documents for each subject in the study, consisting of case and visit 
notes. 
 
 
Prior and Concomitant Therapy 
 
A concomitant therapy is any drug or substance administered from administration of first dose of 
study drug until the last dose of study drug administered.   A concomitant procedure is any 
therapeutic intervention (e.g., surgery/biopsy, physical therapy) or diagnostic assessment performed 
from administration of first dose of study drug until the last dose of study drug administered. No 
new concomitant therapies or procedures will be collected after the administration of last dose of 
study drug. If the subject is being followed for study drug related toxicity the corresponding 
concomitant therapy or procedure will be followed until the event is resolved or stabilized. 
 
The use of concomitant therapies or procedures defined above must be recorded on the subject’s 
eCRF, according to instructions for eCRF completion.  AEs related to administration of these 
therapies or procedures must be documented on the appropriate eCRF. 
 
All medications (prescription and non-prescription), vitamin and mineral supplements, and/or herbs 
taken by the participant will be documented on the concomitant medication eCRF and will include 
generic (preferably) or brand name, start and stop date, dose and route of administration, and 
indication. Medications taken for a procedure should also be included. All non-drug therapies must 
be recorded in the respective sections of the eCRF. 
 
Subjects who require oral anticoagulation with warfarin (or other substitutions) may continue 
provided there is increased vigilance with local INR monitoring. 
 
7.4.1 Non-Permitted Concomitant Therapies 
 
Subjects may not receive chemotherapy, radiation therapy (palliative radiation therapy to sites not 
representing PD is acceptable), or immunotherapy during the study.  Subjects may not receive 
interferon or the vaccine for yellow fever.  
 
7.4.2 Permitted Concomitant Therapies 
 
At the discretion of the investigator, any drug or non-drug therapy necessary to treat any condition 
arising during the study, except another systemic therapy (chemotherapy) and/or radiation therapy, 
and/or immunotherapy. 
 
Non-steroidal anti-inflammatory drugs (NSAIDs) will be avoided where possible.  Patients with 
mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) should avoid 
taking, medications such as ibuprofen and aspirin (>1.3 g daily), where possible.  If necessary, they 
should be omitted for 2 days before, on the day of, and 2 days following pemetrexed and cisplatin 
administration. 
 


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7.4.2.1 ADI-PEG 20 
 
Routine treatment with antihistamines or corticosteroids is not recommended before ADI-PEG 20 
treatment, but may be instituted at the discretion of the treating physician if clinically necessary in a 
patient that has experienced an allergic reaction while on ADI-PEG 20 treatment. Investigators may 
prescribe all other concomitant medications or treatments deemed necessary to provide adequate 
patient care. Thus corticosteroid may be given prior to pemetrexed administration (see below). 
 
For management of Grade 3 or greater hyperuricemia, allopurinol therapy will be administered to 
subjects until serum uric acid levels have normalized and symptoms have resolved.  If the 
hyperuricemia does not respond to allopurinol therapy, uricase (rasburicase) therapy may be 
administered. 
 
7.4.2.2 Pemetrexed and Cisplatin 
 
To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior 
to, on the day of, and the day after pemetrexed administration.  The corticosteroid should be 
equivalent to 4 mg of dexamethasone administered orally twice a day. 
 
To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation.  
Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1,000 micrograms) 
on a daily basis.  At least five doses of folic acid must be taken during the seven days preceding the 
first dose of pemetrexed, and dosing must continue during the full course of therapy and for 21 days 
after the last dose of pemetrexed.  Patients must also receive an IM injection of vitamin B12 
(1,000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles 
thereafter.  Subsequent vitamin B12 injections may be given on the same day as pemetrexed. 
 
Supportive and pre-medications to include the following (or equivalent substitutions) or as per local 
policy: 
• Folic acid 400 mcg daily, oral 
• Hydroxycobalamin 1000 mcg IM injection  
• Dexamethasone 4 mg bd (3 doses) preceding hospital visit. Dexamethasone may also be 
administered i.v. and at a dose per local policy. 
• Anti-emetic e.g. 5HT3 antagonist, domperidone and dexamethasone 8 mg 
• Furosemide 40 mg oral once 
 
8 
EFFICACY ASSESSMENTS 
 
 
Efficacy Parameters 
 
See Section 3.  
 
8.1.1 Timing and Methods of Efficacy Assessments 
 


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Overall survival will be assessed by the time from randomization until death or censoring. PFS will 
be assessed as the time from randomization until objective tumor progression or death. 
 
The Schedule of Assessments (Section 1.4) lists the timing of imaging studies.  
 
Subjects that miss a scheduled efficacy assessment, whether a laboratory test, clinic visit procedure 
or CT/MRI, should be contacted by study site personnel with the request that the subject have the 
missed assessment performed. 
 
If clinical progression is suspected, an efficacy assessment (i.e. CT/MRI scan) should be performed 
at that time and results obtained prior to removing a subject from study treatment.   
 
A blinded independent central review (BICR) of the CT/MRI scans will be established, and details 
will be provided in a separate document to describe the imaging requirements and BICR process. 
 
 
Appropriateness of Efficacy Assessments 
 
The measures of efficacy to be used in this study reflect accepted standard of care, i.e., should be 
widely used and generally recognized as reliable, accurate, relevant and able to discriminate 
between effective and ineffective treatment agents. 
 
9 
SAFETY ASSESSMENTS 
 
Laboratory tests, vital sign measurements, physical examinations and subject medical history will 
be performed to detect new abnormalities and any deterioration in pre-existing conditions.  All 
clinically significant abnormalities and deteriorations should be recorded in the eCRFs as AEs and 
graded according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 4.03. 
 
Safety monitoring will be performed by the Sponsor and the CRO, if applicable, on a regular basis. 
 
 
Vital Signs 
 
• Systolic and diastolic blood pressure using an appropriate cuff size  
• Respiration rate 
• Heart rate 
• Body temperature 
Note that any clinically significant abnormalities should be noted in the eCRFs as AEs. 
 
 
Laboratory Tests 
 
Samples will be obtained for the clinical laboratory tests outlined in Table 9.2 and as per Section 1.4 
SCHEDULE OF ASSESSMENTS AND PROCEDURES.  
 


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A central laboratory will be utilized to process and provide results for the clinical laboratory tests.  
The baseline laboratory test results for clinical assessment for a particular test will be defined as the 
last measurement prior to the initial dose of study drug.  
 
However, a local laboratory may be used as well on days of chemotherapy administration to 
determine whether or not to give the chemotherapy.  Central laboratory samples are to be collected 
at the same time as local samples and sent in for testing. 
 
Hematology and Chemistry sampling from Cycle X/Day 1 should follow the chemotherapy 
administration day in case of a chemotherapy dosing delay.  Clinically significant local laboratory 
findings that directly inform a dosing decision will be recorded as an adverse event. 
 
A central laboratory will be utilized to process and provide results of blood sampling for special 
tests (pharmacodynamics [peripheral blood arginine and citrulline levels], immunogenicity 
[anti-ADI-PEG 20 antibodies], and pharmacokinetics [peripheral blood ADI-PEG 20 levels]).     
  
Table 9.2 
Clinical Laboratory Tests 
Hematology (CBC) 
Serum Chemistry  
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count 
White blood cell (WBC) count 
Absolute Neutrophil Count (ANC)  
Lymphocytes (Absolute values) 
Monocytes (Absolute values) 
Basophils (Absolute values) 
Eosinophils (Absolute values) 
Platelet count (estimate not acceptable)  
 
Albumin 
Alkaline phosphatase 
Blood urea nitrogen (BUN) 
Calcium 
Chloride  
Creatinine 
Glucose (nonfasting) 
  HCG (at screening only) 
Potassium 
Serum glutamic-oxaloacetic transaminase 
(SGOT/AST) 
Serum glutamic-pyruvic transaminase 
(SGPT/ALT) 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
 
For any laboratory test value outside the reference range that the investigator considers clinically 
significant: 
• The investigator may repeat the test to verify the out-of-range value. 
• The investigator will follow the out-of-range value to a satisfactory clinical resolution or 
stabilization. 
• A laboratory test value that requires a subject to be discontinued from the study or requires a 
subject to receive treatment will be recorded as an AE. 
 


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Special Blood Sampling 
 
Arginine, citrulline, anti-ADI-PEG 20 antibody, and ADI-PEG 20 levels, as well as future research 
will be obtained at the times (before ADI-PEG 20 injection) noted in Section 1.4. 
 
Special blood sampling should follow calendar days; do not adjust for changes in dosing schedule. 
 
 
ECG 
 
ECG and QTcF collection will also be determined.  If the week 4 or week 12 ECG collection 
timepoint is missed due to dosing being delayed or withheld, the ECG should be collected at the 
next visit. 
 
 
Physical Examination 
 
A comprehensive physical examination, including height and weight, will be performed at the 
screening visit.  Physical examination will be performed on Day 1 of every cycle and at other times 
as clinically indicated.  If weight varies by >10%, the BSA and doses should be recalculated.  Any 
clinically significant findings or absence of findings relative to each subject’s physical examination 
will be carefully documented in the subject’s AE eCRF.  Symptom directed examinations may be 
performed more frequently at the discretion of the investigator.  
 
 
Adverse Events 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship with 
the treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
 
Note: The definition above, provided for in the GCP-ICH Guideline E6, is being extended for the 
purpose of Polaris studies to include any events, intercurrent diseases and accidents observed while 
the subject is on study, i.e., during the actual treatment period, as well as during drug-free, pre and 
post-treatment periods.   
 
Subjects will be monitored throughout the study for AEs and every effort must be made to remain 
alert to possible AEs.  At the signing of the ICF, each subject should be given the names and contact 
information of appropriate study site staff for the reporting of AEs and medical emergencies. 
 
For description of a Serious Adverse Event (SAE), see Section 9.5.7. 
 
9.5.1 Assessment of Adverse Events – Relationship to Study Drug 
 
The relationship of all serious and non-serious adverse events to the investigational agent(s) will be 
determined by the Investigator on the basis of their clinical judgment, using 1 of the following terms 


Polaris Group 
 
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(in accordance with FDA Guidance for Industry and Investigators, “Safety Reporting 
Requirements for INDs and BA/BE Studies” released December 2012): 
 
• 
Definitely related (There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out.) 
• 
Probably related (There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely.) 
• 
Possibly related (There is some evidence to suggest a causal relationship (e.g. because the event 
occurs within a reasonable time after administration of the trial medication).  However, the 
influence of other factors may have contributed to the event (e.g. the patient’s clinical 
condition, other concomitant treatments).) 
• 
Unlikely related (There is little evidence to suggest there is a causal relationship (e.g. the event 
did not occur within a reasonable time after administration of the trial medication).  There is 
another reasonable explanation for the event (e.g. the patient’s clinical condition, other 
concomitant treatment).) 
• 
Unrelated (There is no evidence of any causal relationship) 
 
The Investigator must assess the causality of all serious adverse events/reactions to ADI-PEG 20, or 
to pemetrexed or to cisplatin, or to a combination of any or all three in relation to the trial treatment 
according to the definition given. 
 
Note: Information provided in the Investigator’s Brochure may support these evaluations. 
 
9.5.2 Recording of Adverse Events 
 
Any medical sign or symptom a subject may experience post ICF and before first administration of 
study treatment should be recorded as part of patient medical history. Assessment of progressive 
disease is an endpoint of the study and would not typically be recorded as an AE. 
 
Adverse events are to be recorded on the AE page of the eCRF. Severity of all AEs will be graded 
according to the CTCAE scale (Version 4.03).  Disease progression is to be recorded on specific 
tumor assessment pages rather than the AE page of the eCRF. 
 
Adverse events will be recorded from administration of first dose of study drug until 30 days after 
last study drug administration.  If any toxicity or medical sign or symptom a subject may experience 
post signing of ICF meets the definition of Serious Adverse Event (SAE) per Section 9.5.7 they 
must be reported as an SAE per Section 9.5.8 
 
Action taken with study treatment (study drugs) as a result of the AE will be categorized as dose 
increased, dose not changed, dose reduced, drug interrupted, and drug withdrawn, not applicable, 
and unknown. 
 
Action taken to treat the event will be categorized as none, medication, surgical/diagnostic 
procedure, hospitalization, other, and withdrawal from study. 
 


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Event outcome at resolution or time of last follow-up will be recorded as event resolved, resolved 
with sequelae, resolving, not resolved, fatal, and unknown. 
 
9.5.3 Following Adverse Events 
 
Adverse events related to ADI-PEG 20 that were still ongoing at End-of-Treatment visit should be 
followed up until resolution or stabilization or until all attempts to determine resolution of the event 
are exhausted.  
 
The investigator should use his/her discretion in ordering additional tests as necessary to monitor 
the resolution of such events.  
 
Note: All follow-up information pertaining to SAEs must be forwarded to Polaris designee within 
24 hours of receipt. 
 
9.5.4 Discontinuation due to Adverse Events 
 
Subjects may be withdrawn from the study at any time.  Subjects withdrawn from the study due to 
an AE, whether serious or non-serious, must be followed by the Investigator until the clinical 
outcome from the AE is determined.  Any subject who experiences an AE may be withdrawn at any 
time from the study at the discretion of the Investigator.  The AE(s) should be noted on the 
appropriate eCRFs and the subject’s progress should be followed until the AE is resolved.  The 
Polaris medical monitor must be notified.  If the AE may relate to overdose of study treatment, the 
Investigator Brochure should be consulted for details of any specific actions to be taken. 
 
9.5.5 Pregnancy 
 
Although pregnancy itself is not considered an adverse event or a serious adverse event, pregnancy 
should be reported as “Information” (not as an “Adverse Event” or “Other Problem or Event”). 
 
Pregnancy does not have to be reported if the subject has entered study follow-up period and 
conception occurred 30 days after the final dose of study drug administration.   
 
Pregnancy Notification and Outcome Form will be provided to the investigational site to assist in 
reporting of the pregnancy and follow-up information to Polaris. 
 
A subject that becomes pregnant will be discontinued from the study.   
 
The pregnant subject or the partner of a male subject should be followed until termination or to 
partum to ensure absence of congenital anomaly or birth defect that may have resulted from 
maternal exposure or transmission of the study drug via semen following paternal exposure. 
 
A congenital anomaly or birth defect should be promptly reported as a SAE per Sections 9.5.7 and 
9.5.8. 
 


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Investigators should advise all subjects to use a highly effective method of birth control to protect 
the health and safety of the mother and/or child.  Investigators should report the pregnancy of a 
subject or a subject’s partner to their IRB/IEC per IRB/IEC guidelines.   In addition, Investigators 
should follow IRB/IEC guidelines for consenting pregnant partners of study subjects in order to 
obtain pregnancy follow up information. 
 
9.5.6 Post-treatment Adverse Events 
 
Adverse events that are identified at the last assessment visit (or the early termination visit) must be 
recorded on the AE eCRF with the status of the AE noted. AEs that are related to ADI-PEG 20 
should be followed until resolution or deemed stable by the investigator.  All events that are 
ongoing at this time will be recorded as ongoing on the eCRF. Serious adverse events will follow 
the SAE procedures specified. 
 
9.5.7 Serious Adverse Events 
 
Subjects will be monitored throughout the study for SAEs. 
 
An SAE is any untoward medical occurrence that at any dose: 
1. 
Results in death, 
2. 
Is life-threatening*, 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization**, 
4. 
Results in persistent or significant disability or incapacity, 
5. 
Is a congenital anomaly/birth defect, 
6. 
Is another medically important condition***. 
 
*The term “life-threatening” in the definition of “serious” refers to an event in which the subject is 
at risk of death at the time of the event; it does not refer to an event, which hypothetically might 
have caused death if it were more severe. 
 
**The following are not considered SAEs in this Polaris sponsored clinical study: 
 
• 
A visit to the emergency room or other hospital department < 24 hours that does not result in 
admission (unless considered “important medical event” or event life-threatening). 
• 
Elective surgery, planned prior to signing study consent. 
• 
Medical/surgical hospital admission for purpose other than remedying an ill health state and 
was planned prior to entry into the study.  Appropriate documentation is required in these 
cases. 
• 
Routine health assessment requiring hospital admission for baseline/trending of health status 
(e.g., routine colonoscopy). 
• 
Hospital admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 


Polaris Group 
 
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• 
Hospital admission or other medical occurrences (such as prolonged hospitalization or death) 
for adverse events due to the malignant disease under study (including associated signs and 
symptoms of disease progression). Changes in disease are reported separately. 
• 
Hospital admission for study biopsies. 
 
***Medically important conditions that may not result in death, be immediately life-threatening or 
require hospitalization may be considered as SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require intervention to prevent one of the outcomes listed in 
the definition above.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
 
Note: The term “severe” is often used to describe the intensity (severity) of an event (such as: mild, 
moderate, or severe, e.g., pain).  The event itself may be of relatively minor medical significance 
(such as severe headache).  This is not the same as “serious”, which is based on subject/event 
outcome or action criteria usually associated with events that pose a threat to subject’s life or vital 
functions.  Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an untoward and 
unintended response to a study drug, which is not listed is the applicable product information, and 
meets one of the above listed serious criteria. 
 
9.5.8 Reporting Serious Adverse Events  
 
Any Serious Event that is reported or observed that occurs from the time that the subject has signed 
informed consent form until 30 days after the final dose of study treatment regardless of the severity 
of the event or its relationship to study treatment must be reported to the Polaris designee within 
24 hours of the study site staff becoming aware of the event.  Thereafter, serious events should only 
be reported if the Investigator considers it possibly related or related to study treatment. 
 
A report must be submitted to the Polaris designee regardless of the following: 
• 
whether or not the subject has undergone study-related procedures 
• 
whether or not subject has received study treatment 
• 
the severity of the event 
• 
the relationship of the event to study treatment 
 
A serious pre-treatment event is any event that occurs post ICF and prior to first administration of 
study treatment that meets the criteria for SAE.  A serious pre-treatment event should be recorded as 
medical history and the study site needs to contact Polaris designee within 24 hours of site study 
becoming aware of serious pre-treatment event. 
 
All initial and follow-up information pertaining to SAEs must be forwarded to Polaris designee 
within 24 hours of study site staff becoming aware of serious adverse event.  SAEs will be reported 


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using either paper or electronic forms and the sites will be provided with instructions at the time of 
study initiation. 
 
SAE Reporting guidelines will be provided to the investigational site to assist in collecting, 
organizing, and reporting SAEs and follow-up information. 
 
All SAEs should be followed to their resolution, with all SAE related documentation such as 
doctor’s notes, hospital discharge summary, etc. provided to Polaris designee in a timely manner.  
 
SAEs will be reported to all applicable Regulatory Authorities as noted in 21 CFR 312.32(c). 
 
The Sponsor will also comply with responsibilities and requirements concerning SAE/SUSAR 
reporting established in the European Directive 2001/20/EC. 
 
 
Appropriateness of Safety Assessments 
 
Safety evaluations selected for this study are typical of those for this subject population and utilize 
widely accepted measures. 
 
10 PHARMACODYNAMIC, PHARMACOKINETIC, IMMUNOGENICITY AND OTHER 
ASSESSMENTS 
 
 Pharmacodynamic Parameters 
 
Approximately 10 mL of peripheral blood will be collected as plasma prior to ADI-PEG 20 or 
placebo dosing and used for pharmacodynamics, pharmacokinetics and immunogenicity studies.   
 
Pharmacodynamics will be assessed by measurement of peripheral blood levels of arginine and 
citrulline by LCMS. 
 
 Immunogenicity Parameters 
 
Immunogenicity will be assessed for all patients from the ADIPemCis arm by measurement of 
peripheral blood antibodies to ADI-PEG 20. Blood will also be available for testing for anti-PEG 
antibodies. 
 
 Pharmacokinetics  
 
Pharmacokinetics will also be determined for all patients from the ADIPemCis arm.   
 
 Exploratory Research  
 
Additional translational research, including pharmacogenomics and profiling the inflammatory and 
metabolomic effects of ADI-PEG 20 in combination with pemetrexed and cisplatin is now planned. 
This research will be conducted on existing plasma samples from subjects in the US and UK who 


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have consented to their blood samples being used in future research. Also, research will be 
conducted on archival tissue from subjects at selected sites in the UK who have consented to their 
tissue samples being used in future research. 
 
11 STATISTICAL CONSIDERATIONS 
 
Detailed procedures for statistical analyses to be performed for this study will be provided in a 
separate Statistical Analysis Plan that will be finalized prior to the final database lock. Any changes 
to the protocol-specified or SAP-specified planned analyses that are made after the database lock 
will be described in the clinical study report. 
 
This study will employ an adaptive design with two interim analyses to be conducted at the end of 
the Phase 2 portion and when 50% of planned OS events for phase 3 have occurred.  These two 
interim analyses will be performed by an Independent Analysis Group.  The decision rules and 
analysis strategies that will be applied at the interim and final analyses are described in the SAP.   
   
 Statistics and Sample Size Considerations 
 
The sample size calculation for the efficacy endpoint RR assumed that the objective response rate in 
the PlaceboPemCis arm was 15%.  A total sample size of 176 subjects (88 per arm) in the phase 2 
portion of the study will provide approximately 87% power to detect an improvement in the RR 
from 15% to 35% at the interim analysis. 
 
The sample size calculation for the phase-3 primary endpoint (OS) assumed that the median OS was 
6 months in the PlaceboPemCis arm.  Assuming a median OS of 8.4 months in the ADIPemCis arm 
(corresponding to a HR of 0.714), 338 OS events will provide power of approximately 87% for the 
OS analysis.  Assuming uniform accrual over a 24-month period and a total study duration of 36 
months, the planned total sample size in the study was 386 subjects. The target number of events 
may be increased at the second interim analysis, which will affect the total number of patients.  
 
 Analysis Populations  
 
The following patient populations will be used in the analysis of efficacy and safety data: 
 
The Intent-to-Treat (ITT) population will contain all randomized patients.  All analyses using the 
ITT population will group patients according to the randomized treatment, regardless of the 
treatment received during the course of the study. The ITT population will be used in the analysis of 
the efficacy endpoints. 
 
The Per-Protocol (PP) population will include all ITT subjects who have no major protocol 
violations that may potentially affect the primary and secondary efficacy measures (e.g., no MPM, 
no measurable disease).  Subjects to be excluded from the PP Population will be determined prior to 
database lock and prior to breaking the blind of the treatment group assignments.  The major 
protocol deviation criteria will be specified in the SAP and finalized as part of the blinded data 
review prior to the final database lock.  Assignment of subjects to treatment group is based on the 
randomized treatment assignment. 


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The Safety Analysis (SA) population will contain all patients who received at least one dose of the 
study medication. All analyses using the SA population will group patients according to the 
treatment actually received. All safety analyses will be based on this population.   
 
 Demographics and Baseline Characteristics 
 
The number of patients who have been randomized, have received at least one dose of the study 
medication and have completed the clinical trial according to the protocol will be summarized.  The 
number of patients that discontinue the treatment or the study, as well as the reasons for 
discontinuation, will be summarized.  In addition, summary tables with descriptive statistics will be 
generated for demographics, baseline characteristics and relevant disease characteristics and history 
by the treatment arm in the ITT population. 
 
 Safety Analysis  
 
11.4.1 Adverse Events 
 
Adverse events will be graded using the NCI CTCAE (version 4.03), which provides a mechanism 
for grading the severity of the adverse event.  Treatment Emergent Adverse Events (TEAEs) 
include all adverse events that start on or after the first dose of study medication, or adverse events 
that are present prior to the first dose of study medication, but their severity or relationship increases 
after the first dose of study medication up to and including 30 days after the final study medication 
dosing date. 
 
The number and percent of subjects with any TEAEs will be displayed by system organ class and 
preferred term for each treatment group.  Within each preferred term, subjects will be counted only 
once if they had more than one event reported during the treatment period.  The same summary will 
be performed for all serious TEAEs and all TEAEs causing discontinuation of study drug.  
 
TEAEs will also be summarized by greatest reported severity grade (Grades 1-5) for each event 
preferred term.  Counts indicate subjects reporting one or more TEAEs that map to the severity 
grade classification for each preferred term.  At each level of summarization (system organ class or 
event preferred term) subjects are only counted once.  TEAEs will be summarized by greatest 
reported relationship in a similar manner. 
 
A listing will be produced for all subjects who reported serious TEAEs or who discontinued study 
medication due to TEAEs. 
 
All TEAEs will be listed individually by subject.   
 
Formal toxicity monitoring will occur, as described in Section 9, Safety Assessments. Laboratory 
tests, ECGs, vital sign measurements, physical exams and patient interviews will be performed to 
detect new abnormalities and deteriorations of any pre-existing conditions.  All clinically significant 
abnormalities and deteriorations should be recorded in the Case Report Forms as Adverse Events 
and graded according to the NCI CTCAE v4.03.  All subjects who received at least one dose of 


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ADI-PEG 20 will be evaluated for safety and tolerability.  Appropriate summaries of AEs, and 
laboratory data.  AEs will be listed individually per patient according to CTCAE version 4.03, and 
the number of patients experiencing each AE will be summarized using descriptive statistics.  
 
 Efficacy Analysis 
 
11.5.1 Primary Efficacy Endpoints 
 
The number and percent of patients responding, measured by modified RECIST for MPM and 
RECIST 1.1 criteria, as applicable, will be summarized by treatment group.  The analysis of RR 
will be conducted at the end of the phase 2 portion, after adequate response assessment of the 
first176 subjects enrolled.  The treatment groups will be compared using the Cochran-Mantel-
Haenszel (CMH) test, stratified by tumor histology (biphasic versus sarcomatoid). The significance 
level and coverage probability to be used in the RR analysis will be based on alpha=0.05 (two-
sided). 
  
The primary analysis of OS will be performed at the final analysis.  The treatment effect on OS will 
be evaluated using the stratified log-rank test (stratified by tumor histology). The significance levels 
to be used in the OS analysis at the final analyses will be based on α=0.05 (two-sided). 
 
11.5.2 Key Secondary Efficacy Endpoints 
 
The key secondary objective of the phase 2 portion (DOR) will be analyzed at the end of the phase 
2 portion.  
 
The key secondary endpoint for the phase 3 portion is PFS, which will be analyzed only if the 
analysis of OS is statistically significant at the final analysis, with alpha level of 0.05 (two-sided) 
using the same statistical methodologies as applied to OS.     
 
 Multiplicity Adjustment 
 
Details are described in the SAP.  
 
 Interim Analysis 
 
This study will include two separate interim analyses:  
• The first interim analysis will be conducted at the end of the phase 2 portion, after adequate 
response assessment of the first 176 subjects enrolled.  This interim analysis will evaluate 
the treatment effect on RR in the ITT population.  
• The second interim analysis will be performed once 50% of the planned OS events for phase 
3 have occurred (ie, 169 of the 338 planned OS events). This interim analysis will evaluate 
OS in the ITT population in an unblinded manner.  
 
The RR data will be analyzed at the end of phase 2 portion to support accelerated approval.  The OS 
data at the second interim analysis will be analyzed to support the following decisions: 
• Futility stopping: Terminate the study due to futility at the interim analysis. 


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• Sample size re-estimation: Increase the target number of OS events after the second interim 
analysis. 
 
The decision-making rules associated with these decisions are described in the SAP. 
 
A DSMB will be instituted for this study to ensure the safety of the subjects. Recommendations for 
continuation of the study will be guided by safety evaluations at safety data reviews. The committee 
will include two independent oncologists with experience in thoracic oncology and an independent 
statistician. Safety meetings will be held as per the DSMB charter, approximately every 6 months 
and more often if deemed necessary. Decisions on study termination, amendment, or cessation of 
subject recruitment, based on safety or outcome findings, will be made after recommendations from 
the DSMB have been assessed by Polaris. The DSMB will not be expected to conduct the efficacy 
analyses at the interim or final analyses. 
 
In addition to the explicit adjustment of the target number of OS events based on an unblinded 
interim analysis described above, the number of enrolled patients may be adjusted in a blinded 
manner to achieve the desired number of OS events.  This will be accomplished using standard 
event forecasting methods (see, for example, Anisimov 2011). 
 
 Pharmacodynamics 
 
Blood levels of arginine and citrulline will be summarized descriptively for each group and for all 
subjects by time point for the observed value.  
 
 Immunogenicity 
 
Blood levels of antibodies to ADI-PEG 20 will be summarized descriptively for each treatment 
group and for all subjects by time point for the observed value as well as for the change from 
baseline value.  
 
  Pharmacokinetics 
 
Pharmacokinetics will also be summarized descriptively for each group and for all subjects by time 
by time point for the observed value.  
 
12 ETHICS 
 
 Institutional Review Board / Independent Ethics Committee 
 
The investigator will ensure that the protocol and consent form are reviewed and approved by the 
appropriate Institutional Review Board/Independent Ethics Committee (IRB/IEC) prior to the start 
of any study procedures.  The IRB/IEC will be appropriately constituted and will perform its 
functions in accordance with Food and Drug Administration (FDA) regulations, International 
Conference on Harmonisation (ICH) good clinical practice (GCP) guidelines, and applicable local 
regulatory requirements as applicable. 
 


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In addition, the IRB/IEC will approve all protocol amendments (except for logistical or 
administrative changes), written informed consent documents and document updates, subject 
recruitment procedures, written information to be provided to the subjects, available safety 
information, information about payment and compensation available to subjects, the investigator’s 
curriculum vitae and/or other evidence of qualifications, and any other documents requested by the 
IRB/IEC and regulatory authority as applicable. 
 
 Ethical Conduct of the Study 
 
This study will be conducted in accordance with the Declaration of Helsinki and GCP according to 
ICH guidelines. Specifically, this study is based on adequately performed laboratory and animal 
experimentation; the study will be conducted under a protocol reviewed by an IRB or IEC; the 
study will be conducted by scientifically and medically qualified persons; the benefits of the study 
are in proportion to the risks; the rights and welfare of the subjects will be respected; the physicians 
conducting the study do not find the hazards to outweigh the potential benefits; and each subject 
will give his or her written, informed consent before any protocol-driven tests or evaluations are 
performed. 
 
 Informed Consent 
 
The nature and purpose of the study will be fully explained to each subject.  Written informed 
consent must be obtained from each subject prior to any study procedures being performed.  The 
consent documents to be used for the study will include all the required elements of informed 
consent per regulatory requirements and will be reviewed and approved by the appropriate IRB/IEC 
before use. 
 
 Changes to Protocol 
 
Only Polaris may modify the protocol.  Amendments to the protocol will be made only after 
consultation and agreement between Polaris and the investigator.  The only exception is when the 
investigator assesses a subject’s safety will be compromised without immediate action.  In these 
circumstances, immediate approval of the chairman of the IRB/IEC must be sought, and the 
investigator should inform Polaris and the full IRB/IEC within 5 working days after the emergency 
occurred.  All amendments that have a significant impact on subject risk or the study objectives, or 
require revision of the informed consent forms, must receive approval from the IRB/IEC prior to 
their implementation. 
 
13 STUDY MONITORING 
 
 Data Reporting and Electronic Case Report Forms 
 
The investigator will permit the site monitor to review study data as frequently as is deemed 
necessary to ensure data is being recorded in an adequate manner and protocol adherence is 
satisfactory. The investigator will access medical records for the monitor to verify eCRF entries. 
The investigator, as part of his or her responsibilities, is expected to cooperate with the 
Sponsor/designee in ensuring the study adheres to GCP requirements. The investigator may not 


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recruit subjects into the study until an initial visit, or, with the agreement of Sponsor, attendance at a 
site initiation visit has been made by the Sponsor/designee to conduct a detailed review of the 
protocol and eCRFs.   
 
13.1.1 Pre-Study Requirements 
 
The following is required before study drug can be shipped to the study site: 
• Signed Statement of Investigator 
• Regulatory Approval (e.g., active IND or IMPD) 
• Ethics Committee approval of Protocol and Informed Consent Forms 
• Executed Clinical Trial Agreement (if applicable) 
 
13.1.2 Study Master Files 
 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(“Study Master File”) of all study-related documentation that is suitable for inspection by Polaris 
and regulatory authorities.  Upon completion of the study, the Investigator is required to submit a 
summary report to Sponsor at the discretion of the Sponsor. 
 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by Sponsor.  No part of the Study Master File shall be destroyed or relocated without 
prior written agreement between Sponsor and the Investigator. 
 
13.1.3 Study Records 
 
The study documents must be maintained as specified in the ICH guidelines for GCP and as 
required by the applicable regulatory requirements.  The investigator/institution should take 
measures to prevent accidental or premature destruction of these documents. 
 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with 
Sponsor.  It is the responsibility of Sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
 
13.1.4 Electronic Case Report Forms (eCRFs) 
 
An electronic data capture system will be used for this trial. Instructional materials will be provided 
to the sites as appropriate. The investigator and site staff will ensure all data from subject visits are 
promptly entered into the electronic Case Report Forms (eCRFs) in accordance with study specific 
eCRF completion guidelines. The investigator must approve the eCRFs within the electronic system 
to verify the integrity of the data recorded.  
 


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A list of the normal ranges for all laboratory tests to be undertaken forms part of the documentation 
to be collated prior to trial start. If a central laboratory has been selected to conduct any or all tests, 
it is essential all samples be analyzed at that laboratory. The investigator must maintain source 
documents such as laboratory reports and complete history and physical examination reports.  
 
 Access to Source Data/Documents 
 
The investigator will provide direct access to source data and documents to individuals conducting 
study-related monitoring, audits, IRB/IEC review, and regulatory review.  The investigator must 
inform the study subject that his/her study-related records may be reviewed by the above 
individuals without violating the subject’s privacy of personal health information. 
 
 Confidentiality 
 
Attention is drawn to the regulations promulgated by the FDA under the Freedom of Information 
Act providing, in part, that information furnished to clinical investigators and IRBs/IECs will be 
kept confidential by the FDA only if maintained in confidence by the clinical investigator and 
IRB/IEC.  By signing this protocol, the investigator affirms to Sponsor that the investigator will 
maintain, in confidence, information furnished to him by Sponsor and will divulge such information 
to the IRB/IEC under an appropriate understanding of confidentiality with such board. 
 
 Retention of Data 
 
All records and documents pertaining to the study will be maintained by the investigator for a 
period of: (a) 2 years after approval of the drug; (b) 5 years after non-approval of the NDA or 
ANDA; or (c) 2 years after withdrawal of the IND under which this study was conducted.  In order 
to avoid any possible errors, the investigator will contact Sponsor prior to the destruction of any 
study records.  The investigator will promptly notify Sponsor in the event of accidental loss or 
destruction of any study records. 
 
 Quality Control and Quality Assurance 
 
Sponsor/designee will implement and maintain quality control and quality assurance procedures 
with written standard operating procedures to ensure the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirements.  This study will be conducted in accordance with the provisions of the Declaration of 
Helsinki and all revisions thereof (Tokyo 2004), and in accordance with the FDA Code of Federal 
Regulations (CFR §312.50 and §312.56) and the ICH (E6) Guidelines on GCP 
(CPMP/ICH/135/95and the provisions of the EU Clinical Trial Directives 2001/20/EC and 
2002/20/EC.  
 
14 ADMINISTRATIVE INFORMATION 
 
 Financing and Insurance 
 
These issues will be addressed in a separate agreement between Sponsor and the investigator. 


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 Publication Policy 
 
Sponsor will retain ownership of all data.  All proposed publications based on this study will be 
subject to Polaris’s approval requirements. 
 
Any and all data and results and intellectual property rights in the data and results derived from this 
study are the property of Sponsor.  Sponsor may utilize the data in a variety of ways, including but 
not limited to submission to government regulatory agencies/authorities or disclosure to other 
investigators.  An investigator in this study, while free to utilize data derived from the study for 
scientific purposes, must discuss any publication with Sponsor prior to release and obtain written 
consent of Sponsor on and for the intended publication.  Sponsor recognizes the right of the 
investigators to publish the results upon the completion of the study.  However, the investigator(s) 
must send a draft manuscript of the intended publication or abstract to Sponsor thirty (30) days in 
advance of submission in order to obtain the approval of Sponsor prior to submission of the final 
version for intended publication.  This draft will be reviewed promptly and approval will not be 
withheld unreasonably.  In case of a difference of opinion between Sponsor and the investigator(s), 
the contents of the draft will be discussed in order to find a solution which satisfies both parties. 
 
 Protocol Amendments 
 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
IRB/IEC and, if required, the regulatory authorities.  Amendments that are intended to eliminate an 
apparent immediate hazard to subjects may be implemented prior to such approvals.  However, in 
this case, approval must be obtained as soon as possible after implementation.  Implementation of 
administrative amendments that do not affect the safety of the subjects do usually not require prior 
IRB/IEC approval, just notification, unless otherwise required by local ethics committees.  
 
 Premature Trial Termination 
 
Sponsor and Investigator have the right to prematurely terminate the study.  In such case, one party 
must notify the other in advance in writing about the intent of and the reasons for the termination.  
The investigator must also notify the appropriate IRB/IEC accordingly. 
 
 Language 
 
The protocol is written in English.  All correspondence between the study site and Sponsor should 
be maintained in English.  Case Report Forms must be completed in English.  All written material 
to be used by subjects and para-clinical staff must use vocabulary that is clearly understood, and be 
in the language appropriate for the study site. 
 


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16 APPENDIX A: MODIFIED RECIST CRITERIA FOR MALIGNANT PLEURAL 
MESOTHELIOMA 
 
Tumour thickness perpendicular to the chest wall or mediastinum was measured in two positions at 
three separate levels on transverse cuts of CT scan. The sum of the six measurements defined a 
pleural unidimensional measure. Transverse cuts at least 1 cm apart and related to anatomical 
landmarks in the thorax were chosen to allow reproducible assessment at later time points. If 
measureable tumour was present, transverse cuts in the upper thorax, above the level of division of 
the main bronchi were preferred. At reassessment, pleural thickness was measured at the same 
position at the same level and by the same observer. This was not necessarily the greatest tumour 
thickness at that level. Nodal, subcutaneous and other bidimensionally measurable lesions were 
measured unidimensionally as per the RECIST criteria. Unidimensional measurements were added 
to obtain the total tumour measurement. 
 
Response Criteria Definition 
CR 
disappearance of all target lesions with no evidence of tumour 
elsewhere 
PR 
at least a 30% reduction from baseline in the total tumour 
measurement 
PD 
an increase of at least 20% in the total tumour measurement over 
the nadir measurement, or the appearance of one or more new 
lesions 
SD 
those who fulfilled the criteria for neither PR nor PD 
 
A confirmed response required a repeat observation on two occasions 4 weeks apart.  
Byrne MJ, Nowak AK. 2004. Modified RECIST criteria for assessment of response in malignant 
pleural mesothelioma.  Ann Oncol15:257–260. 
 
A practical guide to modified RECIST for MPM also has been published: Tsao AS, Garland L, 
Redman M, Kernstine K, Gandara D, Marom EM. 2011. A practical guide of the Southwest 
Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and modified 
RECIST criteria. J Thorac Oncol 6:598-601. 
 
 


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Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
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17 APPENDIX B: RECIST 1.1 CRITERIA 
 
Category 
RECIST 1.1 
Minimum size 
measurable lesions 
• CT 10 mm; delete reference to spiral scan 
• Clinical:  
 10 mm (must be measurable with calipers) 
Lymph Node 
• CT: 
      >15 mm short axis for target 
      >10–<15 mm for non-target 
      <10 mm is non-pathological 
Special 
considerations on 
lesion measurability 
Notes included on bone lesions, cystic lesions 
Overall tumor 
burden 
5 lesions (2 per organ) 
Response criteria 
target disease 
• CR lymph nodes must be <10 mm short axis 
• PR at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters 
• PD 20% increase over smallest sum on study (including 
baseline if that is smallest) and at least 5 mm increase or 
new lesions 
Response criteria 
non-target disease 
 
More detailed description of ‘unequivocal progression’ to 
indicate that it should not normally trump target disease status. 
It must be representative of overall disease status change, not a 
single lesion increase 
New lesions 
New section on New lesions 
Overall response 
• Two tables: one integrating target and non-target and the 
other of non-target only 
• Special notes: 
-How to assess and measure lymph nodes 
-CR in face of residual tissue 
-Discussion of ‘equivocal’ progression 
Confirmatory 
measure 
Retain this requirement ONLY for non-randomized trials with 
primary endpoint of response 
Progression-free 
survival 
-More specific comments on use of PFS (or proportion 
progression-free) as phase II endpoint 
-Greater detail on PFS assessment in phase III trials 
Reporting of 
response results 
-Divided into phase II and phase III 
-9 categories collapsed into 5 
-In phase III, guidance given about reporting response 
Response in phase 
III trials 
This section removed and referenced in section above: no need 
to have different criteria for phase II and III  


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Imaging appendix 
- Appendix II: updated with detailed guidance on use of MRI, 
PET/CT (Note that for this study, non-CT/MRI scanning are not 
required and but may be completed as standard of care) 
- Other practical guidance included  
New appendices 
- Appendix I: comparison of RECIST 1.0 and 1.1 
- Appendix III: frequently asked questions 
Appendix I. Summary of major changes RECIST 1.0 to RECIST 1.1 in E.A. Eisenhauer, P. 
Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. 
Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). EUROPEAN 
JOURNAL OF CANCER 45 (2009) 228-247. 
 
Response Evaluation Criteria in Solid Tumors - Quick Reference 
 
Eligibility 
 
Only patients with measurable disease at baseline should be included in protocols where objective 
tumor response is the primary endpoint.  
 
Measurable disease is defined by the presence of at least one measurable lesion. 
 
In studies where the primary endpoint is tumor progression (either time to progression or proportion 
with progression at a fixed date), the protocol must specify if entry is restricted to those with 
measurable disease or whether patients having non-measurable disease only are eligible. 
 
Measurement of Tumors at Baseline: Measurable vs. Non-Measurable Lesions 
 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
 
Measurable 
 
 
Tumor lesions: measure at least longest diameter with a minimum size of: 
 
 
10 mm using CT scan (CT scan thickness no greater than 5 mm), or 
 
 
10 mm caliper measurements on clinical exam (lesions which cannot be 
  
 
 
accurately measured with calipers should be recorded as non-measurable, or 
 
 
 
20 mm by chest x-ray 
 
Malignant lymph nodes: measure at short axis with a minimum size of ≥ 15 mm 
 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <10 mm) or 
pathological lymph nodes with ≥ 10 to ≤ 15 mm (short axis).  Lesions considered truly non-
measureable: leptomeningeal disease, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and also abdominal masses/organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques 


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Special considerations 
 
Bone lesions 
 
Bone scan, PET scan or plain films are not considered adequate imaging techniques, however, these 
lesions can be used to confirm the presence or disappearance of bone lesions 
 
Cystic lesions 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered as 
malignant lesions  
 
“Cystic lesions” thought to represent cystic metastases can be considered as measurable lesions, if 
they met the definition of measurability described above 
 
Lesions with prior local treatment 
 
Lesions in a previously irradiated area or in an area subject to other loco-regional therapy are 
usually not considered measurable unless there has been demonstrated progression in the area 
 
Measurement of Lesions 
• All measurements should be taken and recorded in metric notation, using 
calipers if clinically assessed. 
• All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
• The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up.   
 
Methods of Measurement 
 
Clinical lesions - will only be considered measurable when they are superficial and ≥ 10 mm 
diameter as assessed using calipers (e.g., skin nodules and palpable lymph nodes).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
  
CT and MRI – CT is the best currently available and reproducible methods to measure target lesions 
selected for response assessment. CT should be performed with cuts of 5 mm or less in slice 
thickness contiguously.  When CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations.  
 
Chest x-ray – chest CT is preferred over chest x-ray. However, lesions on chest x-ray may be 
considered measurable if they are clearly defined and surrounded by aerated lung. 


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Ultrasound – is not useful in assessment of lesion size and should not be used as a method of 
measurement. 
 
Endoscopy, laparoscopy – utilization of these techniques for objective tumor evaluation is not 
advised.  However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
 
Tumor markers – alone cannot be used to assess objective tumor response. If markers are initially 
above the upper limit of normal, however, they must normalize for a patient to be considered in 
complete response.  
 
Cytology, histology – can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumor types such as germ cell tumors where know 
residual benign disease can remain).  When effusions are known to be potential adverse effect of 
treatment (e.g., with certain taxanes or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or stable disease in order to differentiate between 
response or stable disease and progressive disease. 
 
Baseline Documentation of “Target” and “Non-Target” Lesions 
 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in instances 
where patients have only one or two organ sites involved, a maximum of two and four lesions 
respectively will be recorded).  
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and lend themselves to reproducible repeated measurements. 
 
Lymph nodes are normal anatomic structures which may be visible by imaging even if not involved 
by tumor.  As noted above, pathological nodes are defined as measurable and may be identified as 
target lesions if the short axis is ≥ 15 mm. 
 
A sum of the diameters (longest diameter [LD] for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters.  The baseline 
sum diameters will be used as reference by which to characterize any objective tumor regression. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-up.  


Polaris Group 
 
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Response Criteria 
 
Evaluation of target lesions: 
Complete Response 
(CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
< 10 mm. 
Partial Response 
(PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease 
(PD): 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. The appearance 
of one or more new lesions is also considered progression.  
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters on study. 
 
Special notes on assessment of target lesions: 
• Lymph nodes 
• The short axis should be measured. Thus, the “sum” of lesions may not be zero even if CR 
response criteria are met, since a normal lymph node is defined as having a short axis < 10 
mm. 
• Target lesions that have become “too small to measure” 
• A number should be recorded.  If, in the opinion of the radiologist, that the lesion has 
disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned (5 mm is derived from the 5 mm CT slice thickness). 
• Lesions that split or coalesce 
• The longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  If the lesions have truly coalesced, the vector of the longest diameter 
should be the maximal longest diameter for the “coalesced lesion.” 
 
Evaluation of non-target lesions: 
Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological 
in size (< 10 mm short axis). 
Incomplete Response/ 
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits. 
Progressive Disease 
(PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
 
 


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• When the patient also has measurable disease, to achieve “unequivocal progression” on the 
basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression. 
• When the patient has only non-measureable disease, the same general concepts apply. 
 
New Lesions 
 
The appearance of new malignant lesions denotes progression.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging modality 
or findings thought to represent something other than tumor (for example, some “new” bone lesions 
may be simply healing or flare of pre-existing lesions). 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. 
 
It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible “new” disease).  FDG-PET scanning is 
not specifically required by the protocol but may be considered as part of standard of care.  New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive (“positive” FDG-PET scan lesion means one 
which is FDG avid with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image) FDG-PET at follow-up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow up: 
i) 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
ii) 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET). 
iii) 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 
 
Evaluation of Best Overall Response 
 
• The best overall response is the best response recorded from the start of the treatment until 
the end of treatment taking into account any requirement for confirmation.  
• When no imaging/measurement is done at a particular time point, the patient is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, 
usually the case is considered NE at that time point, unless a convincing argument can be 
made that the contribution of the missing lesion(s) would not change the assigned time point 
response. 


Polaris Group 
 
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Date: 21 September 2021 - Version 6 
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Target 
lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PR 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”.  Every effort should be made to document the objective progression even after 
discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
FDG-PET may be used to upgrade a lesion to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. 
 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected. 
 
Confirmation 
 
In non-randomized studies where response is the primary end-point, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. In randomized trials 
(phase II or III) or studies where stable disease or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of trial 
results.  
 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to the 
type and schedule of treatment. However, in the context of phase II studies where the beneficial 
therapy is not known, follow-up every 6-8 weeks (timed to coincide with the end of a cycle) is 


Polaris Group 
 
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Date: 21 September 2021 - Version 6 
CONFIDENTIAL 
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reasonable. Smaller or greater time intervals than these could be justified in specific regimens or 
circumstances. 
 
At the end of treatment, the need for repetitive tumor evaluations depends on whether the trial has a 
goal the response rate or the time to an event (progression/death).  If “time to an event” (e.g., time 
to progression, disease-free survival, progression-free survival) is the main endpoint, then routine 
scheduled re-evaluation of protocol specified sites of disease is warranted. 
 
Duration of Overall Response 
 
The duration of overall response is measured from the time measurement criteria are met for CR or 
PR (whichever status is recorded) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded on study. 
 
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease 
 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for disease progression are met, taking as reference the smallest 
sum on study measurements recorded since the treatment started. 
 
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of patients achieving SD for a minimum period of time is an endpoint of importance in a 
particular trial, the protocol should specify the minimal time interval requited between two 
measurements for determination of SD.  
 
Progression-Free Survival/Proportion Progression-Free 
 
Phase II trials 
 
• In some circumstances, “response rate” may not be the optimal method to assess the potential 
anticancer activity of new agents/regimens.  In such cases “progression-free survival” (PFS) or 
the “proportion progression-free” at landmark time points, might be considered appropriate 
alternatives to provide an initial signal of biologic effect of new agents.  It is clear, however, 
that in an uncontrolled trial, these measures are subject to criticism since an apparently 
promising observation may be related to biological factors such as patient selection and not the 
impact of the intervention.  Thus, phase II screening trials utilizing these endpoints are best 
designed with randomized control.  
 
Phase III trials 
 
• Assessment of progression is relatively straightforward if the protocol requires all patients to 
have measurable disease.  However, restricting entry to this subset of patients is subject to 


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criticism: it may result in a trial where the results are less likely to be generalizable if, in the 
disease under study, a substantial proportion of patients would be excluded. 
 
Response Review 
 
For trials were objective response (CR + PR) is the primary endpoint, and in particular where key 
drug development decisions are based on the observation of a minimum number of responders, it is 
recommended that all claimed responses be reviewed by an expert(s) independent of the study.  If 
the study is a randomized trial, ideally reviewers should be blinded to treatment assignment. 
Simultaneous review of the patients’ files and radiographical images is the best approach. 
 
Reporting of Results 
 
Phase II Trials 
 
• When response is the primary endpoint, and thus all patients must have measurable disease to 
enter the trial, all patients included in the study must be accounted for in the report of the 
results, even if there are major protocol treatment deviations or they are not evaluable.  Each 
patient will be assigned one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) unevaluable for response: specify reasons 
(for example: early death, malignant disease; early death, toxicity; tumor assessments not 
repeated/incomplete; other [specify]).  Normally, all eligible patients should be included in the 
denominator for the calculation of the response rate for phase ii trials (in some protocols it will 
be appropriate to include all treated patients).  It is generally preferred that 95% two-sided 
confidence limits are given for the calculated response rate.  
• Trial conclusions should be based on the response rate for all eligible (or all treated) patients 
and should not be based on a selected “evaluable” subset.  
 
Phase III trials 
• Response evaluation in phase III trials may be an indicator of the relative anti-tumor activity 
of the treatments evaluated and is almost always a secondary endpoint.  Observed 
differences in response rate may not predict the clinically relevant therapeutic benefit for the 
population studied.  
 
 


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Date: 21 September 2021 - Version 6 
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18 APPENDIX C: PERFORMANCE STATUS PERFORMANCE SCALES (KARNOFSKY, 
ECOG-WHO-ZUBROD) 
 
These scales are used by practicing oncologists and researchers to assess how a patient's disease is 
progressing, to assess how the disease affects the daily life, and to determine appropriate treatment 
and prognosis. 
Status 
Karnofsky Grade ECOG 
Normal, no complaints 
100 
0 
Fully active, able to carry on 
all pre-disease performance 
without restriction 
Able to carry on normal activities. 
Minor signs or symptoms of disease 
90 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or 
sedentary nature, e.g., light 
housework, office work 
Normal activity with effort 
80 
Care for self. Unable to carry on 
normal activity or to do active work 
70 
2 
Ambulatory and capable of all 
selfcare but unable to carry 
out any work activities. Up 
and about more than 50% of 
waking hours 
Requires occasional assistance, but 
able to care for most of his needs 
60 
Requires considerable assistance and 
frequent medical care 
50 
3 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours 
Disabled. Requires special care and 
assistance 
40 
Severely disabled. Hospitalization 
indicated though death nonimminent 
30 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair 
Very sick. Hospitalization necessary. 
Active supportive treatment necessary 
20 
Moribund 
10 
Dead 
0 
5 
Dead 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair.  


Polaris Group 
Statistical Analysis Plan
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Version 4.0; 4 January 2022
 
 
Confidential 
 
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STATISTICAL ANALYSIS PLAN 
Polaris Group 
POLARIS2015-003 
 
 
 
 
Protocol Title: 
Randomized, Double-Blind, Phase 2/3 Study in Subjects with 
Malignant Pleural Mesothelioma to Assess ADI-PEG 20 with 
Pemetrexed and Cisplatin (ATOMIC-Meso Phase 2/3 Study) 
Protocol Version 
and Date: 
Version 6; 21 September 2021 
 
Sponsor: 
Polaris Group 
10675 Sorrento Valley Road, Suite 200 
San Diego, CA 92121 USA 
Prepared By: 
Brian Beus 
Precision for Medicine 
6005 Hidden Valley Road, Suite 170 
Carlsbad, CA 92011 
Document Version 
and Date: 
Version 4.0; 4 January 2022 
 


Polaris Group 
Statistical Analysis Plan
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Version 4.0; 4 January 2022
 
 
Confidential 
 
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1 STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
Polaris Group 
Clinical Protocol Number: POLARIS2015-003 
Protocol Title: 
Randomized, Double-Blind, Phase 2/3 Study in Subjects 
with Malignant Pleural Mesothelioma to Assess ADI-PEG 
20 with Pemetrexed and Cisplatin (ATOMIC-Meso Phase 
2/3 Study) 
Document File Name: 
Polaris_POLARIS2015-003_SAP_V4.0_04JAN2022.pdf 
Document Version and 
Effective Date: 
Version 4.0; 4 January 2022 
Approved By: 
 
 
 
  
John S. Bomalaski, M.D. 
Exec. VP, Medical Affairs 
Polaris Pharmaceuticals, Inc. 
 Date 
 
  
 
  
Amanda Johnston, Ph.D. 
SVP, Clinical Affairs 
Polaris Pharmaceuticals, Inc. 
 Date 
 
  
 
  
Brian Beus 
Principal Statistician 
Precision for Medicine 
 Date 
 
  
 
  
Kun He 
Consultant, Statistics 
 Date 
05-Jan-2022
05-Jan-2022
05-Jan-2022
05-Jan-2022


Polaris Group 
Statistical Analysis Plan
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2 TABLE OF CONTENTS 
1 
Statistical Analysis Plan Approval ............................................................................2 
2 
Table of Contents ........................................................................................................3 
3 
List of Abbreviations ..................................................................................................6 
4 
Introduction .................................................................................................................8 
5 
Study Objectives .........................................................................................................9 
5.1 
Primary Study Objective .......................................................................................9 
5.2 
Secondary Study Objectives..................................................................................9 
6 
Investigational Plan ..................................................................................................10 
6.1 
Overall Study Design ...........................................................................................10 
6.2 
Schedule of Assessments ......................................................................................11 
6.3 
Treatments ............................................................................................................11 
6.3.1 
Treatments Administered .............................................................................11 
6.3.2 
Method of Assigning Subjects to Treatment Groups .................................12 
6.4 
Efficacy and Safety Variables .............................................................................12 
6.4.1 
Efficacy Variables ..........................................................................................12 
6.4.2 
Description of Safety Variables ....................................................................14 
6.4.3 
Description of Pharmacodynamic, Immunogenicity, and 
Pharmacokinetic Variables ...........................................................................16 
6.5 
Data Quality Assurance .......................................................................................16 
7 
Statistical Methods ....................................................................................................17 
7.1 
General Methodology ..........................................................................................17 
7.1.1 
Reporting Conventions ..................................................................................17 
7.1.2 
Summarization by Visit .................................................................................18 
7.1.3 
Standard Calculations ...................................................................................18 
7.2 
Analysis Populations ............................................................................................18 
7.3 
Study Subjects ......................................................................................................19 
7.3.1 
Disposition of Subjects ...................................................................................19 
7.3.2 
Protocol Deviations ........................................................................................19 
7.4 
Efficacy..................................................................................................................20 
7.4.1 
Datasets Analyzed ..........................................................................................20 
7.4.2 
Demographic and Other Baseline Characteristics......................................20 
7.4.3 
Primary Efficacy Endpoint Analysis Methods ............................................20 
7.4.4 
Secondary Efficacy Endpoint Analysis Methods ........................................21 
7.4.5 
Statistical/Analytical Issues ...........................................................................22 
7.4.6 
Pharmacodynamics ........................................................................................24 
7.4.7 
Immunogenicity..............................................................................................24 
7.4.8 
Pharmacokinetics ...........................................................................................24 
7.5 
Safety Analysis .....................................................................................................25 
7.5.1 
Extent of Exposure and Treatment Compliance.........................................25 
7.5.2 
Adverse Events ...............................................................................................25 
7.5.3 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...............................................................................................26 
7.5.4 
Clinical Laboratory Evaluation ....................................................................27 


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7.5.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety ...............................................................................................................27 
7.6 
Determination of Sample Size .............................................................................28 
7.7 
Changes in the Conduct of the Study or Planned Analyses .............................29 
8 
Reference List ............................................................................................................29 
Appendix A: List of Tables, Figures and Data Listings ...............................................31 
 
 
 


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TABLE OF TABLES 
Table 1 
List of Abbreviations .................................................................................6 
Table 2 
Clinical Laboratory Tests........................................................................15 
 
 
 


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3 LIST OF ABBREVIATIONS  
Table 1 
List of Abbreviations  
Abbreviation 
Definition  
ADI 
Arginine deiminase 
ADIPemPlatinum 
Combination therapy of ADI-PEG 20, pemetrexed and cisplatin 
(or carboplatin) 
AE 
Adverse event 
ALT 
Alanine transaminase (also known as SGPT) 
ANC 
Absolute neutrophil count 
ASS1 
Argininosuccinate synthetase (also known as ASS) 
AST 
Aspartate transaminase (also known as SGOT) 
BICR 
Blinded independent central review 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CP 
Conditional power 
CR 
Complete response 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DCR 
Disease Control Rate 
DOR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End-of-treatment 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IM 
Intramuscular 
ITT 
Intent- to-treat 
IWRS 
Interactive Web Response System 
LCMS 
Liquid chromatography mass spectrometry 


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Abbreviation 
Definition  
MedDRA 
Medical Dictionary for Regulatory Activities 
MPM 
Malignant pleural mesothelioma  
MRI 
Magnetic Resonance Imaging 
NE 
Not evaluable 
OS 
Overall survival 
PD 
Progressive disease 
PEG 
Polyethylene glycol 
PFS 
Progression free survival 
PlaceboPemPlatinum Combination therapy of placebo, pemetrexed and cisplatin (or 
carboplatin) 
PP 
Per-Protocol 
PR 
Partial response 
QTcF 
Corrected QT interval using Fridericia’s correction  
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation or stable disease depending on context 
SE 
Standard error 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SI 
Système International 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood cell count 
WHO 
World Health Organization 
 


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4 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide comprehensive and 
detailed descriptions of the methods and presentation of data analyses proposed for 
Polaris Group, Protocol POLARIS2015-003 (Randomized, Double-Blind, Phase 2/3 
Study in Subjects with Malignant Pleural Mesothelioma to Assess ADI-PEG 20 with 
Pemetrexed and Cisplatin (ATOMIC-Meso Phase 2/3 Study)). Descriptions of planned 
analyses are provided in order to avoid post hoc decisions that may affect the 
interpretation of the statistical analysis. The statistical methods applied in the design and 
planned analyses of this study are consistent with the International Conference on 
Harmonization (ICH) guideline Statistical Principals for Clinical Trials (E9) (1998).  
This SAP will be finalized prior to data analysis and before treatment unblinding and 
database lock at the interim analysis to provide full details, including templates for tables, 
listings, and figures, to be presented in the clinical study report (CSR). Any changes 
between the statistical methods provided in the clinical study protocol and this SAP will 
be explained herein; any changes or deviations from this SAP relative to the final analysis 
will be fully documented in the CSR. Minor changes or deviations from the templates for 
tables, figures, and listings need not be documented in the CSR. 
Notable changes from version 1.0 to version 2.0 of this SAP correspond to similar 
changes from version 4 to version 5 of the protocol and include: 
•
Removal of secondary endpoints of objective response rate and duration of
response in phase 3. Both endpoints will remain as endpoints for phase 2.
•
Removal of disease control rate as a secondary endpoint in phase 3.
•
The timing of the interim analysis to assess futility and potential sample size
increase was modified from occurring at the end phase 2 to be performed at a
separate time from the end of phase 2 analysis when 50% of planned overall
survival events have occurred in order to obtain more reliable sample size
estimates for phase 3.
•
Removal of the subject population selection rule at the interim analysis. Interim
analysis methods and options were updated and simplified accordingly.
•
The cap for percent increase in sample size at the interim analysis was modified
from 50% to 30%.
•
Methods for addressing multiplicity were modified based on the removal of
secondary endpoints and the removal of the subject population selection rule at
the interim analysis.
Changes from version 2.0 to version 4.0 of this SAP are based on DSMB 
recommendations and other minor clarifications as follows: 


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• The original planned sample size will be changed from 386 subjects to all 
enrolled up to August 15, 2021 (249 subjects); and the deaths for the original 
planned final analysis of OS will be changed from 338 to the actual number of 
deaths occurred on August 14, 2022. Also, an administrative penalty of 
α=0.00001 will be paid for second interim analysis, and the allocated α=0.04999 
will be used for the final analysis. 
5 STUDY OBJECTIVES 
5.1 
Primary Study Objective 
The primary objective of this study is: 
• Determine efficacy as determined by the objective response rate (RR), measured 
by modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for 
local pleural disease and RECIST 1.1 criteria for metastatic lesions (phase 2 
portion) and overall survival (OS) (phase 3 portion) 
5.2 
Secondary Study Objectives 
The secondary objective of the phase 2 portion is: 
• Determine the duration of response (DOR) 
The secondary objective of the phase 3 portion is: 
• Assess progression free survival (PFS) 
Other objectives of this study are:  
• Assess safety and tolerability of ADI-PEG 20 in combination with pemetrexed 
and cisplatin   
• Determine the pharmacodynamics of ADI-PEG 20 in combination with 
pemetrexed and cisplatin  
• Determine the immunogenicity of ADI-PEG 20 in combination with pemetrexed 
and cisplatin  
• Determine the pharmacokinetics of ADI-PEG 20 in combination with pemetrexed 
and cisplatin 
The goal of the phase 2 portion of the trial is to provide data to support accelerated 
approval by the United States Food & Drug Administration (FDA), and the goal of the 
phase 3 portion of the trial is to provide a confirmatory study that would be ongoing at 
the time of the marketing application. 


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6 INVESTIGATIONAL PLAN 
6.1 
Overall Study Design 
This is a randomized, double-blind, multi-center, phase 2/3 trial of ADI-PEG 20 in 
combination with pemetrexed and cisplatin in subjects with unresectable malignant 
pleural mesothelioma (MPM) of sarcomatoid or biphasic histologies. 
Weekly ADI-PEG 20 at 36 mg/m2 (or placebo) will be combined with pemetrexed 500 
mg/m2 and cisplatin 75 mg/m2 both given every 3 weeks as first-line chemotherapy to 
non-epithelioid (biphasic and sarcomatoid) MPM. Eligible subjects will be randomized in 
a 1:1 ratio to ADI-PEG 20 with pemetrexed and cisplatin (ADIPemPlatinum) or Placebo 
with pemetrexed and cisplatin (PlaceboPemPlatinum). The randomization will be 
stratified by tumor histology (biphasic or sarcomatoid). Subjects may receive a maximum 
of 6, 3-week cycles of ADIPemPlatinum or PlaceboPemPlatinum for a total of 18 weeks 
of treatment. Those subjects completing ADIPemPlatinum or PlaceboPemPlatinum 
treatment may continue on ADI-PEG 20 or placebo monotherapy if they have stable 
disease (SD) or better. Subjects who do not tolerate cisplatin may be switched to 
carboplatin. 
Approximately 176 subjects (88 per arm) will be enrolled in the phase 2 portion of the 
trial and 386 subjects (193 per arm) in the whole phase 2/3 trial. At the end of the phase 2 
portion of the trial an interim analysis will be conducted to evaluate RR in the first 176 
subjects (phase-2 subjects). A second interim analysis will be conducted once 50% of the 
estimated OS events for phase 3 have occurred to determine whether to terminate the 
study for futility or for possible sample size re-estimation for the phase 3 portion of the 
trial.  
Based on DSMB recommendations, the original planned sample size will be changed 
from 386 subjects to all enrolled up to August 15, 2021 (249 subjects). Radiological 
(CT/MRI) scans for assessing tumor response will be performed at baseline, every 6 
weeks during ADIPemPlatinum or PlaceboPemPlatinum dosing, and every 8 weeks 
during ADI-PEG 20 or placebo only dosing. Tumor response will be assessed using 
modified RECIST for MPM for intra-thoracic pleural disease and RECIST 1.1 for extra-
pleural metastatic disease as applicable. In case of tumor response (complete or partial 
response) repeat imaging will be performed 4 weeks later to confirm response.  The same 
imaging modality is to be used throughout the triplet treatment duration. 
Efficacy endpoints include RR, DOR, OS, and PFS; RR and DOR will be derived based 
on the tumor response assessments by a blinded independent central review (BICR) for 
phase 2 and PFS will be derived based on the tumor response assessments by the 
investigator for phase 3. Safety assessments include adverse events (AEs), laboratory 
tests, vital signs, electrocardiograms (ECGs) and physical examinations.  Efficacy and 
safety endpoints are described in Section 6.4 and will be measured according to the 
Schedule of Assessments described in Section 6.2. 


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6.2 
Schedule of Assessments 
For the complete schedule of assessments, refer to Section 1.4 of the clinical study 
protocol. Schedule of assessments for the blinded and open-label extension at study end 
is presented in Section 4.1.2 of the clinical study protocol. 
6.3 
Treatments 
6.3.1 
Treatments Administered 
ADI-PEG 20 at 36 mg/m2 (or placebo) will be administered weekly by intramuscular 
(IM) injection. Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 will be administered 
intravenously every 3 weeks. For each cycle, day 1 administration of ADI-PEG 20 (or 
placebo) will be administered 60-90 minutes prior to pemetrexed and cisplatin, except for 
the first cycle where the doublet chemotherapy will be administered on day 3.  
The starting dose represents 100% of the recommended dose of cisplatin and pemetrexed 
and ADI-PEG 20 as determined in the phase 1 trial. Criteria for withholding treatment, 
dose adjustments, or switching from cisplatin to carboplatin based on toxicity are 
described in Section 7.3.4 of the clinical study protocol. 
Tumor response will be evaluated at the end of week 6. In the event of disease 
progression, the triplet chemotherapy will be stopped, and the subject offered an 
alternative treatment plan.  In the absence of disease progression requiring other 
therapeutic interventions, subjects may receive additional cycles of ADIPemPlatinum or 
PlaceboPemPlatinum treatment following the same procedures and schedule as week 7 
and onward for up to 18 weeks.   
Subjects may continue to receive treatments unless, one of the following occurs at any 
time during the course of therapy: (1) unacceptable AEs, or (2) death, or (3) progressive 
disease, or (4) significant noncompliance on the part of the subject, or (5) refusal of the 
subject to continue treatment or observations, or (6) decision by the Investigator that 
termination is in the subject’s best medical interest, or (7) unrelated medical illness or 
complication, or (8) lost to follow-up.  Any subject with tumor and stable disease or 
partial response should continue treatment until progression, unless the investigator 
thinks a better option is available.  Thus, subjects completing ADIPemPlatinum or 
PlaceboPemPlatinum may continue to receive ADI-PEG 20 or placebo treatment, 
following the schema of week 13 and onward or week 19 and onward if 12 or 18 weeks 
of triple therapy is completed.  Any subject with a complete response may receive 4 more 
weekly treatments of ADI-PEG 20 or placebo.  The maximum number of cycles of 
pemetrexed + cisplatin is 6 (18 weeks at every 3 weeks cycle).  
Subjects ongoing at study end (once the required number of events have been observed 
for the final analysis) may continue to receive treatment on ADIPemPlatinum or 
PlaceboPemPlatinum (or ADI-PEG 20/placebo alone), depending on where the subjects 
are in the treatment schedule, until the study is unblinded. Once the study treatment 
assignments are known, the subjects receiving ADI-PEG 20 may continue to receive 
ADIPemPlatinum (or ADI-PEG 20 alone) until 1 of the following occurs: (1) 


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unacceptable AEs, or (2) death, (3) progressive disease (PD) or (4) decision by the 
Sponsor. Subjects receiving placebo should be consulted regarding alternative treatment 
options. 
6.3.2 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned in a 1:1 ratio to receive ADI-PEG 20 drug product or 
matching placebo in a double-blind fashion via a centralized Interactive Web Response 
System (IWRS) system. ADI-PEG 20 drug product and placebo will be identical in 
appearance in order to preserve the blinding. The randomization will be stratified by 
tumor histology (biphasic or sarcomatoid). 
6.4 
Efficacy and Safety Variables 
6.4.1 
Efficacy Variables 
6.4.1.1 
Primary Efficacy Variables 
The primary efficacy endpoint of the phase 2 portion of the study is: 
• Objective response rate (RR): calculated as the proportion of subjects whose best 
tumor response from all post-baseline tumor assessments is complete response 
(CR) or partial response (PR) 
Tumor response at each time point where CT/MRI scans are performed will be assigned 
by the BICR as complete response (CR), partial response (PR), progressive disease (PD), 
or stable disease (SD). In case of CR or PR, repeat imaging will be performed 4 weeks 
later to confirm response. If the response is not confirmed by the repeat assessment, the 
response of CR or PR will be treated as SD for that time point. 
For subjects with intra-thoracic pleural disease, modified RECIST for MPM 
(Byrne 2004) will be used to determine response at each post-baseline time point as 
follows: 
 
Modified RECIST Criteria for MPM 
Response Definition 
CR 
disappearance of all target lesions with no evidence of tumor elsewhere 
PR 
at least a 30% reduction in the total tumor measurement 
PD 
an increase of at least 20% in the total tumor measurement over the nadir 
measurement, or the appearance of one or more new lesions 
SD 
those who fulfilled the criteria for neither PR nor PD 
For subject with extra-pleural metastatic disease, RECIST 1.1 (Eisenhauer 2009) will be 
used to determine response at each post-baseline time point. Assessment of target lesions, 
non-target lesions, new lesions, and overall response will be assigned as follows: 


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RECIST 1.1 evaluation of target lesions: 
Response 
Definition 
CR 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 
mm. 
PR 
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
PD 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm. The appearance of one or more new lesions is also considered 
progression.  
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters on study. 
 
RECIST 1.1 evaluation of non-target lesions: 
Response 
Definition 
CR 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm 
short axis). 
SD  
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
PD 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. 
 
RECIST 1.1 overall response: 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PR 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
The primary efficacy endpoint of the phase 3 portion of the study is: 
• Overall survival (OS): calculated as the time from randomization until death. In 
the event that no death is documented prior to study termination or analysis 


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cutoff, OS will be censored at the last known date the subject is known to be 
alive, either through completion of on-study visits or through survival follow-up 
contact. 
6.4.1.2 
Secondary Efficacy Variables 
The secondary efficacy endpoint of the phase 2 portion of the study is: 
• Duration of response (DOR): calculated for subjects who have a best tumor 
response of CR or PR as the time from date of initial response of CR or PR until 
date of tumor progression or death. Subjects without tumor progression or death 
at the end of treatment will be censored using the date of the last tumor 
assessment demonstrating no tumor progression. 
The secondary efficacy endpoint of the phase 3 portion of the study is:  
• Progression-free survival (PFS): calculated as the time from randomization until 
date of tumor progression or death. In the event that no tumor progression or 
death is documented prior to end of treatment, analysis cutoff, or the start of 
confounding anticancer therapy, PFS will be censored at the date of the last 
tumor assessment demonstrating no tumor progression. 
6.4.2 
Description of Safety Variables 
6.4.2.1 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
Note: The definition above, provided for in the GCP-ICH Guideline E6, is being 
extended for the purpose of Polaris studies to include any events, intercurrent diseases 
and accidents observed while the subject is on study, i.e., during the actual treatment 
period, as well as during drug-free, pre- and post-treatment periods. 
Adverse events will be recorded from administration of first dose of study drug until 30 
days after last study drug administration. Adverse events related to ADI-PEG 20 that 
were still ongoing at end of treatment (EOT) visit should be followed up until resolution 
or stabilization or until all attempts to determine resolution of the event are exhausted. 
6.4.2.2 
Laboratory Parameters 
Clinical laboratory tests listed in Table 2 will be obtained as per the schedule of events. 
Blood samples will be collected before ADI-PEG 20 or placebo administration. A 


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certified laboratory will be utilized to process and provide results for the clinical 
laboratory tests. 
Table 2 
Clinical Laboratory Tests  
Hematology (CBC) 
Serum Chemistry 
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count 
White blood cell (WBC) count 
Absolute Neutrophil Count (ANC) 
Lymphocytes (Absolute values) 
Monocytes (Absolute values) 
Basophils (Absolute values) 
Eosinophils (Absolute values) 
Platelet count (estimate not acceptable) 
 
Albumin 
Alkaline phosphatase 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Glucose (non-fasting) 
HCG (at screening only) 
Potassium 
Serum glutamic-oxaloacetic transaminase 
(SGOT/AST) 
Serum glutamic-pyruvic transaminase 
(SGPT/ALT) 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
6.4.2.3 
Vital Signs 
Vital signs (blood pressure, respiratory rate, heart rate, and temperature) will be obtained 
at screening, weekly during ADI-PEG 20/placebo treatment, and at the EOT visit. On 
days of ADI-PEG 20/placebo administration, vital signs will be obtained before and 1 
hour (± 15 minutes) after ADI-PEG 20 or placebo treatment. 
6.4.2.4 
Electrocardiograms 
ECG will be performed at screening, day 1 of cycle 2, day 15 of cycle 4, and during cycle 
6 and beyond only as clinically indicated. On days of ADI-PEG 20/placebo 
administration, ECGs will be performed 1 hour (± 15 minutes) after ADI-PEG 20 or 
placebo treatment.  
The results will include ventricular rate, P-R interval, R-R interval, QRS duration, QT 
interval, QTcF interval, and overall interpretation (normal, abnormal and not clinically 
significant, abnormal and clinically significant).  
The corrected QT interval will be corrected for respiratory rate using Fridericia’s 
correction: QTcF = QT/R-R0.33. 


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6.4.2.5 
Physical Examination 
A comprehensive physical examination, including height and weight, will be performed 
at the screening visit. Weight and body surface area (BSA) will be captured on day 1 of 
each cycle. Symptom directed examinations may be performed as clinically indicated.  
6.4.3 
Description of Pharmacodynamic, Immunogenicity, and Pharmacokinetic 
Variables 
Approximately 10 mL of peripheral blood will be collected as plasma prior to 
ADI-PEG 20 or placebo dosing and used for pharmacodynamics, pharmacokinetics and 
immunogenicity studies. A central laboratory will be utilized to process and provide 
results of blood sampling. 
Pharmacodynamics will be assessed by measurement of peripheral blood levels of 
arginine and citrulline by liquid chromatography mass spectrometry (LCMS).  Subjects 
will also be assessed to determine if they experience arginine depletion and/or citrulline 
increase. Arginine depletion will be defined as blood levels ≤10 µM and citrulline 
increase will be defined as increase from baseline ≥50%.  
Immunogenicity will be assessed by measurement of peripheral blood antibodies to 
ADI-PEG 20. Blood will also be available for testing for anti-PEG antibodies.   
Pharmacokinetics will be assessed by measurement of peripheral blood ADI-PEG 20 
levels. 
Arginine, citrulline, anti-ADI-PEG 20 antibody, and ADI-PEG 20 levels will be obtained 
on day 1 and day 8 of cycle 1, day 1 of each subsequent cycle during combination 
therapy, and at weeks 19, 22, and 25 of ADI-PEG 20 or placebo only treatment. 
6.5 
Data Quality Assurance 
Report summaries will be generated using validated Base SAS software, version 9.4 or 
higher, on a PC or server-based platform. Additional validated software may be used to 
generate analyses, as needed.  
All SAS programs that create outputs or supporting analysis datasets will be validated by 
a second statistical programmer or biostatistician. At a minimum, validation of programs 
will consist of a review of the program log, review of output or dataset format and 
structure, and independent confirmatory programming to verify output results or dataset 
content. Additionally, all outputs will undergo a review by a senior level team member 
before finalization. 
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians. Data will be checked for missing values, invalid records, 
and extreme outliers through defensive programming applications, analysis-based edit 
checks, and other programmatic testing procedures. All findings will be forwarded to the 
project data manager for appropriate action and resolution.  


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7 STATISTICAL METHODS 
7.1 
General Methodology 
Data will be analyzed by Precision for Medicine biostatistics personnel. Statistical 
analyses will be reported with tables, figures, and listings, presented in rich text format, 
and using recommended ICH numbering. Output specifications for all tables, figures, and 
listings will be in conformance with guidelines specified by the ICH in Appendix 7 of the 
Electronic Common Technical Document Specification (Apr 2003).  
7.1.1 
Reporting Conventions 
Tables and figures will be summarized by treatment group. Tables summarizing 
demographics and other baseline characteristics will also include a column for all 
subjects combined. In general, all data collected and any derived data will be presented in 
subject data listings, for all enrolled subjects. Listings will be ordered by site, subject 
number, treatment group, and assessment or event date. The treatment group presented in 
listings will be based on the planned assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the population sample 
size (N), number of subjects with available data (n), mean, standard deviation (SD), 
median, minimum, and maximum values. Categorical variables will be summarized by 
the N, n, number of subjects in each category, and the percentage of subjects in each 
category. Unless otherwise noted, the denominator to determine the percentage of 
subjects in each category will be based on the number of subjects with available data. 
Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form (i.e., on the electronic case report form 
[eCRF] or as provided within an external file) and are outlined as follows: 
• The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization; 
• Measures of variability (e.g., SD, SE) will be rounded to two more decimal places 
than the precision of the variable of summarization; and 
• Minimum and maximum values will be presented using the same precision as the 
variable of summarization. 
Other statistics (e.g., CIs) will be presented using the same general rules outlined above, 
or assessed for the most appropriate presentation based on the underlying data. 
P-values will be reported for all statistical tests, rounded to four decimal places. P-values 
less than 0.0001 will be displayed as “<0.0001”; p-values greater than 0.9999 will be 
displayed as “>0.9999”.  


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7.1.2 
Summarization by Visit 
Data summarized by study visit (e.g., laboratory and vital signs) will be based on the 
nominal, scheduled visit label as reported on the eCRF including the EOT assessment 
where applicable.  
7.1.3 
Standard Calculations 
Where appropriate, the calculated study day of each assessment or event will be 
presented with the assessment or event date on subject data listings, where study day will 
be determined as: 
• The assessment/event date minus the date of first dose, if the assessment/event 
date is prior to the date of first dose; and 
• The assessment/event date minus the date of first dose, plus one, if the 
assessment/event date is on or after the date of first dose. 
Other variables requiring calculations will be derived using the following formulas: 
• Days: A duration between two dates expressed in days will be calculated using 
the following conventions: 
o Later date – (earlier date + 1), if the earlier date is on or after the date of 
first dose of study drug; or 
o Later date – earlier date, if the earlier date is prior to the date of first dose 
of study drug. 
• Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 / 12); 
• Years: A duration expressed in years will be calculated by dividing the duration 
in days by 365.25; 
• Change from Baseline: Change from baseline will be calculated as the 
post-baseline value minus the baseline value; 
• Percentage Change from Baseline: Percentage change from baseline will be 
calculated as the change from baseline divided by the baseline value, multiplied 
by 100. 
7.2 
Analysis Populations 
The analysis populations are defined as follows:  


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• Safety Population: Includes all randomized subjects who received at least one 
dose of the study medication. Assignment of subjects to treatment group is based 
on the treatment actually received. 
• Intent-to-Treat (ITT) Population: Includes all randomized subjects. Assignment of 
subjects to treatment group is based on the randomized treatment assignment. 
• Per-Protocol (PP) Population: Includes all ITT subjects who have no major 
protocol violations that may potentially affect the primary and secondary efficacy 
measures (e.g., no MPM, no measurable disease). Subjects to be excluded from 
the PP Population will be determined prior to database lock and prior to breaking 
the blind of the treatment group assignments. Assignment of subjects to treatment 
group is based on the randomized treatment assignment. 
Data summaries to be presented on both the Safety Population and the ITT Population 
will only be produced on both analysis sets if there is a difference in the population 
groups (e.g., at least one subject receives a different treatment than they were originally 
assigned).   
7.3 
Study Subjects 
7.3.1 
Disposition of Subjects 
Subject disposition will be summarized for all randomized subjects by treatment group 
and over all subjects combined. Summaries will include the number and percentage of 
subjects in each analysis population, the primary reason for discontinuing ADI-PEG 20 
or Placebo, and the primary reason for study termination. Subject disposition will also be 
summarized separately for each study center. 
7.3.2 
Protocol Deviations 
Major protocol deviations will be summarized by treatment group and over all subjects 
combined for the ITT Population. Major protocol deviations will be identified, reviewed, 
and entered into the database as described in a separate Protocol Deviation Management 
Guideline document.  
All major protocol deviations will be determined and appropriately categorized prior to 
database lock and prior to breaking the blind of the treatment group assignments. The 
number and percentage of subjects with any major protocol deviations as well as the 
number and percentage of subjects with deviations within each category will be 
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7.4 
Efficacy 
7.4.1 
Datasets Analyzed 
All efficacy summaries will be based the ITT Population; select efficacy summaries will 
also be produced on the PP Population. A data listing of subjects excluded from the ITT 
or PP Population, to include the reason for exclusion, will be presented. 
7.4.2 
Demographic and Other Baseline Characteristics 
Demographic variables including age, sex, ethnicity and race, will be summarized by 
treatment group and over all subjects combined for the Safety, ITT, and PP Populations. 
Age will be calculated relative to date of informed consent, as follows: 
• If the month and day portion of the informed consent date is prior to the month 
and day portion of the birth date, age will be calculated as the year of informed 
consent minus the year of birth, minus one; 
• If the month and day portion of the informed consent date is on or after the month 
and day portion of the birthdate, age will be calculated as the year of informed 
consent minus the year of birth. 
Age will be summarized using descriptive statistics. Sex, ethnicity, and race will be 
summarized with the number and percentage of subjects in each parameter category. 
Baseline characteristics include: medical history, disease history (type of histology, stage 
of MPM, any radiation or surgery treatment for actual cancer), height, weight, BSA, and 
Eastern Cooperative Oncology Group (ECOG) performance status. Height, weight, and 
body mass index (BMI) at baseline will be summarized using descriptive statistics. 
ECOG performance status and disease history will be summarized using frequency 
counts and percentages. Subjects reporting abnormal medical history will be presented 
only in subject data listings by subject and body system. All other baseline characteristics 
will be summarized by treatment group and over all subjects combined for the Safety, 
ITT, and PP Populations.  
7.4.3 
Primary Efficacy Endpoint Analysis Methods 
7.4.3.1 
Objective Response Rate 
The analysis of RR will be performed at the first interim analysis at the end of the phase 2 
portion. The number and percentages of subjects responding (CR or PR) as well as the 
number and percentages of subjects in each best tumor response category (CR, PR, SD, 
PD, missing or not evaluable) will be summarized by treatment group. The objective 
response rate will be compared between treatment groups using the Cochran-Mantel-
Haenszel (CMH) test, stratified by tumor histology (biphasic versus sarcomatoid). The 
point estimate of the relative risk ratio and the corresponding two-sided confidence 
interval will be provided.  The significance level and coverage probability to be used in 
the RR analysis will be based on α=0.05 (two-sided). The RR will only be tested once at 


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the end of the phase 2 regardless of its significance. The analysis will be based on the ITT 
Population. Summaries will also be provided for the PP population.  
7.4.3.2 
Overall Survival 
The primary analysis of OS will be performed at the final analysis. Results will be 
presented by treatment group. The Kaplan-Meier method will be used to provide 
estimates of the OS curves, including the median, 25th and 75th percentiles and their 
corresponding 95% CIs. The number and percentage of subjects with an OS event and 
those who are censored will be presented along with minimum and maximum survival 
times. The Kaplan-Meier curves will also be plotted. A Cox proportional hazard model 
with an adjustment for tumor histology (biphasic versus sarcomatoid) will be used to 
compute the estimated hazard ratio and two-sided 95% confidence interval. The treatment 
effect on OS will be evaluated using the stratified log-rank test (stratified by tumor 
histology). The significance level to be used in the OS analysis at the final analysis will 
be based on α=0.04999 (two-sided). The analysis will be based on the ITT Population. 
Summaries will also be provided for the PP population. 
There will be an interim analysis of OS once 50% of the planned OS events for phase 3 
have occurred and will be used to determine whether to terminate the study for futility or 
for possible sample size re-estimation for the phase 3 portion of the trial as described in 
Section 7.4.5.3. An administrative penalty of α=0.00001 will be paid for this interim 
analysis, and the allocated α=0.04999 will be used for the final analysis. Based on DSMB 
recommendations, the deaths for the original planned final analysis of OS will be 
changed from 338 to the actual number of deaths occurring by August 14, 2022. 
To take into consideration  subjects who received therapies for MPM after the end of 
study treatment, a sensitivity analysis using rank preserving structural failure time models 
(Robins and Tsiatis, 1991) will be performed to evaluate the impacts introduced by such 
actions. 
7.4.4 
Secondary Efficacy Endpoint Analysis Methods 
The secondary efficacy endpoint for phase 2 to be performed at the first interim analysis 
is DOR. DOR will be analyzed using the K-M curves to estimate its median and 95% 
confidence intervals. 
The secondary efficacy endpoint for phase 3 to be performed at the final analysis is PFS, 
which will be analyzed only if the analysis of OS is statistically significant at the final 
analysis, with alpha level of 0.05 two-sided using the same statistical methodologies as 
applied to OS as described in Section 7.4.3.2.  
Summaries of secondary efficacy endpoints will be provided for the ITT and PP 
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7.4.5 
Statistical/Analytical Issues 
7.4.5.1 
Adjustments for Covariates 
The analyses of each of the primary and secondary efficacy endpoints will be adjusted for 
the randomization stratification factor (biphasic histology versus sarcomatoid histology).  
7.4.5.2 
Handling of Dropouts or Missing Data 
Subjects with no post-baseline tumor response will be included in the denominator for 
calculation of RR and will be treated as non-responders.  
For time to event endpoints (OS, PFS, DOR), subjects with no follow-up assessment will 
be censored using a censored value of 1 day.  
No other imputations of missing data will be made. 
7.4.5.3 
Interim Analyses and Data Monitoring 
This study will include two separate interim analyses: 
• The first interim analysis will be conducted at the end of the phase 2 portion, after 
adequate response assessment of the first 176 subjects enrolled.  This interim 
analysis will evaluate the treatment effect on RR in the ITT population.  
• The second interim analysis will be performed once 50% of the planned OS 
events for phase 3 have occurred (ie, 169 of the 338 planned OS events). This 
interim analysis will evaluate OS in the ITT population in an unblinded manner.   
The RR data will be analyzed at the end of the phase 2 portion to support accelerated 
approval.  The OS data at the second interim analysis will be analyzed to support the 
following decisions: 
• Futility stopping: Terminate the study due to futility at the interim analysis. 
• Sample size re-estimation: Increase the target number of OS events after the 
second interim analysis. 
A futility stopping rule will be applied at the second interim analysis to support a 
decision to terminate the study due to futility.  The treatment’s futility will be evaluated 
based on the comparison of the median OS times in the ADIPemPlatinum or 
PlaceboPemPlatinum groups.  The study may be terminated if the median OS in the 
ADIPemPlatinum group is less than that in the PlaceboPemPlatinum group.  This futility 
stopping rule will be non-binding and can be overridden by the Data Safety Monitoring 
Board (DSMB) and/or Polaris. 
A sample size re-estimation rule will be applied at the second interim analysis to support 
a decision to increase the target number of OS events.  The target number of OS events 


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may be modified based on the conditional power (CP) for the OS evaluation in the ITT 
population.  
The following sample size re-estimation rule will be applied: 
• Option 1: Retain the planned target number of OS events, i.e., 338 events, if CP is 
greater than 80% or less than 50% and the futility stopping rule is not met.   
 
• Option 2: Increase the target number of OS events if CP is between 50% and 
80%, and the futility stopping rule is not met.  The target number of OS events 
will be increased to achieve CP of 80% or increased by 30%, whichever is smaller 
based on Chen et al. (2004). Target enrollment adjustments will be accomplished 
using standard event forecasting methods (Anisimov 2011). 
An administrative penalty of α=0.00001 will be paid for second interim analysis, and the 
allocated α=0.04999 will be used for the final analysis. Based on Chen et al. (2004), the 
final test statistic after the sample size re-estimation will be the conventional test 
statistical which is identical to that used in a group sequential design. 
A DSMB will be instituted for this study to ensure the safety of the subjects. 
Recommendations for continuation of the study will be guided by safety evaluations at 
safety data reviews. The committee will include two independent oncologists with 
experience in thoracic oncology and an independent statistician. Safety meetings will be 
held as per the DSMB charter, approximately every 6 months and more often if deemed 
necessary. Decisions on study termination, amendment, or cessation of subject 
recruitment, based on safety or outcome findings, will be made after recommendations 
from the DSMB have been assessed by Polaris. The DSMB will not be expected to 
conduct the efficacy analyses at the interim or final analyses. 
7.4.5.4 
Multicenter Studies 
This is a global, multicenter study. Efficacy data collected from all study centers will be 
pooled for data analysis. The effect of study center on the efficacy analysis results may be 
explored post-hoc, as needed. 
7.4.5.5 
Multiple Comparisons/Multiplicity 
The efficacy endpoint (RR) will be evaluated at the end of the phase 2 portion at α = 0.05 
(two-sided) for the purpose of determining if the data supports accelerated approval.  
Since comparison of RR will only be tested at the end of the phase 2 portion for the 
purpose of providing support for accelerated approval, the type I error for phase 3 will be 
maintained at α = 0.05.  
The primary endpoint (OS) will be tested at α = 0.04999 (two-sided) at the final analysis 
at the end of the phase 3 portion.  The analysis of OS at the second interim analysis will 
be performed for the purposes of testing for futility and possible re-estimation of sample 
size as described in Section 7.4.5.3. Analysis at the interim and final analysis will be 


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performed based on Chen et al. (2004) in order to maintain the type 1 error at α = 0.05 
for OS at the final analysis. An administrative penalty of α=0.00001 will be paid for 
second interim analysis, and the allocated α=0.04999 will be used for the final analysis. 
The secondary endpoint of PFS will be tested only if the primary analysis of OS is 
statistically significant, thus maintaining the type 1 error at α = 0.05. 
7.4.5.6 
Use of an “Efficacy Subset” of Subjects 
The primary efficacy analysis will be performed on the ITT population; the PP 
population will be utilized as a sensitivity analysis. The PP population will exclude 
subjects who have major protocol violations that may potentially affect the primary and 
secondary efficacy measures.  
7.4.5.7 
Examination of Subgroups 
There are no planned analyses to assess efficacy results by subgroups. 
7.4.6 
Pharmacodynamics 
Blood levels of arginine and citrulline will be summarized for ADI-PEG 20 treated 
subjects. Descriptive statistics (including n, mean, SD, median, Q1, Q3, minimum, and 
maximum values) will be presented for results and change from baseline at each visit 
where blood samples were scheduled to be collected. The baseline value will be defined 
as the last value reported prior to first study drug administration. The number and 
percentage of subjects with arginine depletion and citrulline increase will also be 
presented at each visit. Blood levels of arginine and citrulline will also be displayed 
graphically over time. 
Arginine and citrulline results may also be correlated with RR and OS by examining RR 
and OS results for subjects who demonstrate arginine depletion or citrulline increase at 
select time points compared to those subjects who do not. 
7.4.7 
Immunogenicity 
Blood levels of antibodies to ADI-PEG 20 and anti-PEG antibodies will be summarized 
for ADI-PEG 20 treated subjects. Descriptive statistics will be presented for results and 
change from baseline at each visit where blood samples were scheduled to be collected. 
The baseline value will be defined as the last value reported prior to first study drug 
administration. Blood levels of antibodies to ADI-PEG 20 and anti-PEG antibodies will 
also be displayed graphically over time. 
7.4.8 
Pharmacokinetics 
Blood concentration levels of ADI-PEG 20 will be summarized for ADI-PEG 20 treated 
subjects. Descriptive statistics will be presented for observed concentrations at each visit 
where blood samples were scheduled to be collected. Blood concentration levels of 
ADI-PEG 20 will also be displayed graphically over time. 


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Analysis of derived pharmacokinetic parameters or correlation to efficacy endpoints may 
be performed and summarized in a separate report and is outside the scope of this SAP. 
7.5 
Safety Analysis 
Safety analysis will be carried out for the Safety Population, to include all subjects who 
receive at least one dose of study drug. Subjects who do not complete the study, for 
whatever reason, will have all available data up until the time of termination included in 
the analysis. For safety analysis presented by study visit, the baseline value will be 
defined as the last value reported prior to first study drug administration. 
7.5.1 
Extent of Exposure and Treatment Compliance 
Extent of exposure to study treatment will be summarized for the Safety Population by 
treatment group. The number of doses taken and the total dose administered will be 
summarized for each study drug: ADI-PEG 20/Placebo, Pemetrexed, Cisplatin, and 
Carboplatin.  The number and percentages of subjects who had at least one dose withheld 
and the number and percentages of subjects who at least one dose reduced along with the 
corresponding reasons for doses being withheld or reduced for each study drug, where 
applicable, will be summarized.  
Compliance will not be evaluated as study drug is administered by staff in the clinic..  
7.5.2 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset after 
the first dose of study drug or existing events that worsened after the first dose during the 
study. Treatment-emergent AEs will be summarized by treatment group. Events reported 
with a partial onset date (e.g., month and year are reported but the day is missing) will be 
considered to be treatment-emergent if it cannot be confirmed that the event onset was 
prior to the first dose of study drug based on the available date entries. 
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using the Medical Dictionary for Regulatory Activities (MedDRA, version 19.0 
or most current version at the time of analysis).   
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending incidence of system organ class and preferred term within each system 
organ class. Summaries displayed by preferred term only will be ordered by descending 
incidence of preferred term. Summaries of the following types will be presented: 
• Overall summary of number of unique TEAEs and treatment-emergent serious 
adverse events (SAEs) and subject incidence of TEAEs meeting various criteria; 
• Subject incidence of TEAEs by MedDRA system organ class and preferred term; 
• Subject incidence of the most frequently-occurring TEAEs (e.g., TEAEs 
occurring in ≥ 10% of the Safety Population) by MedDRA preferred term; 


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• Subject incidence of TEAEs by common terminology criteria for adverse events 
(CTCAE) grade, MedDRA system organ class, and preferred term; 
• Subject incidence of TEAEs by relationship to ADI-PEG 20/Placebo, MedDRA 
system organ class, and preferred term;  
• Subject incidence of TEAEs by relationship to Pemetrexed, MedDRA system 
organ class, and preferred term;  
• Subject incidence of TEAEs by relationship to the Platinum agent (Cisplatin or 
Carboplatin), MedDRA system organ class, and preferred term;  
• Subject incidence of ≥ Grade 3 TEAEs related to ADI-PEG 20/Placebo by 
MedDRA system organ class and preferred term;  
• Subject incidence of ≥ Grade 3 TEAEs related to Pemetrexed by MedDRA 
system organ class and preferred term;  
• Subject incidence of ≥ Grade 3 TEAEs related to the Platinum agent (Cisplatin or 
Carboplatin) by MedDRA system organ class and preferred term;  
• Subject incidence of TEAEs leading to discontinuation of ADI-PEG 20/Placebo 
by MedDRA system organ class and preferred term;  
• Subject incidence of TEAEs leading to discontinuation of Pemetrexed by 
MedDRA system organ class and preferred term;  
• Subject incidence of TEAEs leading to discontinuation of the Platinum agent 
(Cisplatin or Carboplatin) by MedDRA system organ class and preferred term; 
and 
• Subject incidence of SAEs by MedDRA system organ class and preferred term. 
At each level of summarization (e.g., any AE, system organ class, and preferred term), 
subjects experiencing more than one TEAE will be counted only once. In the summary of 
TEAEs by CTCAE grade, subjects will be counted once at the highest CTCAE grade 
reported at each level of summarization; in the summary of TEAEs by relationship, 
subjects will be counted once at the closest relationship to study drug.  
Adverse event data will be presented in data listings by subject, treatment group, and 
event. Serious AEs and AEs leading to discontinuation of ADI-PEG 20/Placebo, 
Pemetrexed, Cisplatin, and Carboplatin will be presented in separate data listings. 
7.5.3 
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events 
All deaths during the study, including the post treatment follow-up period, will be listed 
by subject, to include the primary cause of death. Serious AEs and AEs that led to 


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withdrawal, interruption, or dose reduction of ADI-PEG 20/Placebo, Pemetrexed, 
Cisplatin, and Carboplatin, will be provided in separate subject data listings. 
7.5.4 
Clinical Laboratory Evaluation 
All descriptive summaries of laboratory results will be based on data analyzed by the 
central laboratory and presented in Système International (SI) units, as suggested by the 
Center for Biologics Evaluation and Research and the Center for Drug Evaluation and 
Research Position on Use of SI Units for Lab Tests (Oct 2013). All data will be included 
in by-subject data listings. Laboratory measurements identified as abnormal (i.e., outside 
the normal range) will also be listed separately by subject, laboratory test, and unit. 
Clinical laboratory measurements, including serum chemistry and hematology, will be 
summarized by treatment group. Descriptive statistics will be presented for observed 
values and changes from baseline at each visit where parameters were scheduled to be 
collected per the clinical study protocol.  
Where applicable, hematology and chemistry results for select parameters will be 
assigned a toxicity grade based on the U.S. Department of Health and Human Services 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (Jun 2010). 
Five-by-five contingency tables will be presented for lab tests where toxicity grading can 
be applied to summarize the shift from the baseline grade to the worst post-baseline 
grade. Grades will be presented as none (Grade 0), mild (Grade 1), moderate (Grade 2), 
severe (Grade 3), or life-threatening (Grade 4). Death related to AE (i.e., Grade 5) cannot 
be determined with available laboratory-based data collection and, thus, will not be 
summarized as a category. Summary results will include the count and percentage of 
subjects within each shift category. 
Where applicable, laboratory results will be classified as “low,” “normal,” or “high” with 
respect to the parameter-specific reference ranges (i.e., below the lower limit of the 
normal range, within the normal range, or above the upper limit of the normal range). 
Three-by-three contingency tables will be presented for laboratory parameter that cannot 
be assigned a CTCAE toxicity grade to summarize the shift from the baseline category to 
the worst post-baseline measurement, defined as the value numerically farthest outside of 
the normal range across all post-baseline visits through the end of the study. Summary 
results will include the count and percentage of subjects within each shift category and 
treatment group. 
7.5.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety 
7.5.5.1 
Vital Signs 
Vital sign parameter measurements will be presented in subject data listings by subject 
and study visit. 


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7.5.5.2 
12-Lead Electrocardiogram 
Twelve-Lead ECG interval parameters will be summarized by treatment group. 
Descriptive statistics will be presented for observed values and changes from baseline at 
each visit where parameters were scheduled to be collected. 
Twelve-lead ECG will be classified by the investigator as “normal,” “abnormal, not 
clinically significant,” or “abnormal, clinically significant.” Three-by-three contingency 
tables will be presented to summarize the shift from the baseline category to the worst 
post-baseline value. Summary results will include the count and percentage of subjects 
within each shift category and treatment group. 
Prolonged QT intervals will be summarized as QTcF measurements (msec) that are 
> 450, > 470, and > 500 at each visit where ECG is routinely collected per the clinical 
study protocol. Change from baseline categories will also be summarized for 
measurements that represent a change > 30 or > 60 relative to the baseline value. 
Summary results will include the percentage of subjects within each category and 
treatment group. 
7.5.5.3 
Physical Examination 
Results of any symptom directed physical examination will be presented in subject data 
listings by subject and study visit. 
7.5.5.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO Drug 2016Q1, 
enhanced) dictionary. Medications entered on the eCRF will be mapped to Anatomic 
Therapeutic Chemical (ATC) drug class (level 4) and drug name.  
Concomitant medications will be summarized by treatment group for all medications 
reported on the Concomitant Medications eCRF. The number and percentage of subjects 
receiving any medication will be summarized by treatment group, as will the number and 
percentage receiving any medication by ATC drug class and generic drug name. Subjects 
reporting use of more than one medication at each level of summarization (any 
medication received, ATC class, and generic drug name) will be counted only once. ATC 
class terms will be displayed by descending order of incidence, as will generic drug 
names within each ATC class.  
7.6 
Determination of Sample Size 
The sample size calculation for the phase 2 primary endpoint (RR) assumed that the 
objective response rate in the PlaceboPemPlatinum arm was 15%.  A total sample size of 
176 subjects (88 per arm) in the phase 2 portion of the study will provide approximately 
87% power to detect an improvement in the RR from 15% to 35% at the interim analysis 
at the end of the phase 2 portion. 


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The sample size calculation for the phase 3 primary endpoint (OS) assumed that the 
median OS was 6 months in the PlaceboPemPlatinum arm.  Assuming a median OS of 
8.4 months in the ADIPemPlatinum arm (corresponding to a HR of 0.714), 338 OS 
events will provide power of approximately 87% for the OS analysis.  Assuming uniform 
accrual over a 24-month period and a total study duration of 36 months, the planned total 
sample size in the study was 386 subjects. The target number of events may be increased 
at the second interim analysis, which will affect the total number of subjects.  
The study will include an unblinded interim analysis once 50% of the planned OS events 
for phase 3 have occurred, which will be performed by an Independent Analysis Group.  
The DSMB will review the interim analysis report and provide final recommendations 
related to futility stopping and sample size re-estimation after the second interim analysis.  
The interim analysis decision rules are defined in Section 7.4.5.3. 
Based on DSMB recommendations, the original planned sample size will be changed 
from 386 subjects to all enrolled up to August 15, 2021 (249 subjects); and the deaths for 
the original planned final analysis of OS will be changed from 338 to the actual number 
of deaths occurring by August 14, 2022. The estimated power with 249 subjects would be 
in a range of 73% to 80% if the true HR is in a range of 0.71 to 0.68. 
7.7 
Changes in the Conduct of the Study or Planned Analyses 
This SAP follows the planned analyses as described in the protocol (Version 6; 
September 2021). Changes from the previous versions of the SAP and protocol are 
specified in Section 4.  
As mentioned above, the original planned sample size will be changed from 386 subjects 
to all enrolled up to August 15, 2021 (249 subjects); and the deaths for the original 
planned final analysis of OS will be changed from 338 to the actual number of deaths 
occurring by August 14, 2022.  
8 REFERENCE LIST 
1. International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. Statistical principles for clinical 
trials (E9). International Conference on Harmonization; 1998. 
2. M2 eCTD: Electronic Common Technical Document Specification Appendix 7, 
provided by the International Conference on Harmonization. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/ucm073240.pdf 
3. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in 
malignant pleural mesothelioma. Ann Oncol 2004; 15:257–260. 


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4. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey 
J, Arbuch S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247. 
5. Anisimov V. Predictive event modelling in multicentre clinical trials with waiting 
time to response. Pharmaceutical Statistics 2011; 10:517-522. 
6. Chen YHJ,  DeMets DL, Lan KKG, Increasing the sample size when the 
unblinded interim result is promising, Statistics in medicine 2004; 23:1023–1038 
7. Robins JM, Tsiatis AA, Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models, Communication in statistics – 
theory and methods 1991; 20 (8): 2609-2631. 
8. Data Standards: Position on Use of SI Units for Lab Tests. U.S Food and Drug 
Administration; 25 October 2013. Available from: 
http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm372553.
htm  
9. U.S. Department of Health and Human Services. Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.03. 14 June 2010. Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
 
 


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APPENDIX A: LIST OF TABLES, FIGURES AND DATA LISTINGS 
List of Tables 
Number 
Description 
Analysis Set 
Source 
Listing(s) 
14.1 
Demographic Data 
Summaries 
 
 
14.1.1.1 
Subject Disposition  
All Randomized 
Subjects 
16.2.1 
14.1.1.2 
Subject Disposition by Study 
Center  
All Randomized 
Subjects 
16.2.1 
14.1.2 
Major Protocol Deviations  
ITT Population 
16.2.2.1 
14.1.3.1 
Demographic Characteristics  
Safety 
Population 
16.2.4.1 
14.1.3.2 
Demographic Characteristics  
ITT Population 
16.2.4.1 
14.1.3.3 
Demographic Characteristics  
PP Population 
16.2.4.1 
14.1.4.1 
Baseline Characteristics  
Safety 
Population 
16.2.9.1, 16.2.9.5 
14.1.4.2 
Baseline Characteristics  
ITT Population 
16.2.9.1, 16.2.9.5 
14.1.4.3 
Baseline Characteristics  
PP Population 
16.2.9.1, 16.2.9.5 
14.1.5.1 
Disease History  
Safety 
Population 
16.2.2.2, 
16.2.4.3, 16.2.4.4 
14.1.5.2 
Disease History  
ITT Population 
16.2.2.2, 
16.2.4.3, 16.2.4.4 
14.1.5.3 
Disease History  
PP Population 
16.2.2.2, 
16.2.4.3, 16.2.4.4 
14.2 
Efficacy Data Summary 
Tables 
 
 
14.2.1.1 
Objective Response Rate – 
Phase 2 Subjects 
ITT Population 
16.2.6.1 
14.2.1.2 
Objective Response Rate – 
Phase 2 Subjects 
PP Population 
16.2.6.1 
14.2.2.1 
Duration of Response – Phase 
2 Subjects 
ITT Population 
16.2.6.1 
14.2.2.2 
Duration of Response – Phase 
2 Subjects 
PP Population 
16.2.6.1 
14.2.3.1 
Overall Survival  
ITT Population 
16.2.6.1 
14.2.3.2 
Overall Survival 
PP Population 
16.2.6.1 
14.2.3.3 
Overall Survival by Tumor 
Histology 
ITT Population 
16.2.6.1 
14.2.3.4 
Overall Survival by Tumor 
Histology 
PP Population 
16.2.6.1 
14.2.4.1 
Progression Free Survival 
ITT Population 
16.2.6.1 
14.2.4.2 
Progression Free Survival 
PP Population 
16.2.6.1 


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Number 
Description 
Analysis Set 
Source 
Listing(s) 
14.2.4.3 
Progression Free Survival by 
Tumor Histology 
ITT Population 
16.2.6.1 
14.2.4.4 
Progression Free Survival by 
Tumor Histology 
PP Population 
16.2.6.1 
14.2.5.1 
Pharmacodynamic Parameters  
ITT Population 
16.2.5.6 
14.2.5.2 
Immunogenicity Parameters 
ITT Population 
16.2.5.7 
14.2.5.3 
Pharmacokinetic 
Concentrations  
ITT Population 
16.2.5.8 
14.3 
Safety Data Summaries 
 
 
14.3.1  
Displays of Adverse Events 
 
 
14.3.1.1 
Overall Summary of 
Treatment-Emergent Adverse 
Events  
Safety 
Population 
16.2.7 
14.3.1.2 
Treatment-Emergent Adverse 
Events by System Organ Class 
and Preferred Term 
Safety 
Population 
16.2.7 
14.3.1.3 
Most Frequently-Occurring (≥ 
10% Overall) Treatment-
Emergent Adverse Events by 
Preferred Term  
Safety 
Population 
16.2.7 
14.3.1.4 
Treatment-Emergent Adverse 
Events by CTCAE Grade, 
System Organ Class, and 
Preferred Term 
Safety 
Population 
16.2.7 
14.3.1.5 
Treatment-Emergent Adverse 
Events by Relationship to 
ADI-PEG 20/Placebo, System 
Organ Class, and Preferred 
Term 
Safety 
Population 
16.2.7 
14.3.1.6 
Treatment-Emergent Adverse 
Events by Relationship to 
Pemetrexed, System Organ 
Class, and Preferred Term 
Safety 
Population 
16.2.7 
14.3.1.7 
Treatment-Emergent Adverse 
Events by Relationship to the 
Platinum Agent, System Organ 
Class, and Preferred Term 
Safety 
Population 
16.2.7 
14.3.1.8 
Treatment-Emergent ≥ Grade 3 
Adverse Events Related to 
ADI-PEG 20/Placebo by 
System Organ Class and 
Preferred Term 
Safety 
Population 
16.2.7 


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Number 
Description 
Analysis Set 
Source 
Listing(s) 
14.3.1.9 
Treatment-Emergent ≥ Grade 3 
Adverse Events Related to 
Pemetrexed by System Organ 
Class and Preferred Term 
Safety 
Population 
16.2.7 
14.3.1.10 
Treatment-Emergent ≥ Grade 3 
Adverse Events Related to the 
Platimun Agent by System 
Organ Class and Preferred 
Term 
Safety 
Population 
16.2.7 
14.3.1.11 
Treatment-Emergent Adverse 
Events Leading to 
Discontinuation of 
ADI-PEG 20/Placebo by 
System Organ Class and 
Preferred Term 
Safety 
Population 
16.2.7 
14.3.1.12 
Treatment-Emergent Adverse 
Events Leading to 
Discontinuation of Pemetrexed 
by System Organ Class and 
Preferred Term 
Safety 
Population 
16.2.7 
14.3.1.13 
Treatment-Emergent Adverse 
Events Leading to 
Discontinuation of the 
Platinum Agent by System 
Organ Class and Preferred 
Term 
Safety 
Population 
16.2.7 
14.3.1.14 
Treatment-Emergent Serious 
Adverse Events by System 
Organ Class and Preferred 
Term 
Safety 
Population 
16.2.7, 14.3.2.2 
14.3.2 
Listing of Deaths, Other 
Serious and Significant 
Adverse Events 
 
 
14.3.2.1 
Listing of Deaths  
Safety 
Population 
N/A 
14.3.2.2 
Listing of Serious Adverse 
Events  
Safety 
Population 
N/A 
14.3.2.3 
Listing of Adverse Events 
Leading to ADI-PEG 20/ 
Placebo Discontinuation or 
Interruption 
Safety 
Population 
N/A 


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Number 
Description 
Analysis Set 
Source 
Listing(s) 
14.3.2.4 
Listing of Adverse Events 
Leading to Pemetrexed 
Discontinuation, Reduction or 
Interruption 
Safety 
Population 
N/A 
14.3.2.5 
Listing of Adverse Events 
Leading to Cisplatin 
Discontinuation, Reduction or 
Interruption 
Safety 
Population 
N/A 
14.3.2.6 
Listing of Adverse Events 
Leading to Carboplatin 
Discontinuation, Reduction or 
Interruption 
Safety 
Population 
N/A 
14.3.3 
Narratives of Deaths, Other 
Serious Adverse Events, and 
Certain Other Significant 
Adverse Events* 
 
 
14.3.4 
Abnormal Laboratory 
Values Listing 
 
 
14.3.4.1 
Listing of Abnormal 
Hematology Values  
Safety 
Population 
N/A 
14.3.4.2 
Listing of Abnormal Chemistry 
Values  
Safety 
Population 
N/A 
14.3.5 
Extent of Exposure 
 
 
14.3.5.1 
Extent of Exposure  
Safety 
Population 
16.2.5.1, 
16.2.5.2, 
16.2.5.3, 16.2.5.4 
14.3.6 
Laboratory Summaries 
 
 
14.3.6.1 
Hematology – Univariate 
Summary by Parameter and 
Visit 
Safety 
Population 
14.3.4.1, 16.2.8.1 
14.3.6.2 
Hematology – Shift from 
Baseline to Worst Post-
Baseline Value by Parameter 
Safety 
Population 
14.3.4.1, 16.2.8.1 
14.3.6.3 
Chemistry – Univariate 
Summary by Parameter and 
Visit 
Safety 
Population 
14.3.4.2, 16.2.8.2 
14.3.6.4 
Chemistry – Shift from 
Baseline to Worst Post-
Baseline Value by Parameter 
Safety 
Population 
14.3.4.2, 16.2.8.2 
14.3.6.5 
Shift from Baseline to Worst 
Post-Baseline NCI CTCAE 
Toxicity Grade by Laboratory 
Parameter 
Safety 
Population 
14.3.4.1, 
14.3.4.2, 
16.2.8.1, 16.2.8.2 


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Number 
Description 
Analysis Set 
Source 
Listing(s) 
14.3.7 
Vital Signs, Physical Findings 
and Other Observations 
 
 
14.3.7.1 
12-Lead Electrocardiogram – 
Univariate Summary by 
Parameter and Visit 
Safety 
Population 
16.2.9.3 
14.3.7.2 
12-Lead Electrocardiogram 
Interpretation – Shift from 
Baseline to Worst Post-
Baseline Value 
Safety 
Population 
16.2.9.3 
14.3.7.3 
12-Lead Electrocardiogram – 
QT Interval Categories  
Safety 
Population 
16.2.9.3 
14.3.7.4 
Concomitant Medications  
Safety 
Population 
16.2.9.4 
*Narratives of deaths, other serious adverse events, and certain other significant adverse 
events will not be generated by analysis programming and are outside the scope of this 
analysis plan.  
 
 


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List of Figures 
Number 
Description 
Analysis Set 
Source Tables 
and/or Listing(s) 
14.4 
Efficacy Data Figures 
 
 
14.4.1.1 
Overall Survival  
ITT Population 
14.2.1.1, 16.2.6.1 
14.4.1.2 
Overall Survival  
PP Population 
14.2.1.1, 16.2.6.1 
14.4.2.1 
Progression Free Survival  
ITT Population 
14.2.1.1, 16.2.6.1 
14.4.2.2 
Progression Free Survival  
PP Population 
14.2.1.1, 16.2.6.1 
14.4.3.1 
Arginine Blood Levels Over 
Time 
ITT Population 
16.2.5.6 
14.4.3.2 
Citrulline Blood Levels Over 
Time  
ITT Population 
16.2.5.6 
14.4.3.3 
ADI-PEG 20 Antibody Blood 
Levels Over Time  
ITT Population 
16.2.5.7 
14.4.3.4 
Anti-PEG Antibody Blood 
Levels Over Time  
ITT Population 
16.2.5.7 
14.4.3.5 
ADI-PEG 20 Concentration 
Levels Over Time  
ITT Population 
16.2.5.8 
 
 


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Subject Data Listings 
Number 
Description 
16.1.7 
Randomization 
16.1.7 
Randomization Scheme and Codes 
16.2.1 
Discontinued Subjects 
16.2.1 
Subject Disposition 
16.2.2 
Protocol Deviations 
16.2.2.1 
Major Protocol Deviations 
16.2.2.2 
Informed Consent and Eligibility Criteria 
16.2.3 
Subjects Excluded from the Efficacy Analysis 
16.2.3 
Subjects Excluded from the Efficacy Analysis 
16.2.4 
Demographic Data 
16.2.4.1 
Demographics 
16.2.4.2 
Medical History 
16.2.4.3 
Prior Radiation Treatments to Treat Cancer 
16.2.4.4 
Prior Surgeries to Treat Cancer 
16.2.5 
Compliance and/or Drug Concentration Data 
16.2.5.1 
ADI-PEG 20/ Placebo Administration 
16.2.5.2 
Pemetrexed Administration 
16.2.5.3 
Cisplatin Administration 
16.2.5.4 
Carboplatin Administration 
16.2.5.5 
Pharmacodynamic and Immunogenicity Blood Sampling 
16.2.5.6 
ADI-PEG 20 Concentration Data 
16.2.6 
Individual Efficacy Response Data 
16.2.6.1 
Derived Efficacy Data 
16.2.6.2 
Response Assessment: RECIST Criteria – Phase 2 Subjects 
16.2.6.3 
Target Lesions – Phase 2 Subjects 
16.2.6.4 
Non Target Lesions – Phase 2 Subjects 
16.2.6.5 
New Lesions – Phase 2 Subjects 
16.2.6.6 
Survival Status 
16.2.7 
Adverse Events 
16.2.7 
Adverse Events 
16.2.8 
Listing of Individual Laboratory Measurements 
16.2.8.1 
Hematology 
16.2.8.2 
Chemistry 
16.2.8.3 
Pregnancy Test 
16.2.9 
Additional Safety Listings 
16.2.9.1 
Vital Signs 
16.2.9.2 
Physical Examination 
16.2.9.3 
12-Lead Electrocardiogram 
16.2.9.4 
Chest X-ray 
16.2.9.5 
ECOG Performance Status 
16.2.9.6 
Concomitant Medications  


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Number 
Description 
16.2.9.7 
Non-Medication Therapies or Treatment/Procedures 
16.2.9.8 
Therapeutic Procedures After End of Treatment 
 
 


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