Clinical trial NCT02899195
Conditions: Mesothelioma Pleural Mesothelioma
Keywords: Unresectable Mesothelioma Durvalumab Anti-Programmed Death-Ligand 1 Antibody
Sponsor: PrECOG, LLC.
Start date: 2017-06-13; Completion date: 2023-06-29
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients with pleural mesothelioma that can not be surgically removed will receive durvalumab, in combination with standard chemotherapy of pemetrexed and cisplatin as first-line treatment.

Durvalumab is a type of drug called a monoclonal antibody (a type of protein). Laboratory tests show that it works by allowing the immune system to detect your cancer and reactivates the immune response. This may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see whether adding durvalumab to standard chemotherapy will improve overall survival (OS).

Detailed description:
Mesothelioma is a malignant tumor of the mesothelial surfaces primarily arising in the thoracic pleura and is estimated to cause 43,000 deaths worldwide each year with over 3300 cases occurring annually in the United States. Approximately 80% of cases of mesothelioma are due to inflammation induced by prior asbestos exposure with a lead time from exposure to development of cancer of 20-30 years.

This is a single arm, open label phase II study of the anti-PD-L1 antibody, durvalumab, in combination with standard chemotherapy. Pemetrexed and cisplatin will be given for up to six 3-week cycles with the addition of concurrent durvalumab dosed every 3 weeks. The first 6 patients who are enrolled and commence treatment will be monitored for safety of the combination. Use of carboplatin in place of cisplatin will be permitted for patients who are ineligible for cisplatin due to impaired renal function at screening, however these patients must otherwise fulfill the eligibility criteria for the study. For patients that receive cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin related toxicity (e.g., grade 3 ototoxicity, grade 3 nausea) at the investigator's discretion. After completion of Cycle 6 of concurrent therapy, patients with stable or responding disease per modified RECIST for malignant mesothelioma will continue on single agent durvalumab every 3 weeks until progression. Maximum duration of durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment (inclusive of any treatment delays or missed treatments).

Tumor assessments will be performed approximately every 6 weeks during concurrent therapy and every 9 weeks during the maintenance phase.

Mandatory pre-treatment tumor tissue sample (i.e., obtained during a previous procedure or biopsy) and blood samples (prior to Cycle 1, Cycle 2 and Cycle 5) for research will also be required.

Arms: arm 1: Pemetrexed/cisplatin will be given for up to six 3-week cycles with the addition of concurrent durvalumab every 3 weeks. The first 6 patients who are enrolled and commence treatment will be monitored for safety of the combination. Use of carboplatin in place of cisplatin will be permitted for patients who are ineligible for cisplatin due to impaired renal function at screening. For patients that receive cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin related toxicity (e.g., grade 3 ototoxicity, grade 3 nausea) at the investigator's discretion. After completion of Cycle 6 of concurrent therapy, patients with stable or responding disease per modified RECIST for malignant mesothelioma will continue on single agent durvalumab every 3 weeks until progression. Maximum duration of durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment (inclusive of any treatment delays or missed treatments).
Interventions: intervention 1: Durvalumab
Intervention descriptions: intervention 1: On Day 1 of each 21 day cycle: Durvalumab 1120 mg IV will be administered before pemetrexed and cisplatin chemotherapy over approximately 60 minutes. Approximately 30 minutes after the durvalumab infusion is complete, pemetrexed 500 mg/m² IV will be administered over 10 minutes. Cisplatin 75 mg/m² IV over 2 hours will begin approximately 30 minutes after the end of pemetrexed administration. If carboplatin is substituted for cisplatin, carboplatin Area Under the Concentration-Time Curve (AUC) 5 will be infused over 30 minutes beginning approximately 15-30 minutes after the end of the pemetrexed administration. Maintenance: On Day 1 of each 21 day cycle: Durvalumab 1120 mg IV over approximately 60 minutes.

Protocol documents:
Prot_000.pdf: 
PrECOG Protocol Number: PrE0505 
Date: 3/19/2018 
 
1 
 
 
PrECOG Protocol Number: PrE0505 
Open Label, Phase II Study of Anti - Programmed Death – 
Ligand 1 Antibody, Durvalumab (MEDI4736), in Combination 
with Chemotherapy for the First-Line Treatment of 
Unresectable Mesothelioma 
 
NCT #: 
NCT02899195 
IND #: 
130722 
Protocol Version Number: 
5.0 
Version Date: 
March 19, 2018 
 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
 
 
PrECOG Protocol Number: PrE0505 
Open Label, Phase II Study of Anti - Programmed Death – 
Ligand 1 Antibody, Durvalumab (MEDI4736), in Combination 
with Chemotherapy for the First-Line Treatment of 
Unresectable Mesothelioma 
STUDY CHAIR: 
Patrick Forde, MD 
STUDY CO-CHAIR: 
 
ECOG-ACRIN THORACIC COMMITTEE CHAIR: 
 
STATISTICIAN: 
 
PRECOG STUDY SITE CONTACT: 
Carolyn Andrews, RN 
MEDICAL MONITOR: 
 
(Internal Use Only) AstraZeneca US Ref. ID Number: ESR-15-10792 
 
 
IND #: 
130722 
Version Number: 
5.0 
Version Date: 
March 19, 2018 
 
 
Release/Revision History 
Version 1.0: 7/7/2016 
Released to Sites 
Version 2.0: 10/13/2016 
Released to Sites 
Version 3.0: 2/6/2017 
Released to Sites 
Version 4.0: 5/30/2017 
Released to Sites 
Version 5.0: 3/19/2018 
Released to Sites 
 
 
 
 
 
 
 
This protocol contains information that is confidential and proprietary 


PrECOG Protocol Number: PrE0505 
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2 
Table of Contents 
List of Abbreviations ........................................................................................................................................6 
1. 
Introduction- Background and Rationale ......................................................................................... 10 
1.1 
Mesothelioma – Disease Overview ................................................................................. 10 
1.2 
Background/Rationale ..................................................................................................... 10 
1.3 
Study Drug - Durvalumab [30] ......................................................................................... 11 
1.4 
Study Drugs – Pemetrexed and Cisplatin or Carboplatin ................................................ 15 
1.5 
Summary of Rationale for Proposed Study ..................................................................... 16 
1.6 
Synopsis of Study Design ............................................................................................... 17 
2. 
Study Objectives ............................................................................................................................. 19 
2.1 
Primary Objective ............................................................................................................ 19 
2.2 
Secondary Objectives...................................................................................................... 19 
3. 
Selection of Patients ....................................................................................................................... 20 
4. 
Registration Procedures .................................................................................................................. 23 
4.1 
Ethics ............................................................................................................................... 23 
4.2 
Regulatory Requirements ................................................................................................ 23 
4.3 
Patient Registration ......................................................................................................... 23 
4.4 
Research Tissue and Blood Samples ............................................................................. 23 
5. 
Study Design ................................................................................................................................... 24 
5.1 
Overview .......................................................................................................................... 24 
5.2 
Initial Enrollment of Six Patients with Safety Monitoring ................................................. 24 
5.3 
Expansion ........................................................................................................................ 24 
5.4 
Evaluation of Subjects ..................................................................................................... 24 
6. 
Treatment Plan ................................................................................................................................ 26 
6.1 
Overview .......................................................................................................................... 26 
6.2 
Dose Limiting Toxicity - Definition ................................................................................... 28 
6.3 
Dose Delays & Modifications ........................................................................................... 29 
6.4 
Concurrent Therapies ...................................................................................................... 52 
6.5 
Supportive Care ............................................................................................................... 52 
7. 
Study Duration and Discontinuation of Therapy ............................................................................. 53 
7.1 
Study Duration ................................................................................................................. 53 
7.2 
Duration of Follow-Up ...................................................................................................... 53 
7.3 
Criteria for Removal from Study Treatment..................................................................... 53 
8. 
Adverse Event Reporting ................................................................................................................ 55 
8.1 
Collection of Safety Information ...................................................................................... 55 
8.2 
Definition of Adverse Events of Special Interest (AESI) .................................................. 56 
8.3 
Handling of Serious Adverse Events (SAEs) .................................................................. 59 
8.4 
SAE Reporting Requirements ......................................................................................... 59 
8.5 
Reporting of Other Second Primary Cancers .................................................................. 61 


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8.6 
Procedures in Case of Pregnancy ................................................................................... 61 
8.7 
Durvalumab Overdose..................................................................................................... 62 
9. 
Measurement of Effect .................................................................................................................... 63 
9.1 
Solid Tumor Response Criteria (RECIST Version 1.1) ................................................... 63 
9.2 
Evaluation of Patient’s Best Overall Response ............................................................... 67 
10. 
Study Parameters ........................................................................................................................... 70 
11. 
Drug Formulation and Procurement ................................................................................................ 76 
11.1 
Durvalumab ..................................................................................................................... 76 
11.2 
Pemetrexed [36] and Cisplatin [37] ................................................................................. 78 
12. 
Statistical Considerations ................................................................................................................ 81 
12.1 
Study Design & Sample Size Considerations – Safety Run-In ....................................... 81 
12.2 
Expansion Phase ............................................................................................................. 81 
13. 
Laboratory and Pathology Correlative Studies ............................................................................... 84 
13.1 
Correlative Studies: Mandatory Tumor and Peripheral Blood Samples .......................... 84 
13.2 
Assay Methodology ......................................................................................................... 85 
13.3 
Pathology Sample Processing and Shipment ................................................................. 85 
13.4 
Peripheral Blood Samples Processing and Shipment ..................................................... 85 
14. 
Administrative .................................................................................................................................. 87 
14.1 
Protocol Compliance ....................................................................................................... 87 
14.2 
Institutional Review Board ............................................................................................... 87 
14.3 
Informed Consent Procedures ........................................................................................ 87 
14.4 
Safety Communication .................................................................................................... 88 
14.5 
Monitoring ........................................................................................................................ 88 
14.6 
Study Records ................................................................................................................. 88 
14.7 
Electronic Case Report Form (eCRF) Information .......................................................... 89 
14.8 
Records Retention ........................................................................................................... 89 
15. 
References ...................................................................................................................................... 90 
Appendix I: 
ECOG Performance Status ............................................................................................. 93 
Appendix II: 
Cockcroft-Gault Formula ................................................................................................. 94 
Appendix III: 
Rule of Nines ................................................................................................................... 95 
Appendix IV: 
Investigator’s Statement .................................................................................................. 96 
 
 
 


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4 
PrECOG STUDY SITE CONTACT 
MEDICAL MONITOR 
Carolyn Andrews, RN 
Project Manager 
PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
Phone: 215-789-7001 
Email: candrews@precogllc.org 
Dorothea Astl, MD 
1000 Continental Drive 
Suite 200 
King of Prussia, PA 19406 
During normal business hours 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
Email: dastl@precogllc.org 
SAE Fax: 888-276-9606 
SAE Email: PrE0505SAE@qdservices.com 


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Brief Protocol Synopsis 
See Protocol Document Sections for complete details 
This is a single arm, open label phase II study of the anti-PD-L1 antibody, durvalumab, in combination with 
pemetrexed and cisplatin chemotherapy in the first-line treatment of patients with unresectable pleural 
mesothelioma. Standard chemotherapy with pemetrexed/cisplatin will be given for up to six 3-week cycles 
with the addition of concurrent durvalumab dosed at 1120 mg every 3 weeks. The first 6 patients who are 
enrolled and commence treatment will be monitored for safety of the combination. Use of carboplatin in place 
of cisplatin will be permitted for patients who are ineligible for cisplatin due to a documented contraindication 
(e.g., ototoxicity, renal function), however these patients must otherwise fulfill the eligibility criteria for the 
study. For patients who receive cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin 
related toxicity (e.g., grade 3 ototoxicity, grade 3 nausea) at the investigator’s discretion. After completion of 
Cycle 6 of concurrent therapy, patients with stable or responding disease per modified RECIST for malignant 
mesothelioma will continue on single agent durvalumab 1120 mg every 3 weeks until progression. Maximum 
duration of durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment (inclusive of 
any treatment delays or missed treatments). 
The primary endpoint of the study is overall survival (OS) as compared with historical control. 
Study Schema 
 
me  
 
 
 
 
 
 
 
Treatment should begin within 10 working days of registration. 
PR: Partial Response; SD: Stable Disease; PD: Progression 
* Maximum duration of durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment. 
Accrual: This study will enroll 55 patients (of whom 50 will be expected to be eligible and commence 
treatment). The first 6 patients who are enrolled and commence treatment will be monitored for safety of the 
combination, safety will be further evaluated after 15 patients have been enrolled. 
NOTE: Carboplatin may be substituted for cisplatin as indicated in Section 3.9 and Section 5.1. 
Newly Diagnosed 
Unresectable Pleural 
Mesothelioma 
• ECOG 0-1 
• No Prior Anti-Cancer 
Therapy 
• Baseline Tumor Biopsy 
Specimen Available 
Pemetrexed/Cisplatin with 
Concurrent Durvalumab 
every 3 weeks x 6 cycles 
PR 
or 
SD 
Durvalumab every 
3 weeks until PD* 


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List of Abbreviations 
Abbreviation 
Term 
AChE 
Acetylcholine Esterase 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody-Dependent Cell-Mediated Cytotoxicity 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
Anti-HBc 
Hepatitis B Core Antibody 
AR 
Accumulation Ratio 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
BID 
Twice a Day 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CBC 
Complete Blood Count 
CD 
Cluster of Differentiation 
CDC 
Complement Dependent Cytotoxicity 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Peak Concentration 
CR 
Complete Response 
CNS 
Central Nervous System 
CrCl 
Creatinine Clearance 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Antigen 4 
DCO 
Data Cut-Off 
DCR 
Disease Control Rate 
dL 
Deciliter 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 


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DOR 
Duration of Response 
EA CBPF 
ECOG-ACRIN Central Biorepository and Pathology Facility 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
EDTA 
Disodium Edetate Dihydrate 
ELISA 
Enzyme-Linked Immunosorbent Assay 
F 
Fahrenheit 
Fcγ 
Fragment Crystallizable Gamma 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
g 
grams 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFN-γ 
Interferon Gamma 
IG 
Immunoglobulin 
IgG1κ 
Immunoglobulin G1 Kappa 
IHC 
Immunohistochemistry  
ILD 
Interstitial Lung Disease 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
imAE 
Immune-Mediated Adverse Event 
IRB 
Institutional Review Board 


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IV 
Intravenous(ly) 
IVIG 
Intravenous Immunoglobulin 
kDa 
Kilodalton 
kg 
Kilogram 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
MAb 
Monoclonal Antibody 
mCR 
Marrow Complete Remission 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
m2 
Square Meter 
mm3 
Cubic Millimeter 
MRI 
Magnetic Resonance Imaging 
ms 
Milliseconds 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NOAEL 
No-Observed-Adverse-Effect Level 
NSAIDs 
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PJP 
Pneumocystis Jirovecii Pneumonia 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death 1 
PD-L1 
Programmed Cell Death Ligand 1 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Oral 
PPD 
Purified Protein Derivative 
PR 
Partial Response 
PT 
Prothrombin Time 


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Q2W 
Every 2 Weeks 
Q3W 
Every 3 Weeks 
Q4W 
Every 4 Weeks 
QTc 
The Time Between the Start of the Q wave and the End of the T 
Wave Corrected for Heart Rate 
QTcF 
QT Interval on ECG Corrected using the Frederica’s Formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SD 
Stable Disease 
sPD-L1 
Soluble Programmed Cell Death Ligand 1 
SRM 
Study Reference Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Half-Life 
TBD 
To Be Determined 
TBSA 
Total Body Surface Area 
T-Cell 
T Lymphocyte 
TNBC 
Triple-Negative Breast Cancer 
TNF 
Tumor Necrosis Factor 
TNF-α 
Tumor Necrosis Factor- Alpha 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States 
W/V 
Weight/Volume 
 


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1. 
Introduction- Background and Rationale 
1.1 
Mesothelioma – Disease Overview 
Mesothelioma is a malignant tumor of mesothelial surfaces primarily arising in the thoracic 
pleura and is estimated to cause 43,000 deaths worldwide each year with over 3300 cases 
occurring annually in the United States [1, 2]. Approximately 80% of cases of mesothelioma 
are due to inflammation induced by prior asbestos exposure with a lead time from exposure 
to development of cancer of 20-30 years [1]. It is predicted that the incidence of 
mesothelioma due to previous exposure will rise significantly in many countries over the 
next two decades particularly in Europe, China, Russia and Japan [3, 4]. The median 
survival for all patients diagnosed with mesothelioma is extremely poor at 6-18 months and 
the vast majority of patients will relapse after surgical resection or present with unresectable 
disease [5, 6]. The known role of asbestos and chronic inflammation in the etiology of 
mesothelioma has led to the discovery of the pivotal role the immune system plays in the 
initiation and progression of mesothelioma [7]. Immunotherapy is one of the most promising 
avenues of clinical investigation in mesothelioma at present and several clinical trials are 
evaluating immune modulating agents [8]. 
1.2 
Background/Rationale 
1.2.1 
PD-L1 in Immune Evasion 
Immune responses directed against tumors are one of the body’s natural defenses 
against the growth and proliferation of cancer cells. However, over time and under 
pressure from immune attack, cancers develop strategies to evade immune-
mediated killing allowing them to develop unchecked. One such mechanism 
involves upregulation of surface proteins that deliver inhibitory signals to cytotoxic 
T cells. Programmed cell death ligand 1 (PD-L1) is one such protein, and is 
upregulated in a broad range of cancers with a high frequency, with up to 88% 
expression in some tumor types. In a number of these cancers, including lung [9], 
renal [10, 11, 12], pancreatic [13, 14, 15], ovarian cancer [16], and hematologic 
malignancies [17, 18] tumor cell expression of PD-L1 is associated with reduced 
survival and an unfavourable prognosis. 
Programmed cell death ligand 1 is part of a complex system of receptors and 
ligands that are involved in controlling T-cell activation. PD-L1 acts at multiple sites 
in the body to help regulate normal immune responses and is utilized by tumors to 
help evade detection and elimination by the host immune system tumor response. 
In the lymph nodes, PD-L1 on antigen-presenting cells binds to PD-1 or CD80 on 
activated T cells and delivers an inhibitory signal to the T cell [19, 20]. This results 
in reduced T-cell activation and fewer activated T cells in circulation. In the tumor 
microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and CD80 on 
activated T cells reaching the tumor. This delivers an inhibitory signal to those T 
cells, preventing them from killing target cancer cells and protecting the tumor from 
immune elimination [21]. 
1.2.2 
PD-L1 is Highly Expressed in Mesothelioma 
Preclinical data suggests that one of two ligands of PD-1, programmed death-ligand 
1 (PD-L1) is highly expressed in mesothelioma tumor cells [22]. PD-L1 is a putative 
predictive marker for response to PD-L1- and PD-1-directed therapeutics in multiple 
tumor types across multiple early and late phase studies [23-25]. 
We have recently performed PD-L1 immunohistochemical (IHC) testing, using the 
murine anti-human PD-L1 monoclonal antibody 5H1, on standard formalin-fixed 
paraffin-embedded (FFPE) tissue sections of large biopsy or resection specimens 
from 25 pleural (17 epithelioid, 7 biphasic & 1 sarcomatoid) and 8 peritoneal 
mesotheliomas. Based on earlier published studies tumor cells or tumor infiltrating 


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lymphocytes were considered positive if at least 5% exhibited membranous staining 
[23]. The mesothelioma tumor cells in the analyzed cohort demonstrated high levels 
of PD-L1 expression, 17 of 33 tumors (52%) were PD-L1 positive and high level 
expression (>50% staining) was present in 14 of 33 tumors (42%). Another group 
has recently reported similar findings from 224 patient cases analyzed 
retrospectively using the 5H1 antibody [26]. Using a 5% cutoff for positivity, 40% of 
mesothelioma tumors expressed PD-L1 (89/224). PD-L1 expression was 
associated with worse overall survival (6 months vs. 14 months, p<0.0001) even 
when adjusted for age, gender, lymphocytic infiltration and therapeutic surgery 
(p<0.0002). 
Recent analysis of gene expression suggests high levels of CD8 infiltration in 32% 
of mesotheliomas and high level PD-L1 expression in 12 of 44 tumors (27%) 
providing a further rationale for PD1/PD-L1-directed therapy in mesothelioma [27]. 
In addition recent data from a mesothelioma cohort enrolled in a phase Ib clinical 
trial of the anti-PD-1 antibody, pembrolizumab, were highly promising with 28% 
(7/25) of chemo-refractory patients have an objective response by modified 
Response Evaluation Criteria in Solid Tumors (RECIST) for mesothelioma and a 
further 48% (12/25) having prolonged stable disease [28]. This has led to a phase 
II single arm clinical trial of pembrolizumab in the second- and third-line setting [29]. 
1.3 
Study Drug - Durvalumab [30] 
1.3.1 
Description of Durvalumab (MEDI4736) 
Durvalumab is briefly described below. Investigators should refer to the current 
Investigator’s Brochure (IB) for details. 
1.3.2 
Product Derivation 
Durvalumab is being developed as a potential anticancer therapy for the treatment 
of multiple tumor types. Durvalumab is a human immunoglobulin (Ig) G1 kappa 
(IgG1κ) monoclonal antibody (MAb) that blocks the interaction of PD-L1 (but not 
programmed cell death ligand-2) with PD-1 on T-lymphocyte (T-cell) and, cluster of 
differentiation on CD80 (B7-1) on immune cells and is engineered to reduce 
antibody-dependent cell-mediated cytotoxicity (ADCC).
 
 
 
 
 
 
1.3.3 
Non Clinical Safety Profile 
The non-clinical experience is fully described in the current version of the 
durvalumab IB. 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its 
interaction with PD-1 and CD80 (B7-1). 
 
 
 
 
 
 
 
 
 


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1.3.4 
Summary of Clinical Experience 
The clinical experience is fully described in the current version of the durvalumab 
IB. 
As of 12 July 2017, an estimated 4067 patients have been exposed to 1 or more 
doses of durvalumab in Phase I-III AstraZeneca or MedImmune sponsored studies, 
either as monotherapy or in combination and 5911 where the treatment arm is 
blinded. Additionally, more than 4000 patients have been exposed to 1 or more 
doses of durvalumab in externally-sponsored/investigator-initiated clinical trials. No 
AstraZeneca or MedImmune study has been terminated prematurely due to toxicity. 
1.3.5 
Clinical Pharmacology 
1.3.5.1 
Pharmacokinetics and Metabolism of Durvalumab in Humans 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3.6 
Clinical Safety & Preliminary Clinical Efficacy 
1.3.6.1 
Study CD-ON-MEDI4736-1108 
Adverse Events (AEs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preliminary Efficacy 
Study CD-ON-MEDI4736-1108: 
• 
 
 
 
 
 
 
 
• 
 
 
 
 
• 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 


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1.3.6.2 
Study D4190C00007 
 
 
 
 
 
 
 
 
AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
Preliminary Efficacy 
 
 
 
 
 
NOTE: 
Further detailed information on adverse events and 
preliminary efficacy noted in clinical studies of durvalumab is 
available in the IB. 
 


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1.3.7 
Dose Rationale 
1.3.7.1 
Fixed Dosing 
A two compartment population PK model was developed for 
durvalumab using monotherapy data from Study CD-ON-MEDI4736-
1108 and the ATLANTIC Study across dose levels and tumor types 
 
 
. 
Population PK analysis indicated only minor impact of body weight on 
PK of durvalumab (coefficient of ≤ 0.5). The impact of body weight-
based (10 mg/kg Q2W or 20 mg/kg Q4W) and fixed dosing (750 mg 
Q2W or 1500 mg Q4W) of durvalumab was evaluated by comparing 
predicted steady state PK exposure (AUCss,0-28, Cmax,ss, and Cmin,ss ) using 
the population PK model. A fixed dose of 750 mg Q2W was selected to 
approximate 10 mg/kg Q2W and a fixed dose of 1500 mg Q4W was 
selected to approximate 20 mg/kg Q4W (based on median body weight 
of ~75 kg). A total of 1000 patients were simulated using body weight 
distribution of 40–110 kg. Simulation results demonstrate that body 
weight-based (10 mg/kg Q2W) and fixed dosing regimens (750 mg 
Q2W) yield similar median steady state exposures and associated 
variability, supporting the potential switch of durvalumab from weight-
based to fixed dose. Similar considerations hold for the Q4W dosing 
regimens (20 mg/kg Q4W versus 1500 mg Q4W). Based on an average 
body weight of 75 kg, fixed doses of 1120 mg q3w (equivalent to 15 
mg/kg q3w) of durvalumab are chosen for this study. 
Similar findings have been reported by others [31-35]. Wang and 
colleagues investigated 12 monoclonal antibodies and found that fixed 
and body size-based dosing perform similarly, with fixed dosing being 
better for 7 of 12 antibodies [32]. In addition, they investigated 18 
therapeutic proteins and peptides. 
1.4 
Study Drugs – Pemetrexed and Cisplatin or Carboplatin 
1.4.1 
Pemetrexed 
Pemetrexed is a folate analog metabolic inhibitor indicated for the treatment of 
mesothelioma in combination with cisplatin. Pemetrexed is administered 
intravenously at a dose of 500 mg/m² on Day 1 of each 21-day cycle. Cisplatin 
should be administered 30 minutes after pemetrexed infusion ends at a dose of 75 
mg/m². The premedication regimen for pemetrexed includes folic acid and vitamin 
B12 as well as dexamethasone or equivalent to reduce cutaneous reactions. 
Subjects receiving pemetrexed should be monitored prior to each dose using 
complete blood count (CBC) and renal function tests. If marrow suppression is 
noted, dose modifications are noted in Section 6.3.2, Table 6-3. For renal toxicity, 
pemetrexed should be held when the creatinine clearance (CrCl) <45 mL/minute. 
Caution should be used among subjects who are receiving nonsteroidal anti-
inflammatory drugs (NSAIDs) and who have mild to moderate renal insufficiency 
(CrCl between 45 and 79 mL/minute). Caution should also be used when 
nephrotoxic drugs are administered with pemetrexed. For preparation and storage, 
please consult the prescribing information for Alimta® [36]. 
 


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1.4.2 
Cisplatin 
Cisplatin is a platinum-based drug that is used in mesothelioma. Cisplatin is 
administered intravenously at a dose of 75 mg/m² starting 30 minutes after 
pemetrexed infusion ends. Subjects who are receiving cisplatin must be monitored 
for nephrotoxicity, ototoxicity and neuropathy in addition to myelosuppression. 
Caution must be observed in the case of nausea, vomiting and dehydration. Dose 
modifications according to toxicities are noted in Section 6.3.2, Table 6-3. For 
preparation and storage, please consult the prescribing information for Cisplatin 
[37]. 
1.4.3 
Carboplatin 
Carboplatin is a platinum-based drug that is used in the treatment of mesothelioma 
in the setting where cisplatin is contraindicated. Carboplatin is administered 
intravenously at a dose of AUC 5 mg/mL*min (per Calvert formula) starting 15 to 30 
minutes after pemetrexed infusion ends. Subjects who are receiving carboplatin 
must be monitored for myelosuppression and anaphylaxis. Dose modifications 
according to toxicities are noted in Section 6.3.2, Table 6-3. For preparation and 
storage, please consult the prescribing information for Paraplatin [38]. 
1.5 
Summary of Rationale for Proposed Study 
1.5.1 
Rationale for the Study Design and Treatment Plan 
1.5.1.1 
Current Standard of Care in Mesothelioma and Role for Maintenance 
Therapy 
Subjects enrolled on this study will have unresectable mesothelioma 
for which they have not received prior systemic therapy. The standard 
first-line therapy for mesothelioma consists of 4-6 cycles of combination 
chemotherapy with pemetrexed/cisplatin, this has been shown to 
extend survival when compared with cisplatin alone and is associated 
with a median OS of 12.1 months [39]. The benefit of second-line 
chemotherapy has not been clearly established [40]. 
No more than 4 to 6 cycles of first-line platinum-based combination 
chemotherapy are generally recommended for patients with advanced 
disease. Therefore, after 4 to 6 cycles of treatment, non-progressing 
patients enter a “watch-and-wait” period with periodic review until 
progression. Trials are ongoing evaluating the role of maintenance 
single agent pemetrexed after initial platinum doublet chemotherapy 
[41]. Further investigation would be advantageous to provide these 
patients with a regimen that could augment and then maintain the 
disease control achieved by first-line therapy. Similar approaches in 
NSCLC have led to the approval of both erlotinib and pemetrexed as 
maintenance treatment in patients who are not progressing following 
first-line platinum-based treatment, on the basis of an observed benefit 
in both median progression-free survival (PFS) and median OS. 
Currently there are no approved therapies following first-line treatment 
for malignant pleural mesothelioma, and there are limited data in the 
maintenance setting. 
1.5.1.2 
Rationale for Combination of Chemotherapy and Durvalumab 
The interaction of a tumor with the immune system is complex. Tumors 
and the tumor microenvironment are known to express a variety of 
factors that impede a robust immune response from eliminating the 
tumor. 


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Cancer 
therapeutics 
such 
as 
chemotherapy 
may 
modulate 
tumor/immune-system interactions in favor of the immune system. 
Chemotherapy can result in tumor cell death with a resultant increase 
in tumor antigen delivery to antigen-presenting cells. Tumor cell death 
may also lead to a reduction in soluble and membrane-bound factors 
inhibiting tumor-infiltrating T-cells. Chemotherapy may also disrupt 
immune system regulatory networks by decreasing numbers of T-
regulatory cells. 
In previously untreated mesothelioma, chemotherapy has the potential 
to prime the immune system through tumor destruction and consequent 
antigen expression. The addition of durvalumab to chemotherapy is 
expected to be synergistic in this regard. Several studies are exploring 
the combination of chemotherapy with anti-PD-L1 therapies with 
promising early response data. 
1.6 
Synopsis of Study Design 
1.6.1 
Initial Enrollment and Evaluation for Safety (Safety Run-In Period)  
As durvalumab has not been previously combined with pemetrexed platinum 
doublet chemotherapy the study will commence with an initial enrollment of 6 
patients who will receive the combination of pemetrexed (500 mg/m2) and cisplatin 
(75 mg/m2) with durvalumab (1120 mg) for up to 6 cycles. Pemetrexed/carboplatin 
is associated with fewer toxicities than pemetrexed/cisplatin therefore both in the 
initial 6 patient cohort and in the later expansion, substitution of carboplatin (AUC 
5) for cisplatin will be permitted specifically as outlined in the eligibility. After up to 
6 cycles of concurrent chemotherapy with durvalumab, patients who have a PR or 
SD will continue on durvalumab until disease progression (maximum duration of 
durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment 
(inclusive of any treatment delays or missed treatments). In this initial safety run-in 
period subjects will be monitored for safety. The combination will be declared 
intolerable if ≥ 2 of the initial 6 patients experience a dose-limiting toxicity (DLT) as 
defined in the protocol and occurring during the first 2 cycles of concurrent therapy. 
The detailed statistical analysis plan is described in the statistical section of this 
protocol. 
1.6.2 
Expansion 
After the initial 6 patients from the above safety run-in period have been monitored 
for safety the study will proceed with enrollment for a total of 55 patients (including 
the initial 6 patient safety run-in) of whom it is expected 50 patients will receive 
treatment (ineligibility rate of 10%). This is an open label, single arm phase II study 
evaluating the benefit of durvalumab in combination with pemetrexed/cisplatin for 
the treatment of first-line unresectable pleural mesothelioma. Durvalumab (1120 mg 
q 3 weeks) will be administered concurrently with up to 6 cycles of first line 
pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) followed by maintenance 
durvalumab until disease progression (maximum duration of durvalumab treatment 
is 12 months starting from Cycle 1 of concurrent treatment (inclusive of any 
treatment delays or missed treatments). Carboplatin (AUC 5) may be substituted 
for cisplatin for patients with a documented contraindication (e.g., ototoxicity, renal 
function) to use of cisplatin and these patients must otherwise fulfill the eligibility 
criteria (Section 3). In addition, for patients who receive cisplatin, carboplatin may 
be substituted after Cycle 1 for cisplatin related toxicity (e.g., grade 3 ototoxicity, 
grade 3 nausea) at the investigator’s discretion. 
 


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1.6.3 
Evaluation of Subjects 
Progression will be assessed locally using modified RECIST Version 1.1. Subjects 
will continue to receive treatment until disease progression or other discontinuation 
criteria are met (maximum duration of durvalumab treatment is 12 months starting 
from Cycle 1 of concurrent treatment (inclusive of any treatment delays or missed 
treatments). Removal of subjects for clinical progression will be at the discretion of 
the Investigator. Response assessments will be performed every 6 weeks (2 doses 
of treatment) for the first 18 weeks. After 18 weeks of treatment, response 
assessments will be performed every 9 weeks (3 doses of treatment). The same 
method of assessment should be used throughout the study. 
Following documentation of non-fatal confirmed disease progression, all subjects 
will be followed for survival (either routine clinic visit or telephone contact) every 3 
months until death or the closure of the study. 


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2. 
Study Objectives 
2.1 
Primary Objective 
The primary objective of this phase II study is to demonstrate improved overall survival (OS) 
compared to a historic control with the addition of concurrent and maintenance durvalumab 
to standard chemotherapy for unresectable pleural mesothelioma. 
2.2 
Secondary Objectives 
1) To evaluate the safety and tolerability of durvalumab and durvalumab in combination 
with chemotherapy in subjects with malignant pleural mesothelioma. 
2) Percentage of patients progression-free at 24 weeks from the time of registration. 
Disease status at 24 weeks will be compared to disease status at the time of 
registration, and response coded based on modified RECIST 1.1 criteria. 
3) Progression-free survival (PFS) will be measured from the time of study registration until 
radiologic progression, clinical progression or death. 
4) Time to progression on durvalumab will be measured from the time concurrent 
treatment with chemotherapy/durvalumab begins until radiologic or clinical progression 
is noted. 
5) Best Objective Response Rate (ORR) evaluation will continue up to 1 year on therapy 
and response will be coded based on modified RECIST Version 1.1 criteria for 
mesothelioma. 
2.3 
Exploratory Objectives 
2.3.1 
Laboratory Correlates of Response (depending on sample availability) 
1) Assessment of tumor baseline PD-L1 expression may be performed. 
2) Assessment of the genomic and neoantigen landscape of baseline tumors may 
be performed. 
3) Assessment of dynamics of circulating cell free tumor DNA (ctDNA) may be 
performed. 
4) Serial assessment of soluble biomarkers may be performed. 


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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be considered 
eligible for this study. Use the checklist to confirm a patient’s eligibility. For each patient, this 
checklist must be photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later 
would be considered Day 28. 
PrECOG Patient No. 
 
 
Patient’s Initials ( F, M, L) 
 
 
Physician Signature and Date 
 
NOTE: All questions regarding eligibility should be directed to the Medical Monitor or Study Site 
Contact. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed, 
signed, and dated prior to registration by the treating physician. 
3.1. 
Histologically and/or cytologically confirmed malignant pleural mesothelioma (any histologic 
subtype of malignant pleural mesothelioma is permitted). 
Date of Diagnosis: _______________ 
3.2 
Unresectable disease (defined as the participant not being a candidate for curative surgery). 
3.3 
Measurable disease, defined as at least 1 lesion (measurable) that can be accurately 
assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) 
and is suitable for repeated assessment (modified RECIST for pleural mesothelioma). 
3.4 
Available unstained archived tumor tissue sample in sufficient quantity to allow for analyses. 
At least fifteen unstained slides or a tumor block (preferred). 
NOTE: 
A fine needle aspiration sample is not sufficient to make the patient eligible for 
enrollment. Given the complexity of mesothelioma pathological diagnosis and that 
these will be newly diagnosed patients it is expected that they will have a core 
needle biopsy or surgical tumor biopsy as part of their initial diagnostic work up. 
3.5 
Age ≥ 18 years. 
3.6 
ECOG performance status of 0-1 (Appendix I). 
3.7 
Ability to understand and willingness to sign IRB-approved informed consent. 
3.8 
Willing to provide archived tumor tissue and blood samples for research (Section 13.0). 
3.9 
Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to 
registration: 
• 
Absolute Neutrophil Count (ANC) ≥ 1500/mm3 
ANC: __________________ 
Date of Test: ____________ 
• 
Hemoglobin ˃9.0 g/dL 
Hemoglobin: ____________ 
Date of Test: ____________ 
• 
Platelets ˃100,000/mm3 
Platelets: _______________ 
Date of Test: ____________ 
_____
_____
_____
_____
_____
_____
_____
_____
_____ 


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• 
Serum creatinine CL>60 mL/min by the Cockcroft-Gault formula (Appendix II) or by 24-
hour urine collection for determination of creatinine clearance: 
Creatinine Clearance: ______ 
Date of Test: ____________ 
NOTE: 
Patients with a creatinine Cl ≥ 45 mL/min however ≤ 60 mL/min may be 
considered for enrollment provided they fulfill all other eligibility criteria, these 
subjects will receive pemetrexed/carboplatin concurrent with durvalumab 
during the combination phase of treatment. Patients with a creatinine CL<45 
mL/min should not be enrolled. 
• 
Albumin ≥ 2.8 g/dL 
Albumin: _________________ 
Date of Test: ____________ 
• 
Total Bilirubin ≤ 1.5x ULN [This will not apply to subjects with confirmed Gilbert’s 
syndrome (persistent 
or recurrent hyperbilirubinemia that 
is predominantly 
unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed to 
enroll only in consultation with their physician.] 
Total Bilirubin: ___________ 
ULN: ________ 
Date of Test: ___________ 
• 
AST/ALT ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases) 
AST/ALT: ______________ 
ULN: _______ 
Date of Test: ___________ 
3.10 
Women must either be of non-reproductive potential (i.e., post-menopausal by history: ≥ 60 
years old and no menses for ≥ 1 year without an alternative medical cause; OR history of 
hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or 
must have a negative serum pregnancy test upon study entry. 
Is the patient a woman of childbearing potential? _____________________ (yes/no) 
If yes, Date of Test: _______________ Results: ____________________________ 
3.11 
Women must not be pregnant or breastfeeding. Females of child-bearing potential who are 
sexually active with a non-sterilized male partner and sexually active men must agree to 
use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) prior to 
study entry, for the duration of study participation, and for 3 months following completion of 
durvalumab. Method of contraception must be documented. 
NOTE: 
Should a woman become pregnant or suspect she is pregnant while participating 
in this study, she should inform her treating physician immediately. 
3.12 
Patient is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow-up. 
3.13 
Patient must not have involvement in the planning and/or conduct of the study. No previous 
enrollment in the present study. 
3.14 
Patients may not have participated in another clinical study with an investigational product 
during the last 4 weeks. 
3.15 
Patients must not have any prior systemic therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, and other investigational agent) for mesothelioma. 
3.16 
No previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or any other 
agent targeting immune checkpoints. 
3.17 
Patients must not have non-pleural mesothelioma e.g. mesothelioma arising in peritoneum, 
tunica vaginalis or any serosal surface other than the pleura. 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 


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3.18 
Patients must not have an active second malignancy other than non-melanoma skin cancer 
or cervical carcinoma in situ. 
NOTE: 
Patients with history of malignancy are not considered to have a “currently active” 
malignancy if they have completed therapy and are now considered by their 
physician to be at less than 30% risk for relapse. 
3.19 
Patients must not have mean QT interval corrected for heart rate (QTc) ≥470 ms calculated 
from 3 electrocardiograms (ECGs) using Fredericia’s Correction. 
3.20 
Patients must not have symptomatic or uncontrolled brain metastases requiring concurrent 
treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids (prednisone 
>10 mg or equivalent). Surgery, radiation and/or corticosteroids (any dose >10 mg 
prednisone equivalent) must have been completed ≥ 2 weeks prior to registration. 
3.21 
Patients must not have uncontrolled seizures. 
3.22 
Patients must not have current or prior use of immunosuppressive medication within 28 
days before the first dose of durvalumab, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 
10 mg/day of prednisone, or an equivalent corticosteroid. Standard steroid premedication 
given prior to chemotherapy or as prophylaxis for imaging contrast allergy should not be 
counted for this criterion. 
3.23 
No active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, 
irritable bowel disease; Wegner syndrome) within the past 2 years. Subjects with vitiligo, 
alopecia, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 3 
years) are not excluded. 
3.24 
No history of primary immunodeficiency. 
3.25 
No history of allogeneic organ transplant. 
3.26 
No history of hypersensitivity to durvalumab, cisplatin, carboplatin, pemetrexed or any of 
their excipients. 
3.27 
No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses 
including any subject known to have psychiatric illness/social situations that would limit 
compliance with study requirements or compromise the ability of the subject to give written 
informed consent. 
3.28 
No active infection including tuberculosis (clinical evaluation including: physical examination 
findings, radiographic findings, positive PPD test, etc.), hepatitis B (known positive HBV 
surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 
1/2 antibodies as defined by a positive ELISA test). Patients with a past or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of 
HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. HIV testing is not required in absence 
of clinical suspicion. 
3.29 
No known history of leptomeningeal carcinomatosis. 
3.30 
Patients must not have received live attenuated vaccination within 30 days prior to study 
entry or within 30 days of receiving durvalumab. 
3.31 
Patients must not have any condition that, in the opinion of the investigator, would interfere 
with evaluation of study treatment or interpretation of patient safety or study results. 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 


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4. 
Registration Procedures 
4.1 
Ethics 
This study will be conducted in accordance with the ethical principles that have their origin 
in the current Declaration of Helsinki and will be consistent with applicable US regulatory 
requirements and International Conference on Harmonization/Good Clinical Practice 
(ICH/GCP). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the patient informed consent will receive Institutional Review Board (IRB) 
approval prior to initiation of the study. 
Freely given written informed consent must be obtained from every patient or their legally 
acceptable representative prior to clinical trial participation, including informed consent for 
any screening procedures conducted to establish patient eligibility for the trial. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of 
investigators or study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
Investigators are responsible for the conduct of the study at their study site. 
4.2 
Regulatory Requirements 
Before a site may enter patients, protocol-specific regulatory and other documents must be 
submitted to PrECOG as noted in study materials. Detailed information regarding document 
submission and control is provided to each site in separate study materials. 
Once required documents are received, reviewed, and approved by PrECOG or their 
representative, a Study Reference Manual (SRM) will be forwarded to the site. Any changes 
to site regulatory documents must be submitted by the investigator to the responsible party 
in a timely manner. Initial study drug shipment will not occur until the regulatory packet is 
complete. No patients will begin protocol therapy without formal registration as per the 
process below. 
4.3 
Patient Registration 
Patients must not start protocol treatment prior to registration. 
Patients must meet all of the eligibility requirements listed in Section 3 prior to registration. 
Treatment should begin ≤ 10 working days from study entry (date of registration). 
An eligibility checklist is included in Section 3. A confirmation of eligibility assessment by 
the investigator and/or site will be performed during the registration process. 
Upon determination that a subject meets eligibility criteria, the subject will be registered in 
the study by site personnel via an electronic data capture (eDC) system. Confirmation of 
registration will be displayed in the eDC system. 
Full information regarding registration procedures and guidelines can be found in the SRM 
provided to your site. Correspondence regarding patient registration must be kept in the 
study records. 
4.4 
Research Tissue and Blood Samples 
Mandatory tumor tissue samples are required to be available for enrollment. 
Mandatory peripheral blood samples will also be collected. 
Time points for tissue and blood samples are outlined in the study parameters (Section 10) 
and specific requirements are outlined in the correlative section of this protocol (Section 13) 
and the lab manual. 


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5. 
Study Design 
5.1 
Overview 
This is a single arm, unblinded, open-label phase 2 study of durvalumab administered 
concurrently with pemetrexed/cisplatin chemotherapy as first-line treatment for 
unresectable pleural mesothelioma. The first six patients enrolled will be monitored for 
safety of the combination. A maximum of 55 patients (50 patients to be treated with expected 
ineligibility rate of 10%) will be enrolled and will receive up to 6 three week cycles of 
concurrent durvalumab with chemotherapy. Patients with responding or stable disease after 
six cycles of concurrent treatment will continue on durvalumab as a single agent 
administered once every 3 weeks. Maximum duration of durvalumab treatment is 12 months 
(inclusive of any treatment delays or missed treatments) starting from Cycle 1 of concurrent 
treatment. 
Carboplatin may be substituted for cisplatin in patients with a documented contraindication 
(e.g., ototoxicity, renal function) to the use of cisplatin. These patients must otherwise fulfill 
the eligibility criteria (Section 3). In addition, for patients who receive cisplatin, carboplatin 
may also be substituted after Cycle 1 for cisplatin related toxicity (e.g., grade 3 ototoxicity, 
grade 3 nausea) at the investigator’s discretion. Once carboplatin is substituted for cisplatin, 
patients cannot change back to cisplatin. 
The study will be conducted at up to 26 US-based study centers. 
All subjects will be evaluated regularly and their clinical status classified according to 
RECIST guidelines Version 1.1 [42] with modifications for pleural mesothelioma. All subjects 
will be followed for survival until the end of study (Section 7.2). AEs and SAEs will be 
followed as per Section 8. The objectives are described in Section 2. 
5.2 
Initial Enrollment of Six Patients with Safety Monitoring 
As durvalumab has not been previously combined with pemetrexed platinum chemotherapy 
the study will commence with an initial enrollment of 6 patients who will receive pemetrexed 
and cisplatin (or carboplatin described in Section 3 and Section 5.1) combined with 
durvalumab for up to 6 cycles. After 6 cycles patients who have a PR or SD will continue on 
durvalumab until disease progression. In this initial run-in period subjects will be monitored 
for safety. The combination will be declared intolerable if ≥ 2 of the 6 patients experience a 
DLT defined in Section 6.2 occurring during the first 2 cycles of concurrent therapy phase. 
The initial 6 patients completed 2 cycles of concurrent therapy with no DLTs. 
The detailed statistical analysis plan is described in Section 12 of this protocol. 
5.3 
Expansion 
The initial six patients were monitored for safety, without suspension to accrual and, the 
study will proceed with enrollment for a total of 55 patients 
An Interim Safety Analysis on the first 15 patients who completed two cycles of therapy was 
also completed without suspension to accrual (Section 12.2.5 for details) and no safety 
concerns noted. It is expected that 50 of the 55 patients enrolled will receive treatment 
(ineligibility rate of 10%). Carboplatin may be substituted for cisplatin for patients with a 
documented contraindication (e.g., ototoxicity, renal function) to use of cisplatin and these 
patients must otherwise fulfill the eligibility criteria as noted in Section 3 and above in Section 
5.1. 
5.4 
Evaluation of Subjects 
Progression will be assessed using RECIST Version 1.1 modified for mesothelioma. 
Subjects will continue to receive treatment until disease progression or other discontinuation 
criteria are met. Removal of subject for clinical progression will be at the discretion of the 
Investigator. If a patient is deriving clinical benefit they may continue durvalumab (either 


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concurrent or single agent) until a repeat scan at least 4 weeks later (Section 9.1.5). 
Response assessments will be performed every 6 weeks for the first 18 weeks. After 18 
weeks of treatment, response assessments will be performed every 9 weeks. The same 
method of assessment should be used throughout the study. 
Following documentation of non-fatal confirmed disease progression, all subjects will be 
followed for survival (either routine clinic visit or telephone contact) every 3 months until 
death or the close of the study. 


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6. 
Treatment Plan 
6.1 
Overview 
This is a single arm, open-label phase 2 study of durvalumab administered concurrently with 
pemetrexed/cisplatin (carboplatin may be substituted for cisplatin only as outlined in Section 
3 and Section 5.1) chemotherapy as first-line treatment for unresectable pleural 
mesothelioma. The first six patients enrolled will be monitored for safety of the combination. 
A maximum of 55 patients will be enrolled and will receive up to six 3 week cycles of 
concurrent durvalumab with chemotherapy. Patients with responding or stable disease after 
6 cycles of concurrent treatment will continue on durvalumab as a single agent administered 
once every 3 weeks. Maximum duration of durvalumab treatment is 12 months (inclusive of 
any treatment delays or missed treatments) starting from Cycle 1 of concurrent treatment. 
6.1.1 
Durvalumab Administration 
Durvalumab will be administered before pemetrexed and cisplatin chemotherapy. 
Durvalumab 1120 mg will be administered by an infusion pump as an IV infusion 
over approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. 
Less than 55 minutes will be considered a deviation. 
Standard infusion time is 1 hour. However, if there are interruptions during infusion, 
the total allowed time should not exceed 8 hours at room temperature. Please refer 
to Section 11.1 and guidelines in Section 11.1.7 and Table 11-1. 
6.1.2 
Pemetrexed/Cisplatin Administration 
The recommended dose of pemetrexed is 500 mg/m2 administered as an 
intravenous infusion over 10 minutes (or per investigator discretion and local 
standard-of-care) on Day 1 of each 21-day cycle. 
During concurrent treatment days, pemetrexed infusion will begin approximately 30 
minutes after the infusion of durvalumab has finished (or per investigator discretion 
and local standard-of-care). 
The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning 
approximately 30 minutes after the end of pemetrexed administration (or per 
investigator discretion and local standard-of-care). Patients should receive 
appropriate hydration prior to and/or after receiving cisplatin. Hydration may 
commence prior to or concurrently with durvalumab. 
If carboplatin is substituted for cisplatin per Section 3.9 and Section 5.1, the 
recommended dose of carboplatin is AUC 5 infused over 30 minutes beginning 
approximately 15-30 minutes after the end of the pemetrexed administration (or per 
investigator discretion and local standard-of-care). 
CALVERT FORMULA FOR CARBOPLATIN DOSING 
Total Dose (mg) = (target AUC) x (CrCL by Cockcroft-Gault [Appendix II] + 25) 
Please refer to Section 11.2 for additional information. 
6.1.2.1 
Pemetrexed Premedication 
Oral corticosteroid should be given according to local standards at a 
dose equivalent to dexamethasone 4 mg BID on the day prior to, the 
day of, and the day after the administration of pemetrexed. Oral folic 
acid 350 to 1000 µg daily should be given starting 1 week prior to the 
first dose of pemetrexed, with at least 5 doses of folic acid administered 
in the 7 days prior to the first dose. Oral folic acid should be continued 
daily throughout the treatment with pemetrexed and for 21 days after 
the last dose of pemetrexed has been administered. Intramuscular (IM) 


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injection of Vitamin B12 1000 µg should be given approximately one 
week prior to the first dose of pemetrexed and repeated on the day that 
the third and sixth pemetrexed treatment is administered. Oral folic acid 
and Vitamin B12 injection may also be given per local standard of care. 
6.1.2.2 
Cisplatin Premedication 
Cisplatin will be administered to patients at least 30 minutes following 
the end of the pemetrexed infusion. Pretreatment hydration for cisplatin 
can follow local standard of care or use of 1 to 2 liters of fluid (per local 
standards) infused IV for 2-4 hours prior to cisplatin infusion is 
recommended. Adequate hydration and urinary output must be 
maintained for at least 24 hours following cisplatin administration. 
Administration and monitoring should be performed according to local 
standards. Use of mannitol following the cisplatin infusion should also 
follow local standard-of-care. 
6.1.2.3 
Carboplatin Premedication 
If carboplatin has been substituted for cisplatin per Section 3.9 or 
Section 5.1, premedication should follow local standard-of-care. 
6.1.2.4 
Antiemetics for use with Pemetrexed/Cisplatin (Carboplatin) 
Antiemetic premedication will be administered according to local 
standards. Recommended antiemetic treatments are dexamethasone 
(dosing according to local standards; an equivalent dose of another 
corticosteroid may be substituted) and a 5-HT3 receptor antagonist 
(type per investigator discretion and local standard-of-care). Additional 
use of antiemetic premedications may be employed at the discretion of 
the Investigator. 
6.1.3 
Pemetrexed/Cisplatin (or Carboplatin) Re-Treatment 
Prior to each treatment with pemetrexed/cisplatin (carboplatin), the following 
conditions must be met. 
• 
ANC must be ≥ 1500/mm3 and platelets ≥ 100,000/mm3 prior to the start of each 
cycle. Growth factor support is permitted, and should be administered per 
American Society of Clinical Oncology (ASCO) guideline. 
• 
Pemetrexed: CrCL ≥ 45. 
• 
Cisplatin: Serum creatinine ≤ 1.5 or CrCL ≥ 50. 
o 
Carboplatin may be substituted for cisplatin in patients with ≤ Grade 2 renal 
function at the investigator’s discretion. Once carboplatin is substituted for 
cisplatin, patients cannot change back to cisplatin. 
• 
Carboplatin: CrCL ≥ 45. 
• 
All other drug-related non-hematologic toxicities must have improved to 
baseline or ≤ Grade 2. Exceptions to this criterion include alopecia and other 
toxicities of non-vital organs. 
Treatment may be delayed for up to 3 weeks to allow sufficient time for recovery 
from treatment-related toxicities. If a delay greater than 3 weeks is required, the 
Investigator should confer with PrECOG to determine the appropriateness of 
continued treatment. In the event of a treatment delay, subsequent cycles should 
occur relative to the delayed cycle (maintaining a 3-week cycle interval). In other 
words, subsequent cycles should not be shortened to “make-up” for any delays. 


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6.2 
Dose Limiting Toxicity - Definition 
DLT, as defined below, will be evaluated for the first 2 cycles (2 doses) of concurrent therapy 
with durvalumab, pemetrexed and cisplatin. Toxicity that is clearly and directly related to the 
primary disease or to another etiology is excluded from this definition. The following will be 
DLTs: 
• 
Any Grade 4 immune-mediated adverse event (imAE) 
• 
Any ≥ Grade 3 colitis 
• 
Any Grade 3 or 4 non-infectious pneumonitis irrespective of duration 
• 
Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the 
initiation of maximal supportive care 
• 
Any Grade 3 imAE, excluding colitis or pneumonitis, that does not downgrade to Grade 
2 within 3 days after onset of the event despite optimal medical management including 
systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days 
• 
Liver transaminase elevation >8x ULN or total bilirubin >5x ULN 
The definition excludes the following conditions: 
• 
Grade 3 fatigue lasting ≤ 7 days 
• 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) 
• 
Concurrent vitiligo or alopecia of any AE grade 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
• 
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia will 
be a DLT regardless of duration or reversibility. 
• 
Grade 3 or 4 lymphopenia 
• 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days 
• 
Isolated Grade 3 electrolyte abnormalities not associated with clinical signs or 
symptoms and reversed with appropriate maximal medical intervention within 3 days 
Immune-mediated AEs are defined as AEs of an immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology. In the absence of a clinically significant abnormality, 
repeat laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT. 
6.2.1 
DLT Assessment – Initial Enrollment of Six Patients 
For the purposes of safety decision making during the initial enrollment of six 
patients, DLTs will be evaluated for the first 2 cycles (2 doses) of concurrent therapy 
with durvalumab, pemetrexed and cisplatin. DLTs occurring beyond this window will 
be taken into account when determining whether to proceed to enroll the full 
planned cohort of 55. DLTs will be monitored for the first 2 cycles (42 days) of 
concurrent therapy. Depending on the rate of accrual and review of the data 
pertaining to DLT evaluation, accrual may be halted to ensure it is safe to continue 
patient enrollment. 


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6.2.2 
Phase II Treatment Administration 
During the total enrollment of 55 patients (50 expected to commence therapy), 
toxicity will continue to be closely monitored. Because this is the first time that 
durvalumab is being combined with pemetrexed/cisplatin in this setting, close 
monitoring of toxicity is an important endpoint of the trial. We will also collect data 
and conduct an interim safety analysis among the first 15 patients who have 
completed the first 2 cycles (6 weeks) of concurrent therapy without suspension to 
accrual. The safety analysis will be done based on the electronic case report form 
(eCRF) database. This preliminary toxicity analysis will occur in addition to the twice 
yearly monitoring for toxicity for the purposes of interim reporting. 
Interim analysis on first 15 patients who completed the first 2 cycles of concurrent 
therapy showed no safety concerns. 
6.3 
Dose Delays & Modifications 
All toxicities should be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V4.03). A copy 
of 
the 
CTCAE 
V4.03 
can 
be 
downloaded 
from 
the 
CTEP 
website 
(http://www.ctep.cancer.gov). 
A 3 day window is allowed for scheduled therapy, tests and/or results except as noted below 
for CBC with differential and platelet count. Delays due to holidays, weekends, bad weather 
or other unforeseen circumstances will be permitted. 
6.3.1 
Durvalumab 
For AEs that are considered at least partly due to administration of durvalumab, the 
following dose adjustment guidance may be applied: 
• 
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity where required). 
• 
If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of durvalumab along with appropriate 
continuing supportive care. If medically appropriate, dose modifications are 
permitted for durvalumab (Table 6-1 and 6-2). 
• 
All dose modifications should be documented with clear reasoning and 
documentation of the approach taken. 
In addition, there are certain circumstances in which durvalumab should be 
permanently discontinued. 
Following the first dose of durvalumab, subsequent administration of durvalumab 
can be modified based on toxicities observed (Table 6-1 and 6-2). Dose reductions 
are not permitted for durvalumab. 
Based on the mechanism of action of durvalumab leading to T-cell activation and 
proliferation, there is the possibility of observing immune mediated Adverse Events 
(imAEs) during the conduct of this study. Potential imAEs include immune-mediated 
enterocolitis, dermatitis, hepatitis, and endocrinopathies. Subjects should be 
monitored for signs and symptoms of imAEs. In the absence of an alternate etiology 
(e.g., infection or PD) signs or symptoms of enterocolitis, dermatitis, hepatitis, and 
endocrinopathy should be considered to be immune-related. 
NOTE: Patients with previous history of bleeding and/or are taking anticoagulant 
medication may have a higher risk of subsequent bleeding. Monitor patients 
closely for possible bleeding. 
 


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Dose modification recommendations and toxicity management guidelines for 
immune-mediated reactions, for infusion-related reactions, and for non-immune-
mediated reactions are detailed in Tables 6-1 and 6-2, respectively. 
Patients must have at least 2 cycles of pemetrexed/cisplatin (or carboplatin) with 
durvalumab in order to be eligible to proceed to maintenance durvalumab. 
In addition, management guidelines for adverse events of special interest (AESIs) 
are detailed in Section 8.2. All toxicities will be graded according to NCI CTCAE 
V4.03.


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Table 6-1 
Dose Modifications and Toxicity Management Guidelines for Immune-Mediated Reactions Associated with Durvalumab 
 
Dose Modifications 
Toxicity Management 
Immune-Mediated 
Adverse Events 
(Overall Management 
For toxicities not noted 
below) 
Drug administration modifications of study drug/study regimen will be made 
to manage potential immune-mediated AEs based on severity of treatment-
emergent toxicities graded per NCI CTCAE V4.03. 
In addition to the criteria for permanent discontinuation of study drug/regimen 
based on CTC grade/severity (table below), permanently discontinue study 
drug/study regimen for  the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤ 10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/regimen. 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing. 
It is recommended that management of immune-mediated 
adverse events (imAEs) follow the guidelines presented in this 
table: 
- 
It is possible that events with an inflammatory or immune 
mediated mechanism could occur in nearly all organs, 
some of them not noted specifically in these guidelines. 
- 
Whether 
specific 
immune-mediated 
events 
(and/or 
laboratory indication of such events) are noted in these 
guidelines or not, patients should be thoroughly evaluated 
to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, infections, etc.) to a 
possible immune-mediated event. In the absence of a clear 
alternative etiology, all such events should be managed as 
if they were immune related. 
General Recommendations: 
- 
Symptomatic and topical therapy should be considered for 
low-grade (Grade 1 or 2, unless otherwise specified) 
events. 
- 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe 
(Grade ≥ 3) events promptly start prednisone 1-2 
mg/kg/day PO or IV equivalent. 
- 
Some events with high likelihood for morbidity and/or 
mortality – e.g., myocarditis, or other similar events even if 
they are not currently noted in the guidelines – should 
progress 
rapidly 
to 
high 
dose 
IV 
corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event 
is Grade 2, and if clinical suspicion is high and/or there has 
been clinical confirmation. Consider, as necessary, 
discussing with the study physician, and promptly pursue 
specialist consultation. 
- 
If symptoms recur or worsen during corticosteroid tapering 
(28 days of taper), increase the corticosteroid dose 
(prednisone dose [e.g. up to 2-4 mg/kg/day PO or IV 
equivalent]) 
until 
stabilization 
or 
improvement 
of 
symptoms, then resume corticosteroid tapering at a slower 
rate (>28 days of taper). 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to 
≤ Grade 1. 
• 
If toxicity worsens then treat as Grade 3 or Grade 4. 
- Study drug/study treatment can be resumed once event 
stabilizes to Grade ≤ 1 after completion of steroid taper. 
- Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
1) 
Event stabilizes and is controlled 
2) 
Patient is clinically stable as per Investigator or treating 
physician’s clinical judgement, and 
3) 
Doses of prednisone are ≤ 10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, may permanently discontinue 
study drug/ study regimen. Please refer to guidelines below. 


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Grade 4 
Permanently discontinue study drug/ study regimen. 
NOTE: For Grade 3 and above asymptomatic amylase or lipase 
levels hold study drug/regimen and if complete work up 
shows no evidence of pancreatitis, may continue or 
resume study drug/regimen. 
NOTE: Study drug/study regimen should be permanently 
discontinued in Grade 3 events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or other 
similar events even if they are not currently noted in the 
guidelines. Similarly, consider whether study drug/study 
regimen should be permanently discontinued in Grade 2 
events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they 
are not currently noted in the guidelines – when they do 
not rapidly improve to Grade <1 upon treatment with 
systemic steroids and following full taper. 
NOTE: There are some exceptions to permanent discontinuation 
of study drug for Grade 4 events (i.e., hypo or hyper-
thyroidism, Type 1 diabetes mellitus) 
- 
More potent immunosuppressives such as TNF inhibitors 
(e.g., infliximab) - (also refer to individual sections of the 
imAE for specific type of immunosuppressive) should be 
considered for events not responding to systemic steroids. 
Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood 
for morbidity and/or mortality – e.g., myocarditis, or other 
similar events even if they are not currently noted in the 
guidelines – when these events are not responding to 
systemic steroids. 
- 
With long-term steroid and other immunosuppressive use, 
consider need for Pneumocystis jirovecii pneumonia (PJP, 
formerly known as Pneumocystis carinii pneumonia) 
prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
- 
Discontinuation of study drug is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor 
response (e.g. inflammatory reaction at sites of metastatic 
disease, lymph nodes etc.). Continuation of study drug in 
this situation should be based upon a benefit/risk analysis 
for that patient. 


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Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
- 
Monitor patients for signs and symptoms of pneumonitis or ILD 
(new onset or worsening shortness of breath or cough). Patients 
should be evaluated with imaging and pulmonary function tests 
including other diagnostic procedures as described below. 
- 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), laboratory 
work-up and high-resolution CT scan. 
Grade 1 
(Asymptomatic, clinical 
or diagnostic 
observations only, 
intervention not 
indicated) 
No dose modification required. However, 
consider holding study drug/study 
regimen dosing as clinically appropriate 
and during diagnostic work-up for other 
etiologies. 
For Grade 1 (Radiographic Changes Only) 
- 
Monitor and closely follow up in 2-4 days for clinical symptoms, 
pulse oximetry (resting and exertion) and laboratory work-up and 
then as clinically indicated. 
- 
Consider Pulmonary and Infectious disease consult. 
Grade 2 
(Symptomatic, medical 
intervention indicated, 
limiting instrumental 
ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1. 
• If toxicity worsens then treat as Grade 
3 or Grade 4. 
• If toxicity improves to ≤ Grade 1, then 
the 
decision 
to 
reinitiate 
study 
drug/regimen will be based upon 
treating physician’s clinical judgment 
and after completion of steroid taper. 
For Grade 2 (Mild to Moderate New Symptoms) 
- 
Monitor symptoms daily and consider hospitalization. 
- 
Promptly start systemic steroids (e.g., prednisone 1-2 mg/kg/day 
PO or IV equivalent). 
- 
Reimaging as clinically indicated. 
- 
If no improvement within 3-5 days, additional workup should be 
considered and prompt treatment with IV methylprednisolone 2-
4 mg/kg/day started. 
- 
If 
still 
no 
improvement 
within 
3-5 
days 
despite 
IV 
methylprednisolone 
at 
2-4 
mg/kg/day, 
promptly 
start 
immunosuppressive therapy such as TNF inhibitors (e.g., 
infliximab at 5 mg/kg every 2 weeks). Caution: Important to rule 
out sepsis and refer to infliximab label for general guidance 
before using infliximab. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider 
prophylactic antibiotics, antifungal 
or 
anti-PJP 
treatment (refer to current NCCN guidelines for treatment of  
cancer-related infections (Category 2B recommendation).43 
- 
Consider pulmonary and infectious disease consult. 
- 
Consider as necessary discussing with study physician. 


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Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
(Grade 3: Severe 
symptoms; limiting self-
care ADL; oxygen 
indicated 
Grade 4: life threatening 
respiratory compromise, 
urgent intervention 
indicated [e.g. 
tracheostomy or 
intubation])  
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life threatening) 
- Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
- Obtain Pulmonary and Infectious disease consult, consider, as 
necessary, discussing with study physician. 
- Hospitalize the patient. 
- Supportive Care (oxygen, etc.). 
- If no improvement within 3-5 days, additional workup should be 
considered 
and 
prompt 
treatment 
with 
additional 
immunosuppressive therapy such as TNF inhibitors (e.g., 
infliximab at 5 mg/kg every 2 weeks dose) started. Caution: rule 
out sepsis and refer to infliximab label for general guidance before 
using infliximab. 
- Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and in particular, 
anti-PJP treatment (please refer to current NCCN guidelines for 
treatment 
of 
cancer-related 
infections 
(Category 
2B 
recommendation).43 
Diarrhea/Colitis 
Any Grade 
General Guidance 
- Monitor for symptoms that may be related to diarrhea/enterocolitis 
(abdominal pain, cramping, or changes in bowel habits such as 
increased frequency over baseline or blood in stool) or related to 
bowel perforation (such as sepsis, peritoneal signs and ileus). 
- Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, infections) 
including testing for clostridium difficile toxin, etc. 
- Steroids should be considered in the absence of clear alternative 
etiology, even for low grade events, in order to prevent potential 
progression to higher grade event. 
- Use analgesics carefully; they can mask symptoms of perforation 
and peritonitis 
Grade 1 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: asymptomatic; 
clinical or diagnostic 
observation only) 
No dose modification 
For Grade 1 Diarrhea 
- Close monitoring for worsening symptoms. 
- Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association 
colitis diet), and loperamide. Use of probiotics as per treating 
physician’s clinical judgment. 


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Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 
(Diarrhea: stool 
frequency of 4-6 over 
baseline per day) 
(Colitis: abdominal pain; 
mucus or blood in stool) 
Hold study drug/study regimen until 
resolution to ≤ Grade 1. 
• If toxicity worsens then treat as 
Grade 3 or Grade 4. 
• If toxicity improves to ≤ Grade 1, then 
study drug/study regimen can be 
resumed after completion of steroid 
taper. 
For Grade 2 Diarrhea 
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, 
dietary 
changes 
(e.g., 
American 
Dietetic 
Association colitis diet), and loperamide and/or budesonide. 
- 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup such as 
imaging and/or colonoscopy to confirm colitis and rule out 
perforation, and prompt treatment with IV methylprednisolone 2-
4 mg/kg/day started. 
- 
If still no improvement within 3-5 days despite 2-4 mg/kg IV 
methylprednisolone, promptly start immunosuppressives such 
as infliximab at 5 mg/kg once every 2 weeks.44 Caution: 
Important to rule out bowel perforation and refer to infliximab 
label for general guidance before using infliximab. 
- 
Consider, as necessary, discussing with study physician if no 
resolution to ≤ Grade 1 in 3-4 days. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti-PJP 
treatment (please refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation]). 
Grade 3 or 4 
(Grade 3 Diarrhea: stool 
frequency of ≥ 7 over 
baseline per day; 
Grade 4 Diarrhea: life 
threatening 
consequences) 
(Grade 3 Colitis: severe 
abdominal pain, change 
in bowel habits, medical 
intervention indicated, 
peritoneal signs; 
Grade 4 Colitis: life-
threatening 
consequences, urgent 
intervention indicated) 
Grade 3 
Permanently discontinue study 
drug/study regimen for Grade 3 if toxicity 
does not improve to Grade ≤ 1 within 14 
days; study drug/study regimen can be 
resumed after completion of steroid 
taper. 
Grade 4 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 Diarrhea 
- 
Promptly initiate empiric IV methylprednisolone 2 to 4 mg/kg/day 
or equivalent. 
- 
Monitor stool frequency and volume and maintain hydration. 
- 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
- 
If still no improvement within 3-5 days of IV methylprednisolone 
2 to 4 mg/kg/day or equivalent, promptly start further 
immunosuppressives (e.g., infliximab at 5 mg/kg once every 2 
weeks). Caution: Ensure GI consult to rule out bowel perforation 
and refer to infliximab label for general guidance before using 
infliximab. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti-PJP 
treatment (please refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation]). 


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Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Hepatitis (Elevated 
Liver Function Tests 
[LFTs]) 
Infliximab should not 
be used for 
management of 
Immune Related 
Hepatitis 
Any Grade 
General Guidance 
- 
Monitor and evaluate liver function test: AST, ALT, ALP and total 
bilirubin. 
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications). 
Grade 1 
(AST or ALT > to 3x ULN 
and/or Total Bili > to 1.5x 
ULN) 
• No dose modification 
• If  it worsens, treat as Grade 2 event 
For Grade 1 AST or ALT and/or Total Bili Elevation 
- 
Continue LFT monitoring per protocol. 
Grade 2 
(AST or ALT >3 to ≤ 5x 
ULN and/or Total Bili 
>1.5 to ≤ 3.0 ULN) 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1. 
• If toxicity worsens then treat as Grade 
3 or Grade 4. 
• If toxicity improves to ≤ Grade 1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2 AST or ALT and or Total Bili Elevation 
- 
Regular and frequent checking of LFTs (e.g. every 1-2 days) until 
elevations of these are improving or resolved. 
- 
If no resolution to ≤ Grade 1 in 1-2 days, consider, as necessary, 
discussing with study physician. 
- 
If event is persistent (>3-5 days) or worsens, promptly start 
prednisone 1-2 mg/kg/day PO or IV equivalent. 
- 
If still no improvement within 3-5 days despite 1-2 mg/kg/day of 
prednisone PO or IV equivalent, consider additional work-up and 
prompt treatment with IV methylprednisolone 2-4 mg/kg/day 
started. 
- 
If still no improvement within 3-5 days despite 2-4 mg/kg/day of 
IV methylprednisolone, promptly start immunosuppressives (i.e., 
mycophenolate mofetil).45 Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab should NOT 
be used. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti-PJP 
treatment (please refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation]). 


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Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 
(AST or ALT >5-20x ULN 
and/or Total Bili >3.0-10x  
ULN) 
For elevations in transaminases ≤ 8x 
ULN, or elevations in bilirubin ≤ 5x ULN. 
• 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 or 
baseline. 
• 
Resume study drug/study regimen if 
elevations downgrade ≤ Grade 1 or 
baseline within 14 days and after 
completion of steroid taper. 
• Permanently 
discontinue 
study 
drug/study regimen if the elevations do 
not downgrade to ≤ Grade 1 or 
baseline within 14 days. 
For elevations in transaminases >8x 
ULN or elevations in bilirubin >5x ULN, 
discontinue study drug/study regimen. 
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria (AST and/or ALT >3x 
ULN + bilirubin >2x ULN without initial 
findings of cholestasis (i.e. elevated 
Alkaline Phosphatase) and in the 
absence of any alternative cause.46 
For Grade 3 or 4 AST or ALT and/or Total Bili Elevation 
- 
Promptly initiate empiric IV methylprednisolone at 1 to 4 
mg/kg/day or equivalent. 
- 
If still no improvement within 3-5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent promptly start treatment 
with immunosuppressive therapy (i.e., mycophenolate mofetil). 
Discuss with study physician if mycophenolate is not available. 
Infliximab should NOT be used. 
- 
Hepatology consult, abdominal workup, and imaging as 
appropriate. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti-PJP 
treatment (please refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation]). 
Grade 4 
(AST or ALT >20x ULN 
and/or Total Bili >10x 
ULN) 
Permanently discontinue study 
drug/study regimen. 


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Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Nephritis 
or 
Renal 
Dysfunction (Elevated 
Serum Creatinine)  
Any Grade 
General Guidance 
- 
Consult with Nephrologist. 
- 
Monitor for signs and symptoms that may be related to changes 
in renal function (e.g. routine urinalysis, elevated serum BUN and 
creatinine, 
decreased 
creatinine 
clearance, 
electrolyte 
imbalance, decrease in urine output, proteinuria, etc.). 
- 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, infections etc.). 
- 
Steroids should be considered in the absence of clear alternative 
etiology even for low grade events (Grade 2), in order to prevent 
potential progression to higher grade event. 
Grade 1 
[Serum Creatinine >1-
1.5x baseline; >ULN to 
1.5x ULN] 
No dose modification 
For Grade 1 Elevated Creatinine 
- 
Monitor serum creatinine weekly and any accompanying 
symptom. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If it worsens, depending on the severity, treat as Grade 2 or 
Grade 3 or 4. 
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc. 
Grade 2 
[Serum Creatinine >1.5-
3.0x baseline; >1.5-3.0x 
ULN] 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline. 
• 
If toxicity worsens then treat as Grade 
3 or Grade 4. 
• 
If toxicity improves to ≤ Grade 1 or 
baseline resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2 Elevated Creatinine 
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc. 
- 
Carefully monitor serum creatinine every 2-3 days and as 
clinically warranted. 
- 
Consult Nephrologist and consider renal biopsy if clinically 
indicated. 
- 
If event is persistent (>3-5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2-4 mg/kg/day started. 


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Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
- 
Once improving gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti-PJP 
treatment (please refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation]). 
- 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: Serum 
Creatinine >3.0x 
baseline; >3.0-6.0x ULN 
Grade 4: Serum 
Creatinine >6.0x ULN) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 Elevated Creatinine 
- 
Carefully monitor serum creatinine on daily basis. 
- 
Consult Nephrologist and consider renal biopsy if clinically 
indicated. 
- 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti-PJP 
treatment (please refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation]. 
Rash (excluding 
bullous skin 
formations) 
Any Grade 
General Guidance 
Monitor for signs and symptoms of dermatitis (rash and pruritus) 
**IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY DRUG 
DISCONTINUED** 
Grade 1 
No dose modification 
For Grade 1 
- 
Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea 
cream). 
Grade 2 
For persistent (>1-2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to ≤ Grade 1 or 
baseline 
• If toxicity worsens then treat as 
Grade 3 
For Grade 2 
- 
Obtain dermatology consult. 
- 
Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea 
cream). 
- 
Consider moderate-strength topical steroid. 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
40 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
• 
If toxicity improves to ≤ Grade 1 or 
baseline, 
then 
resume 
study 
drug/study regimen after completion of 
steroid taper. 
- 
If no improvement of rash/skin lesions occurs within 3-5 days or 
is worsening despite symptomatic treatment and/or use of 
moderate strength topical steroid, consider, as necessary, 
discussing with study physician and promptly start systemic 
steroids prednisone 1-2 mg/kg/day PO or IV equivalent. 
- 
Consider skin biopsy if persistent for >1-2 weeks or recurs. 
Grade 3 
Hold study drug/study regimen until 
resolution to Grade ≤ 1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤ 1 or baseline within 30 days, 
then permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 
- 
Consult dermatology. 
- 
 Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
- 
Consider hospitalization. 
- 
Monitor extent of rash [Rule of Nines (Appendix III)]. 
- 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti-PJP 
treatment (please refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation]). 
- 
Consider, as necessary, discussing with study physician. 
Grade 4 
Permanently discontinue study 
drug/study regimen. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism, Type 
1 diabetes mellitus, 
hypophysitis, 
hypopituitarism, 
adrenal insufficiency, 
exocrine event of 
amylase/lipase 
increased) 
Any Grade 
General Guidance 
- 
Consider consulting an Endocrinologist for endocrine events. 
- 
Consider, as necessary, discussing with study physician. 
- 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension and 
weakness. 
- 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, infections, etc.). 
- 
Depending on suspected endocrinopathy, monitor and evaluate 
thyroid function tests: TSH, free T3 and free T4 and other relevant 
endocrine and related labs (e.g., blood glucose, ketone levels, 
HgA1c). 
- 
For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as there 
are no other signs or symptoms of pancreatic inflammation. 


PrECOG Protocol Number: PrE0505 
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Date: 3/19/2018 
 
41 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
- 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, 
diabetes insipidus), the investigator should send a blood sample 
for appropriate autoimmune antibody testing. 
Grade 1 
No dose modification 
For Grade 1: (including those with asymptomatic TSH 
elevation) 
- 
Monitor patient with appropriate endocrine function tests. 
- 
For 
suspected 
hypophysitis/hypopituitarism, 
consider 
consultation of an endocrinologist to guide assessment of early-
morning ACTH, cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not be useful in 
diagnosing early secondary adrenal insufficiency). 
- 
If TSH < 0.5x LLN, or TSH >2x ULN or consistently out of range 
in 2 subsequent measurements, include FT4 at subsequent 
cycles as clinically indicated and consider consultation of an 
endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism and Type I diabetes 
mellitus, hold study drug/study regimen 
dose until subject is clinically stable. 
• 
If toxicity worsens then treat as Grade 
3 or Grade 4. 
- Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper. 
- Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen on the 
following conditions: 
1) 
Event 
stabilizes 
and 
is 
controlled. 
2) 
Patient is clinically stable as per 
Investigator 
or 
treating 
physician’s clinical judgement. 
For Grade 2: (including those with symptomatic 
endocrinopathy) 
- 
Consult endocrinologist to guide evaluation of endocrine 
function; and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. 
- 
For patients with abnormal endocrine work up, except those with 
isolated hypothyroidism or Type 1 diabetes mellitus, and as 
guided 
by 
an 
endocrinologist, 
consider 
short-term, 
corticosteroids (e.g., 1-2 mg/kg/day methylprednisolone or IV 
equivalent) and prompt initiation of treatment with relevant 
hormone replacement (e.g. hydrocortisone, sex hormones). 
- 
Isolated hypothyroidism may be treated with replacement 
therapy without study drug/study regimen interruption and 
without corticosteroids. 
- 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
42 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
3) 
Doses of prednisone are ≤ 10 
mg/day or equivalent. 
- 
Once improving on steroids, gradually taper immunosuppressive 
steroids (as appropriate and with guidance of endocrinologist) 
over ≥ 28 days and consider prophylactic antibiotics, antifungals 
and anti-PJP treatment (please refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]). 
- 
For patients with normal endocrine work up (lab or MRI scans), 
repeat labs/MRI as clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) 
are controlled. 
• 
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper. 
• Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen on the 
following conditions. 
1) 
The event stabilizes and is 
controlled. 
2) 
The patient is clinically stable as 
per 
investigator 
or 
treating 
physician’s clinical judgement. 
3) 
Doses 
of 
prednisone 
are 
≤10 mg/day or equivalent. 
For Grade 3 or 4 
- 
Consult endocrinologist to guide evaluation of endocrine function 
and, as indicated by suspected endocrinopathy and as clinically 
indicated, consider pituitary scan. Hospitalization recommended. 
- 
For patients with abnormal endocrine work-up, except those with 
isolated hypothyroidism or Type 1 diabetes mellitus, and as 
guided by an endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
- 
For adrenal crisis, severe dehydration, hypotension, or shock: 
immediately 
initiate 
intravenous 
corticosteroids 
with 
mineralocorticoid activity. 
- 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
- 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
- 
Once improving on steroids, gradually taper immunosuppressive 
steroids (as appropriate and with guidance of endocrinologist) 
over ≥ 28 days and consider prophylactic antibiotics, antifungals 
and anti-PJP treatment (please refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]). 
 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
43 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Immune Mediated 
Neurotoxicity 
(to include but not 
limited to limbic 
encephalitis, 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
General Guidance 
- 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes and 
medications, etc.). 
- 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
- 
Consider appropriate diagnostic testing (e.g. electromyogram 
and nerve conduction investigations). 
- 
Symptomatic treatment with neurological consult as appropriate. 
Grade 1 
No dose modifications 
For Grade 1 
See “Any Grade” recommendations above. 
Grade 2 
• For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to 
≤ Grade 1. 
• For sensory neuropathy/neuropathic 
pain, 
consider 
holding 
study 
drug/study 
regimen 
dose 
until 
resolution to ≤ Grade 1. 
o 
If toxicity worsens then treat as 
Grade 3 or Grade 4. 
• Study drug/study regimen can be 
resumed once event improves to 
Grade ≤ 1 and after completion of 
steroid taper. 
For Grade 2 
- 
Consider, as necessary, discussing with the study physician. 
- 
Obtain Neurology Consult. 
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.). 
- 
Promptly start systemic steroids prednisone 1-2 mg/kg/day PO 
or IV equivalent. 
- 
If no improvement within 3-5 days despite 1-2 mg/kg/day 
prednisone PO or IV equivalent consider additional workup and 
promptly treat with additional immunosuppressive therapy (e.g. 
IVIG). 
Grade 3 
• Hold Study drug/study regimen dose 
until resolution to ≤ Grade 1. 
• Permanently 
discontinue 
study 
drug/study regimen if Grade 3 imAE 
does not resolve to ≤ Grade 1 within 
30 days. 
For Grade 3 or 4 
- 
Consider, as necessary, discussing with study physician. 
- 
Obtain Neurology Consult. 
- 
Consider hospitalization. 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
44 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
• Permanently 
discontinue 
study 
drug/study regimen. 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day 
or equivalent. 
- 
If no improvement within 3-5 days despite IV corticosteroids, 
consider additional workup and promptly treat with additional 
immunosuppressants (e.g. IVIG). 
- 
Once stable, gradually taper steroids over ≥ 28 days. 
Immune-Mediated 
Peripheral Neuromotor 
Syndromes, such as 
Guillain-Barre and 
Myasthenia Gravis 
Any Grade 
General Guidance 
- 
The 
prompt 
diagnosis 
of 
immune-mediated 
peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that may predict 
a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or 
autonomic instability. 
- 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes and 
medications, etc.). It should be noted that the diagnosis of 
immune-mediated peripheral neuromotor syndromes can be 
particularly challenging in patients with underlying cancer, due to 
the multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult. 
- 
Neurophysiologic diagnostic testing (e.g., electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon suspicion 
of such conditions and may be best facilitated by means of a 
neurology consultation. 
- 
It is important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered effective. 
Patients requiring treatment should be started with IVIG and 
followed by plasmapheresis if not responsive to IVIG. 
Grade 1 
No dose modification 
For Grade 1 
- 
Consider, as necessary, discussing with the study physician. 
- 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
- 
Obtain a neurology consult. 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
45 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 
Hold study drug/study regimen dose until 
resolution to ≤ Grade 1. 
Permanently discontinue study 
drug/study regimen if it does not resolve 
to ≤ Grade 1 within 30 days or if there 
are signs of respiratory insufficiency or 
autonomic instability. 
Grade 2 
- 
Consider, as necessary, discussing with the study physician. 
- 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
- 
Obtain a Neurology Consult. 
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.). 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia 
Gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening 
of 
myasthenia 
and 
should 
typically 
be 
administered in a monitored setting under supervision of a 
consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIG. Such decisions are 
best made in consultation with a neurologist, taking into 
account the unique needs of each patient. 
o 
If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE 
o 
Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. 
o 
Patients requiring treatment should be started with IVIG and 
followed by plasmapheresis if not responsive to IVIG. 
Grade 3 
Hold study drug/study regimen dose until 
resolution to ≤ Grade 1 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to ≤ Grade 1 within 30 
days or if there are signs of respiratory 
insufficiency or autonomic instability. 
For severe or life threatening (Grade 3 or 4) events 
- 
Consider, as necessary, discussing with study physician. 
- 
Recommend hospitalization. 
- 
Monitor symptoms and obtain neurological consult. 
 
 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
46 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
Permanently discontinue study 
drug/study regimen. 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia 
Gravis. It should typically be administered in a monitored 
setting under supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIG. 
o 
If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE 
o 
It is important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. 
o 
Patients requiring treatment should be started with IVIG and 
followed by plasmapheresis if not responsive to IVIG. 
Myocarditis 
Any grade 
General Guidance 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis 
- 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline cardiopulmonary 
disease and reduced cardiac function. 
- 
Consider, as necessary, discussing with the study physician. 
- 
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt 
assessment of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram (ECHO), monitoring of 
oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or cardiac 
MRI can complement ECHO to assess wall motion abnormalities 
when needed. 
- 
Patients should be thoroughly evaluated to rule out any 
alternative 
etiology 
(e.g., 
disease 
progression, 
other 
medications, or infections). 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
47 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Grade 1 
(asymptomatic with 
laboratory (e.g., BNP) or 
cardiac imaging 
abnormalities) 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical symptoms, 
BNP, cardiac enzymes, ECG, ECHO, pulse oximetry (resting and 
exertion), and laboratory work-up as clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 
Grade 2,3 or 4 
(Grade 2: Symptoms with 
mild to moderate activity 
or exertion) 
(Grade 3: Severe with 
symptoms at rest or with 
minimal 
activity 
or 
exertion; 
intervention 
indicated) 
(Grade 4: 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
(e.g., 
continuous 
IV 
therapy or mechanical 
hemodynamic support)) 
• 
If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/study regimen will be 
based 
upon 
treating 
physician’s 
clinical judgment and after completion 
of steroid taper. If toxicity does not 
rapidly 
improve, 
permanently 
discontinue study drug/study regimen. 
• 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined whether 
and when to complete diagnostic procedures including a cardiac 
biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If 
no 
improvement 
within 
3 
to 
5 
days 
despite 
IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive 
therapy 
such 
as 
TNF 
inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, antifungals, or anti-
PJP treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation]). 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
− 
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, but 
rarely affects the extremities including hands and fingers; also 
difficulty breathing and/or trouble swallowing can occur and 
progress rapidly. Increased general feelings of tiredness and 
fatigue may occur, and there can be new-onset falling, difficulty 
getting up from a fall, and trouble climbing stairs, standing up 
from a seated position, and/or reaching up. 
 
 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
48 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
− 
If poly/myositis is suspected, a Neurology consultation should be 
obtained early, with prompt guidance on diagnostic procedures. 
Myocarditis may co-occur with poly/myositis; refer to guidance 
under Myocarditis. Given breathing complications, refer to 
guidance under Pneumonitis/ILD. Given possibility of an existent 
(but previously unknown) autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine kinase, 
aldolase, LDH, BUN/creatinine, erythrocyte sedimentation rate or 
C-reactive protein level, urine myoglobin, and additional 
laboratory work-up as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider whether a 
rheumatologist consultation is indicated and could guide need for 
rheumatoid factor, antinuclear antibody, anti-smooth muscle, 
antisynthetase [such as anti-Jo-1], and/or signal-recognition 
particle 
antibodies). 
Confirmatory 
testing 
may 
include 
electromyography, nerve conduction studies, MRI of the 
muscles, and/or a muscle biopsy. Consider Barium swallow for 
evaluation of dysphagia or dysphonia. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative 
etiology 
(e.g., 
disease 
progression, 
other 
medications, or infections). 
 
 
Grade 1 
(mild pain) 
No dose modifications 
For Grade 1 
− 
Monitor and closely follow up in 2 to 4 days for clinical symptoms 
and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
49 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities of 
daily living [ADLs]) 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
• Permanently 
discontinue 
study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency. 
For Grade 2 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if difficulty 
breathing and/or trouble swallowing), promptly start IV 
methylprednisolone 2 to 4 mg/kg/day systemic steroids along 
with receiving input from Neurology consultant. 
− 
If clinical course is not rapidly progressive, start systemic steroids 
(e.g., prednisone 1 to 2 mg/kg/day PO or IV equivalent); if no 
improvement within 3 to 5 days, continue additional work up and 
start treatment with IV methylprednisolone 2 to 4 mg/kg/day. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is 
no improvement within 3 to 5 days, consider start of 
immunosuppressive 
therapy 
such 
as 
TNF 
inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, antifungals, or anti-
PJP treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation]). 
 
Grade 3 or 4 
(pain 
associated 
with 
severe weakness; limiting 
self-care ADLs) 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/ 
study regimen if Grade 3 imAE does not 
resolve to Grade ≤1 within 30 days or if 
there 
are 
signs 
of 
respiratory 
insufficiency. 
For Grade 4: 
Permanently 
discontinue 
study 
drug/study regimen 
For Grade 3 or 4 (severe or life-threatening events) 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from Neurology consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is 
no improvement within 3 to 5 days, consider start of 
immunosuppressive 
therapy 
such 
as 
TNF 
inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 


PrECOG Protocol Number: PrE0505 
Confidential 
Date: 3/19/2018 
 
50 
 
Grade of the Event 
(NCI CTCAE V4.03) 
Dose Modifications 
Toxicity Management 
− 
Consider whether patient may require IVIG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, antifungals, or anti-
PJP treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation]). 
 
Table 6-2 
Dosing Modifications and Toxicity Management Guidelines for Non-Immune Mediated Reactions Associated With 
Durvalumab 
CTC Grade/Severity 
(NCI CTCAE V4.03) 
Dose Modification 
Toxicity Management 
Any Grade 
NOTE: Dose modifications are not required for adverse events not deemed to be 
related to study treatment (i.e. events due to underlying disease) or for laboratory 
abnormalities not deemed to be clinically significant. 
Treat accordingly as per institutional standard. 
1 
No dose adjustment 
Treat accordingly as per institutional standard. 
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline. 
Treat accordingly as per institutional standard. 
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline. 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or 
baseline within 14 days, resume study drug/study regimen administration. Otherwise, 
discontinue study drug/study regimen. 
Treat accordingly as per institutional standard. 
4 
Discontinue study drug/study regimen (NOTE: For Grade 4 labs, decision to 
discontinue would be based on accompanying clinical signs/symptoms and as per 
Investigator’s clinical judgment and in consultation with PrECOG). 
Treat accordingly as per institutional standard. 


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6.3.2 
Pemetrexed and Cisplatin (or Carboplatin) 
Chemotherapy dose modifications will be performed according to Table 6-3 below. 
Subjects will be monitored for adverse events while receiving doublet 
chemotherapy regimens. Dose interruptions or reductions may be required. 
Chemotherapy dose modifications must be determined according to standard 
practice and clinical determination as to whether dose modification is necessary. 
Chemotherapy dose modifications are permanent; once the dose of any 
chemotherapy agent had been reduced it will remain reduced or be further reduced 
in subsequent cycles. The dose reductions are not linked and may be adjusted 
independently as summarized below. 
 
Table 6-3 Dose Modifications for Pemetrexed, Cisplatin and Carboplatin 
Dose Level 
Pemetrexed 
Cisplatin 
Carboplatin 
Starting Dose 
500 mg/m2 
75 mg/m2 
AUC 5 
First Dose 
Reduction 
375 mg/m2 
56 mg/m2 
AUC 4 
Second Dose 
Reduction 
250 mg/m2 
38 mg/m2 
AUC 3 
Third Dose 
Reduction 
Stop Drug 
Stop Drug 
Stop Drug 
 
NOTE: 
For renal toxicity, pemetrexed should be held when the CrCl <45 
mL/minute. Caution should be used among subjects who are receiving 
nonsteroidal anti-inflammatory drugs (NSAIDs) and who have mild to 
moderate renal insufficiency (CrCl between 45 and 79 mL/minute). 
Caution should also be used when nephrotoxic drugs are administered 
with pemetrexed. 
Any subject with two prior dose reductions to one agent who experiences a toxicity 
that would cause a third dose reduction must be discontinued from that agent. A 
subject who is discontinued from the chemotherapy treatment will remain on the 
study and receive durvalumab as maintenance monotherapy as per the 
maintenance study calendar. 
Patients must have at least 2 cycles of pemetrexed/cisplatin (or carboplatin) with 
durvalumab in order to be eligible to proceed to maintenance durvalumab provided: 
1. Pemetrexed/cisplatin (or carboplatin) is discontinued before 6 cycles for toxicity 
reasons and the toxicity must have been attributable to the chemotherapy and 
not to the durvalumab. 
AND 
2. Patients have either stable or responsive disease on imaging OR are continuing 
beyond progression per Section 9.1.5 (e.g., renal failure attributed to cisplatin 
and pemetrexed but not to durvalumab and scans show a response or are 
stable, patient could proceed to durvalumab maintenance). 


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6.4 
Concurrent Therapies 
6.4.1 
Permitted 
Investigators may prescribe concomitant medications or treatments (e.g., 
acetaminophen, diphenhydramine) deemed necessary to provide adequate 
prophylactic or supportive care except for those medications identified as 
“excluded” as listed in Section 6.4.2. 
6.4.2 
Not Permitted 
The following medications are not permitted during the study. 
1. Any other investigational anticancer therapy. 
2. Any 
other 
concurrent 
chemotherapy, 
radiotherapy 
(except 
palliative 
radiotherapy), immunotherapy, biologic or hormonal therapy for cancer 
treatment. Concurrent use of hormones for non-cancer-related conditions (e.g., 
insulin for diabetes and hormone replacement therapy) is acceptable. 
NOTE: 
Local treatment of isolated lesions for palliative intent is acceptable 
(e.g., by local surgery or radiotherapy). Palliative radiation may be 
given as clinically indicated and must start at least one week after 
dose of pemetrexed/cisplatin and/or durvalumab or must be 
completed 
at 
least 
one 
week 
before 
next 
dose 
of 
pemetrexed/cisplatin and/or durvalumab 
3. Immunosuppressive medications including, but not limited to systemic 
corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive 
medications for the management of investigational product-related AEs or in 
subjects with contrast allergies is acceptable. In addition, use of inhaled and 
intranasal corticosteroids is permitted. A temporary period of steroids will be 
allowed for different indications, at the discretion of the principal investigator 
(e.g., chronic obstructive pulmonary disease, radiation, nausea, etc.). 
4. Live attenuated vaccines within 30 days of durvalumab dosing (i.e., 30 days 
prior to the first dose, during treatment with durvalumab and for 30 days post 
discontinuation of durvalumab. Inactivated vaccines, such as the injectable 
influenza vaccine and the pneumococcal sub-unit or conjugate vaccine, are 
permitted. Herpes Zoster vaccine is a live attenuated vaccine and is not 
permitted. 
6.5 
Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout the 
study. 
The transfusion of blood products according to institutional practice is at the discretion of 
the investigator. Hematopoietic growth factors are permitted per ASCO guidelines as 
indicated for supportive care of patients. However, their use shall not be utilized to satisfy 
eligibility criteria for study entry. 


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7. 
Study Duration and Discontinuation of Therapy 
7.1 
Study Duration 
Patients will receive protocol therapy unless: 
1. Disease progression per modified RECIST Version.1.1 guidelines (notwithstanding the 
specific criteria for treatment beyond progression outlined in Section 9.1.5) or clinical 
progression. 
2. Toxicities considered unacceptable by either the patient or the investigator, despite 
optimal supportive care and dose modifications. 
3. Development of an inter-current illness that prevents further administration of study 
treatment. 
4. Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient's health, protocol treatment should be discontinued. 
5. Patient withdraws consent or is unable to comply with study procedures. 
7.2 
Duration of Follow-Up 
Patients will be followed for adverse events for 90 days after their last dose of durvalumab 
or until initiation of alternative anticancer therapy. 
If a patient is removed from treatment for reason(s) other than progression, follow with 
regular tumor assessments per standard of care until progression or start of new treatment. 
Following documentation of non-fatal confirmed disease progression, all subjects will be 
followed for survival (either routine clinic visit or telephone contact) every 3 months until 
death or the close of the study. 
For patients who are registered but do not receive any protocol therapy, baseline and follow-
up information per Section 10 will be collected. 
7.3 
Criteria for Removal from Study Treatment  
A genuine effort will be made to determine the reason(s) why a patient fails to return for the 
necessary visits or is discontinued from the trial, should this occur. It will be documented 
whether or not each patient completed the clinical study. If for any patient study treatment 
or observations were discontinued, the reason will be recorded on the appropriate eCRF. 
Reasons that a patient may discontinue treatment in a clinical study are considered to 
constitute one of the following: 
1. Recurrence of disease or documented progression of disease (unless continued 
treatment with study drug is deemed appropriate at the discretion of the investigator). 
2. Intercurrent illness that prevents further administration of treatment per investigator 
discretion. 
3. Dose-limiting toxicity (Section 6.2 for definition of DLT). 
4. Any AE that meets criteria for discontinuation as defined in Section 6.3.1, Table 6-1 and 
Table 6-2. 
5. Unacceptable adverse events. 
6. Grade ≥ 3 infusion reaction to durvalumab 
7. Treatment interruption of more than 6 weeks after a scheduled treatment day. 
8. Investigator discontinues treatment. 
9. Initiation of alternative anticancer therapy including another investigational agent. 
10. Pregnancy or intent to become pregnant. 


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11. Develop a second malignancy (except for non-melanoma skin cancer or cervical 
carcinoma in-situ) that requires treatment, which would interfere with this study. 
12. The patient may choose to withdraw from the study at any time for any reason. 
13. General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 
14. Severe non-compliance to protocol as judged by the investigator. 
15. Lost to follow-up. 
16. Death. 
17. Closure of study by PrECOG. 
Any patient who receives at least one dose of study drug, durvalumab, will be included in 
the safety analysis. Patients who discontinue study treatment early should be followed for 
response assessments, if possible. Follow-up will continue per Section 10, as applicable. 


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8. 
Adverse Event Reporting 
8.1 
Collection of Safety Information 
Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a patient administered a medicinal product in a clinical 
investigation and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a product 
(investigational or marketed), whether or not considered related to the product 
(investigational or marketed). 
After informed consent, but prior to initiation of study treatment (pemetrexed, cisplatin [or 
carboplatin], and/or durvalumab), only AEs/SAEs caused by a protocol-mandated 
intervention will be collected (e.g., SAEs related to invasive procedures such as biopsies). 
After the initiation of study treatment, all identified AEs and SAEs must be recorded and 
described on the appropriate page of the electronic Case Report Form (eCRF). If known, 
the diagnosis of the underlying illness or disorder should be recorded, rather than individual 
symptoms. The following information should be documented for all AEs: date of onset and 
resolution, severity of the event; the investigator’s opinion of the relationship to 
investigational product (see definitions below); treatment required for the AE treatment 
required for the AE; cause of the event (if known); and information regarding 
resolution/outcome. 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the eCRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more-frequent follow-up assessments, 
further diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5x the ULN associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF. If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be 
recorded as the AE or SAE. For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the eCRF unless their severity, 
seriousness, or etiology changes. 
Severity 
The categories and definitions of severity used for clinical trials AEs are defined in the NCI’s 
Common Terminology Criteria (CTCAE) V4.03 (http://ctep.cancer.gov/). 
Attribution 
The following categories and definitions of causal relationship or attribution to study drug 
should be used to assess Adverse Events: 
• Definite: There is a reasonable causal relationship between the study drug and the event. 
The event response to withdrawal of study drug (dechallenge) and recurs with 
rechallenge, if clinically feasible. 
• Probable: There is a reasonable causal relationship between the study drug and the 
event. The event responds to dechallenge. Rechallenge is not required. 
• Possible: There is a reasonable causal relationship between the study drug and the 
event. Dechallenge information is lacking or unclear. 


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• Unlikely: There is doubtful causal relationship between the study drug and the event. 
• Unrelated: There is clearly not a causal relationship between the study drug and the 
event or there is a causal relationship between another drug, concurrent disease, or 
circumstances and the event. 
Categories ‘definite’, ‘probable’ and ‘possible’ are considered study drug related. Categories 
‘unlikely’ and ‘unrelated’ are considered not study drug-related. 
The development of a new cancer should be regarded as an AE. New cancers are those 
that are not the primary reason for administration of study treatment and have been 
identified after inclusion of the patient into the clinical study. 
AEs related to pemetrexed and/or cisplatin (or carboplatin) should be followed for 30 
days after last dose of study therapy or until the initiation of alternative anticancer 
therapy until ≤ grade 1 or stabilization, and reported as SAEs if they become serious. 
Any AEs related to durvalumab should be followed for 90 days after last dose of 
durvalumab or until the initiation of alternative anticancer therapy until ≤ grade 1 or 
stabilization, and reported as SAEs if they become serious. 
Any AE’s (serious or not) that occur after the above time periods but are deemed to 
be at least possibly related to study therapy shall be reported. 
8.2 
Definition of Adverse Events of Special Interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to PrECOG. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product. 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An immune-mediated adverse event (imAE) is defined as an 
adverse event that is associated with drug exposure and is consistent with an immune-
mediated mechanism of action and where there is no clear alternate etiology. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an 
imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the imAE.  
If the Investigator has any questions in regards to an adverse event (AE) being an imAE, 
the Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
• 
Colitis 
• 
Pneumonitis/Interstitial Lung Disease (ILD) 
• 
ALT/AST increases/hepatitis/hepatotoxicity  
• 
Neuropathy/neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e. events of hypophysitis/hypopituitarism, Type I diabetes mellitus, 
adrenal insufficiency, and hyper- and hypothyroidism) 
• 
Dermatitis/Rash/Pruritis 
• 
Nephritis 
• 
Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase, increased 
serum amylase) 


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• 
Myocarditis 
• 
Hypersensitivity/Anaphylactic Reactions 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab Investigator Brochure. 
8.2.1 
Gastrointestinal Disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when 
tremelimumab is used as monotherapy. In rare cases, colon perforation may occur 
that requires surgery (colectomy) or can lead to a fatal outcome if not properly 
managed. 
Guidelines on management of diarrhea and colitis in patients receiving durvalumab 
are provided in Section 6.3.1, Table 6-1. 
8.2.2 
Pneumonitis 
Adverse events of pneumonitis are of interest as pneumonitis has been reported 
with anti-PD-1 MAbs [47]. Initial work-up should include high-resolution CT scan, 
ruling out infection, and pulse oximetry. Pulmonary consultation is highly 
recommended. 
Guidelines for the management of subjects with immune-mediated events including 
pneumonitis are outlined in Section 6.3.1, Table 6-1. 
8.2.3 
Hepatic Function Abnormalities (Hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-
L1/anti-PD-1 antibodies [48]. Inflammatory hepatitis has been reported in 3% to 9% 
of subjects treated with anti CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The 
clinical manifestations of ipilimumab-treated subjects included general weakness, 
fatigue, nausea and/or mild fever and increased liver function tests such as AST, 
ALT, alkaline phosphatase, and/or total bilirubin. 
Hepatic function abnormality is defined as any increase in ALT or AST to greater 
than 3x ULN and concurrent increase in total bilirubin to be greater than 2x ULN. 
Concurrent findings are those that derive from a single blood draw or from separate 
blood draws taken within 8 days of each other. Follow-up investigations and 
inquiries will be initiated promptly by the investigational site to determine whether 
the findings are reproducible and/or whether there is objective evidence that clearly 
supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with 
distended gallbladder) or an agent other than the investigational product.  
Guidelines for management of subjects with hepatic function abnormality are 
outlined in Section 6.3.1, Table 6-1. 
Cases where a subject shows an AST or ALT ≥ 3x ULN or total bilirubin ≥ 2x ULN 
may need to be reported as SAEs. These cases should be reported as SAEs if, 
after evaluation they meet the criteria for a Hy’s Law case or if any of the individual 
liver test parameters fulfill any of the SAE criteria. 
Criteria for Hy’s Law (FDA Guidance 2009) 
• 
The drug causes hepatocellular injury, generally shown by a higher incidence 
of 3-fold or greater elevations above the ULN of ALT or AST than the 
(non-hepatotoxic) control drug or placebo. 
• 
Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3x ULN, one or more also show elevation 
of serum total bilirubin to >2x ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase). 


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• 
No other reason can be found to explain the combination of increased 
aminotransferases and total bilirubin, such as viral hepatitis A, B, or C; pre-
existing or acute liver disease; or another drug capable of causing the observed 
injury. 
8.2.4 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barré, and myasthenia gravis. 
Guidelines for the management of patients with immune-mediated neurotoxic 
events are provided in Section 6.3.1, Table 6-1. 
8.2.5 
Endocrine Disorders 
Immune-mediated endocrinopathies include hypophysitis/hypopituitarism, Type I 
diabetes mellitus, adrenal insufficiency, and hyper- and hypothyroidism. 
Guidelines for the management of patients with immune-mediated endocrine 
events are provided in Section 6.3.1, Table 6-1. 
8.2.6 
Nephritis 
Consult with Nephrologist. Monitor for signs and symptoms that may be related to 
changes in renal function (e.g. routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, proteinuria, etc.). 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression, infections etc.). 
Steroids should be considered in the absence of clear alternative etiology even for 
low grade events (Grade 2), in order to prevent potential progression to higher 
grade event. 
Guidelines for the management of patients with immune-mediated neurotoxic 
events are provided in Section 6.3.1, Table 6-1. 
8.2.7 
Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and 
amylase elevation. 
Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Section 6.3.1, Table 6-1. 
8.2.8 
Myocarditis 
Immune-mediated myocarditis includes decreased ejection fraction, arrhythmias, 
and in particular occurrences of atrioventricular block. 
For patients with suspected myocarditis, investigators should obtain a cardiology 
consult and institute full diagnostic work-up (that includes exclusion of other 
alternate causes such as infection) and the appropriate management that includes 
discontinuing drug (permanently if biopsy-proven immune-mediated myocarditis) 
and the prompt use of steroids or other immunosuppressives. Patients with pre-
existing cardiac disorders should be closely monitored for deterioration in their 
cardiac condition, which could suggest new onset myocarditis. 
 
 


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8.2.9 
Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported 
with anti-PD-L1 and anti-PD-1 therapy [48]. As with the administration of any foreign 
protein and/or other biologic agents, reactions following the infusion of MAbs can 
be caused by various mechanisms, including acute anaphylactic (immunoglobulin 
E-mediated) and anaphylactoid reactions against the MAb, and serum sickness. 
Acute allergic reactions may occur, may be severe, and may result in death. Acute 
allergic reactions may include hypotension, dyspnea, cyanosis, respiratory failure, 
urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, 
cough, dizziness, fatigue, headache, hypertension, myalgia, vomiting and 
unresponsiveness. 
Guidelines for management of subjects with hypersensitivity (including anaphylactic 
reaction) and infusion related reactions are outlined in Section 6.3.1, Table 6-1. 
8.3 
Handling of Serious Adverse Events (SAEs) 
8.3.1 
SAE Definitions 
A serious AE is any untoward medical occurrence occurring after initiation of study 
treatment or that at any dose: 
• 
results in death 
• 
is life-threatening (defined as an event in which the study patient was 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) 
• 
requires inpatient hospitalization or causes prolongation of existing 
hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). 
Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization. 
8.4 
SAE Reporting Requirements 
Serious adverse events (SAE) are defined above. The investigator should inform PrECOG 
of any SAE within 24 hours of being aware of the event. The date of awareness should be 
noted on the report. This must be documented on the PrECOG SAE form. This form must 
be completed and supplied to PrECOG within 24 hours/1 business day at the latest on the 
following working day. The initial report must be as complete as possible, including details 
of the current illness and (serious) adverse event, and an assessment of the causal 
relationship between the event and the investigational product(s). Information not available 
at the time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up PrECOG SAE report form. A 
final report to document resolution of the SAE is required. The investigator is responsible 
for following all SAEs until resolution, until the subject returns to baseline status, or until the 
condition has stabilized with the expectation that it will remain chronic, even if this extends 
beyond study participation. A copy of the fax transmission confirmation of the SAE report to 
PrECOG should be attached to the SAE and retained with the patient records. 


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All SAEs should be faxed to 888-276-9606 or scanned and emailed to 
PrE0505SAE@qdservices.com as per the instructions found in study materials provided 
to the investigator site. 
 
Medical Monitor 
During normal business hours  
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
Email: 
 
Manager, Clinical Safety 
During normal business hours  
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Cell: 484-574-2367 
PrECOG will notify AstraZeneca of all SAE’s within 24 hours of PrECOG’s Awareness Date 
as discussed above. Relevant follow-up information will be provided to AstraZeneca as soon 
as it becomes available. 
Investigators should also report event(s) to their IRB as required. 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed. Thus, follow-up information which becomes 
available as the SAE evolves, as well as supporting documentation (e.g., hospital discharge 
summaries and autopsy reports), should be collected subsequently, if not available at the 
time of the initial report, and immediately sent using the same procedure as the initial SAE 
report. 
All SAEs, regardless of causality (Section 8.4.1 for additional information for hepatic function 
abnormality) must be collected which occur within 90 days of last dose of durvalumab or 
until the initiation of alternative anticancer therapy. This includes all deaths within 90 days 
of last dose of durvalumab, unless related to progression of disease (disease progression 
will be documented, but not reported as an SAE). After 90 days, patients with ongoing 
durvalumab-related SAEs will be continued to be followed for safety. 
In addition, if a subject discontinues from treatment for reasons other than disease 
progression, and therefore continues to have tumor assessments, durvalumab-related 
SAEs must be captured until the patient is considered to have confirmed PD and will have 
no further tumor assessments. 
The Investigator should notify PrECOG or designee of any SAE that may occur after the 
above time period which they believe to be definitely, probably or possibly related to 
investigational product. 
NOTE: 
After study closure, study-drug related SAEs should be reported voluntarily by the 
treating physician to the manufacturer. 
Serious adverse event reporting to regulatory authorities and all participating investigators 
will be conducted by PrECOG (or designee) in accordance with 21CFR312.32, local 
requirements and international regulations, as appropriate. FDA reporting requirement 
timelines will be followed. PrECOG will also concurrently forward any such reports to 
AstraZeneca. 
8.4.1 
Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 8.2.3) in a study subject, with 
or without associated clinical manifestations, is required to be reported as “hepatic 
function abnormal” within 24 hours of knowledge of the event as noted above, 
unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or 
bile duct obstruction) that is unrelated to investigational product has been 
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• 
If the definitive underlying diagnosis for the abnormality has been established 
and is unrelated to investigational product, the decision to continue dosing of 
the study subject will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing 
of the study subject must be interrupted immediately. Follow-up investigations 
and inquiries must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the 
investigator and evaluated by PrECOG. 
8.5 
Reporting of Other Second Primary Cancers 
New cancers are those that are not the primary reason for administration of study treatment 
and have been identified after inclusion of the patient into the clinical study. 
All cases of new primary cancers that occur during or after protocol treatment must be 
reported to PrECOG on a Second Primary Cancer form within 30 days of diagnosis, 
regardless of relationship to protocol treatment. Secondary primary malignancies should 
also be reported as a SAE. The SAE form is not for use for reporting recurrence or 
development of metastatic disease. A copy of the pathology report, if applicable, should be 
sent, if available. 
NOTE: 
Once data regarding survival and remission status are no longer required by the 
protocol, no follow-up data should be submitted. 
8.6 
Procedures in Case of Pregnancy 
Prior to study enrollment, women of childbearing potential (WOCBP) and male patients with 
a female partner of childbearing potential must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy, documented in the informed consent. 
8.6.1 
Maternal Exposure 
If a patient becomes pregnant during the course of the study, the study drugs should 
be discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study 
drugs may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities or birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not 
be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality) 
should be followed up and documented even if the patient was discontinued from 
the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other 
site personnel should inform PrECOG within 1 day, i.e., immediately, but no later 
than 24 hours of when he or she becomes aware of it. 
PrECOG will work with the Investigator to ensure that all relevant information is 
provided to PrECOG within 1 to 5 calendar days for SAEs and within 30 days for all 
other pregnancies. 
The same timelines apply when outcome information is available. 
8.6.2 
Paternal Exposure  
Male patients should refrain from fathering a child or donating sperm during the 
study and for 90 days after the last dose of durvalumab. 


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Pregnancy of the patient’s partner is not considered to be an AE. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) occurring from the date of the 
first dose until 90 days after the last dose should, if possible, be followed up and 
documented. 
Where a report of pregnancy is received, prior to obtaining information about the 
pregnancy, the Investigator must obtain the consent of the patient’s partner.  
Therefore, the local study team should adopt the generic ICF template in line with 
local procedures and submit it to the relevant Ethics Committees (ECs)/Institutional 
Review Boards (IRBs) prior to use. 
8.7 
Durvalumab Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that 
specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to PrECOG. If the 
overdose results in an AE, the AE must also be recorded as an AE (Section 8.1). Overdose 
does not automatically make an AE serious, but if the consequences of the overdose are 
serious, for example death or hospitalization, the event is serious and must be recorded and 
reported as an SAE (Section 8.4). There is currently no specific treatment in the event of an 
overdose of durvalumab. 
The investigator will use clinical judgment to treat any overdose either of durvalumab or the 
chemotherapeutic agents used to treat patients enrolled in this protocol. 


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9. 
Measurement of Effect 
9.1 
Solid Tumor Response Criteria (RECIST Version 1.1) 
9.1.1 
Malignant Disease Evaluation 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline Version 1.1 with standard modifications used in the evaluation 
of mesothelioma [42, 49-50]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in RECIST. 
To assess objective response, it is necessary to estimate the overall tumor burden 
at baseline to which subsequent measurements will be compared. Measurable 
disease is defined by the presence of at least one measurable lesion. 
All measurements should be recorded in metric notation by use of a ruler or calipers. 
The same method of assessment and the same technique should be used to 
characterize each identified lesion at baseline and during follow-up. All baseline 
evaluations should be performed as closely as possible to the beginning of 
treatment and never more than four weeks before registration. 
The term evaluable in reference to measurability will not be used because it does 
not provide additional meaning or accuracy. 
At baseline, tumor lesions will be characterized as either measurable or non-
measurable. 
9.1.1.1 
Measurable 
Measurable tumor lesions are those that can be accurately measured 
in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 
≥ 10 mm by CT scan (irrespective of scanner type) and MRI (no 
less than double the slice thickness and a minimum of 10 mm) 
• 
≥ 10 mm caliper measurement by clinical exam (when superficial) 
• 
≥ 20 mm by chest x-ray (if clearly defined and surrounded by 
aerated lung) 
If the measurable disease is restricted to a solitary lesion, its neoplastic 
nature should be confirmed by cytology/histology. 
9.1.1.2 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis (perpendicular to longest diameter) 
when assessed by CT scan. 
9.1.1.3 
Non-Measurable 
All other lesions (or sites of disease), including small lesions not 
meeting the criteria in 9.1.1.1 and 9.1.1.2, are considered non-
measurable lesions. This includes lymph nodes measured at ≥ 10 to 
<15 mm in the short axis. NOTE: Lymph nodes measured at <10 mm 
in the short axis are considered normal. 
Lesions considered to be non-measurable include the following: 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
inflammatory breast disease, lymphangitic involvement of the skin or 
lung, and abdominal masses/abdominal organomegaly identified by 


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physical exam that is not measurable by reproducible imaging 
techniques. 
NOTE: 
‘Cystic lesions’ that meet the criteria for radiographically 
defined simple cysts should not be considered as malignant 
lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Lytic bone lesions, with an identifiable soft tissue component, evaluated 
by CT or MRI, can be considered as measurable lesions if the soft 
tissue component otherwise meets the definition of measurability in 
Section 9.1.1.1. Blastic bone lesions are non-measurable. 
Tumor lesions that are situated in a previously irradiated area, or in an 
area subjected to other loco-regional therapy, are usually not 
considered measurable unless there has been demonstrated 
progression in the lesion. 
9.1.2 
Definitions of Response 
9.1.2.1 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (those with 
the longest diameters), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured 
reproducibly should be selected. 
The sum of the target lesions (longest diameter for non-nodal lesions, 
short axis for nodal lesions) will be calculated and reported as the 
baseline sum. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum of the 
diameters/axes will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
Complete Response (CR) 
The disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm (the sum may not be “0” if there are target nodes). To be 
assigned a status of complete response, changes in tumor 
measurements must be confirmed by repeat assessments performed 
≥ 4 weeks after the criteria for response are first met. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters/axes of target 
lesions, taking as reference the baseline sum diameters/axes. To be 
assigned a status of partial response, changes in tumor measurements 


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must be confirmed by repeat assessments performed ≥ 4 weeks after 
the criteria for response is met. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters/axes 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 over the nadir. (NOTE: the appearance of 
one or more new lesions is also considered progression). 
Please refer to Section 9.1.5 for Immune-Related Response for 
guidance. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters/axes 
while on study. (NOTE: a change of 20% or more that does not 
increase the sum of the diameters by 5 mm or more is coded as stable 
disease). 
To be assigned a status of stable disease, measurements must have 
met the stable disease criteria at least once after study entry at a 
minimum interval of ≥ 4 weeks. 
9.1.2.2 
Non-Target Lesions 
All other lesions or sites of disease including any measurable lesions 
over and above the 5 target lesions and lymph nodes measured at ≥ 10 
to <15 mm in the short axis 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 unequivocal 
progression of each should be noted throughout follow-up. 
Complete Response (CR) 
The disappearance of all non-target lesions and normalization of tumor 
marker levels, if applicable. All lymph nodes must be non-pathological 
in size (<10 mm short axis). To be assigned a status of complete 
response, changes in tumor measurements must be confirmed by 
repeat assessments performed ≥ 4 weeks after the criteria for response 
are first met. 
NOTE: 
If tumor markers are initially above the upper normal limit, 
they must normalize for a patient to be considered in 
complete clinical response. 
Non-CR/Non-PD 
The persistence of one or more non-target lesion(s) and/or the 
maintenance of tumor marker levels above the normal limits. To be 
assigned a status of Non-CR/Non-PD, measurements must have met 
the Non-CR/Non-PD criteria at least once after study entry at a 
minimum interval of ≥ 4 weeks. 
Progressive Disease (PD) 
The appearance of one or more new lesion(s) and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be 


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representative of overall disease status change, not a single lesion 
increase. 
When the patient also has measurable disease, there must be an 
overall level of substantial worsening in non-target disease such that, 
even in the 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 status. The 
designation of overall progression solely on the basis of change in non-
target disease in the face of SD or PR of target disease will therefore 
be extremely rare. 
When the patient only has non-measurable disease, the increase in 
overall disease burden should be comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: 
i.e., an increase in tumor burden from “trace” to “large”, an increase in 
nodal disease from “localized” to “widespread”, or an increase sufficient 
to require a change in therapy. 
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such 
circumstances. 
Please refer to Section 9.1.5 for Immune-Related Response for 
guidance. 
9.1.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive Disease (PD) however this 
should lead to clinical evaluation as guided by Section 9.1.5 below. 
9.1.4 
Symptomatic Deterioration 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”. Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
9.1.5 
Immune-Related Response 
The response to immunotherapy may differ from the typical responses observed 
with cytotoxic chemotherapy including the following [51, 52]: 
• 
Response to immunotherapy may be delayed. 
• 
Response to immunotherapy may occur after PD by conventional criteria. 
• 
The appearance of new lesions may not represent PD with immunotherapy. 
• 
SD while on immunotherapy may be durable and represent clinical benefit. 
Based on the above-described unique response to immunotherapy and based on 
guidelines from regulatory agencies, e.g., European Medicines Agency’s “Guideline 
on 
the 
evaluation 
of 
anti-cancer 
medicinal 
products 
in 
man” 
(EMA/CHMP/205/95/Rev.4) [53] for immune modulating anti-cancer compounds, 
the study will implement the following in addition to standard RECIST 1.1 criteria: 
• 
RECIST will be modified so that PD must be confirmed at the next scheduled 
visit, preferably, and no earlier than 4 weeks after the initial assessment of PD 
in the absence of clinically significant deterioration. Treatment with durvalumab 
would continue between the initial assessment of progression and confirmation 
for progression. 


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• 
In addition, subjects may continue to receive durvalumab beyond confirmed PD 
in the absence of clinically significant deterioration and if investigators consider 
that subjects continue to receive benefit from treatment. 
Modification of RECIST as described may discourage the early discontinuation of 
durvalumab and provide a more complete evaluation of its anti-tumor activity than 
would be seen with conventional response criteria. Nonetheless, the efficacy 
analysis will be conducted by programmatically deriving each efficacy endpoint 
based on RECIST 1.1 criteria modified for mesothelioma. 
Of note, clinically significant deterioration is considered to be a rapid tumor 
progression that necessitates treatment with anti-cancer therapy other than 
durvalumab or with symptomatic progression that requires urgent medical 
intervention (e.g., symptomatic central nervous system metastasis, respiratory 
failure due to tumor compression, spinal cord compression). 
9.2 
Evaluation of Patient’s Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
confirmed disease progression or non-protocol therapy (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). Assessment of 
best overall response should allow for immune-related response patterns as described in 
Section 9.1.5. The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria (Table 9-1). 
To be assigned a status of complete or partial response, changes in tumor measurements 
must be confirmed by repeat assessments performed ≥ 4 weeks after the criteria for 
response are first met. 
To be assigned a status of stable disease, measurements must have met the stable disease 
criteria at least once after study entry at a minimum interval of ≥ 4 weeks. 
Table 9-1: Overall Response for All Possible Combinations of Tumor 
Response 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesion 
Overall 
Response 
Remarks 
CR 
CR 
No 
CR 
Confirmation at ≥ 4 weeks 
CR 
Non-CR/Non-
PD* 
No 
PR 
Confirmation at ≥ 4 weeks 
CR 
Not Evaluated 
No 
PR 
Confirmation at ≥ 4 weeks 
PR 
Non-PD*/Not 
Evaluated 
No 
PR 
Confirmation at ≥ 4 weeks 
SD 
Non-PD*/Not 
Evaluated 
No 
SD 
Documented at least once ≥ 4 
weeks from study entry 
Not All 
Evaluated 
Non-PD 
No 
Not Evaluable 
 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD* 
Any 
Any 
Yes 
PD 
* PD in non-target lesions should not normally trump target lesion status. It must be representative 
of overall disease status change, not a single lesion increase. Please refer to Section 9.1.2.2 
Non-Target Lesions-Progressive Disease for further explanation. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 


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NOTE: 
If subjects respond to treatment and are able to have their disease resected; the 
patient’s response will be assessed prior to the surgery. However, the patient will 
be considered inevaluable for survival analysis. 
9.2.1 
Methods of Measurement 
Imaging based evaluation is preferred to evaluation by clinical examination. The 
same imaging modality should be used throughout the study to measure disease 
(preferred but not mandated). 
9.2.1.1 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm 
in diameter as assessed using calipers (e.g., skin nodules). In the case 
of skin lesions, documentation by color photography, including a ruler 
to estimate the size of the lesion, is recommended. 
9.2.1.2 
CXR 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable 
lesions when they are clearly defined and surrounded by aerated lung. 
However, CT is preferable. 
9.2.1.3 
CT and MRI 
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If 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 (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up 
should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
9.2.1.4 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time. Note, however, that the PET portion of the 


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CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed. 
9.2.1.5 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot 
be reproduced in their entirety for independent review at a later date 
and, because they are operator dependent, it cannot be guaranteed 
that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised. If there 
is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
9.2.1.6 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following CR or surgical resection is 
an endpoint. 
9.2.1.7 
Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
9.2.1.8 
Cytology, Histology 
These techniques can be used to differentiate between PR and CR in 
rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has 
met criteria for response or SD is mandatory to differentiate between 
response or SD (an effusion may be a side effect of the treatment) and 
PD. 
 


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10. 
Study Parameters 
1. All pre-study scans should be done ≤ 4 weeks prior to registration. 
2. All other pre-study assessments should be done ≤ 2 weeks prior to registration. 
 
Concurrent Treatment Phase - Chemotherapy with Durvalumab 
 
Procedures 
Screening 
Cycle 1* 
(1 Cycle = 21 Days) 
Cycle 2 to Cycle 6* 
Every 6 weeks 
During Concurrent 
Phase of Protocol* 
Off 
Treatment20 
Follow-Up22 
Day 
1 
Day 
81 
Day 
15 
Day 
21 
Day 
1 
Day 
8 
Day 
15 
Day 
21 
 
Written Informed 
Consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Baseline 
Signs & Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam including4 
Weight 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Vital Signs 
(Temperature, Pulse, 
Blood Pressure)5 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Body Surface Area (BSA) 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
Performance Status 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Electrocardiogram6 
X 
X6 
As clinically indicated 
 
CBC/Differential/Platelets7 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Chemistry8 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
TSH9 
X 
X 
 
 
 
X 
 
 
 
 
 
 


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Concurrent Treatment Phase - Chemotherapy with Durvalumab 
 
Procedures 
Screening 
Cycle 1* 
(1 Cycle = 21 Days) 
Cycle 2 to Cycle 6* 
Every 6 weeks 
During Concurrent 
Phase of Protocol* 
Off 
Treatment20 
Follow-Up22 
Day 
1 
Day 
81 
Day 
15 
Day 
21 
Day 
1 
Day 
8 
Day 
15 
Day 
21 
 
Hepatitis B & Hepatitis C10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR 
X 
As Clinically Indicated 
 
Urinalysis11 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
Urine or Serum 
Pregnancy Test12 
X 
As Clinically Indicated 
 
Brain MRI or CT with 
Contrast13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest CT with Contrast 
and Abdomen MRI or CT 
with Contrast 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest CT with Contrast & 
MRI or CT of any other 
Disease Sites 
 
 
 
 
 
 
 
 
 
X19 
X20 
 
 
Archived Tumor Tissue 
Procurement 
(Mandatory)14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Research Blood 
Specimens 
(Mandatory)15 
 
X 
 
 
 
X15 
 
 
 
 
 
 
 
Treatment 
Administration16 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Palliative Radiation 
Therapy17 
As clinically indicated 
 
Concomitant Medication 
Review18 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Adverse Events 
Assessment 
 
X 
X 
 
 
X 
 
 
 
 
X21 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
 


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* 
Scheduled Visits: +/- 3 day window for therapy/tests/visits during therapy. Delay due to holidays, weekends, bad weather or other unforeseen circumstances 
will be permitted. 
1 
Day 8 visit only required on Cycle 1 of concurrent phase of treatment for the 6 safety run-in patients. 
2 
Repeat Informed consent is required for patients continuing on treatment past initial RECIST progression (Section 9.1.5). 
3 
Record date of diagnosis, primary tumor type, histology, stage. 
4 
Full physical examination at baseline, targeted physical examination at other time points. 
5 
Patients will have Temperature, Pulse and Blood Pressure taken at each visit. In addition, patients will have their blood pressure and pulse measured before, 
during and after the durvalumab infusion at the following times (based on a 60-minute infusion): 
• 
At the beginning of the infusion (at 0 minutes) 
• 
At 30 minutes during the infusion (±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 
• 
In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (i.e., 90 and 120 minutes from start of the infusion) (±5 minutes) for 
the first infusion only and then for subsequent infusions as clinically indicated. 
NOTE: If the infusion takes longer than 60 minutes then blood pressure and pulse measurements should be collected every 30 minutes (±5 minutes) and 
as described above or more frequently if clinically indicated. 
6 
ECG during Screening (in triplicate). Cycle 1, Day 1- ECG (single tracing) should be taken within an hour prior to the start of the durvalumab infusion and at 
one time point 0 to 3 hours after the cisplatin (or carboplatin) infusion, thereafter as clinically indicated. Screening and abnormal ECG at any time in triplicate 
(2-5 minutes apart); others single tracing. 
7 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hemoglobin, and Hematocrit required prior to each dose of treatment (Day 1 of 
each cycle and on Day 8 of Cycle 1 only), and results known prior to treatment administration. 
8 
Albumin, BUN/creatinine, uric acid, sodium, potassium, chloride, glucose, calcium, magnesium, alkaline phosphatase, AST, ALT, total bilirubin, LDH and total 
protein. Gamma-glutamyltransferase (GGT), amylase and lipase testing at Screening, and as clinically indicated. 
9 
Free T3 and free T4 will only be measured if TSH is abnormal. Free T3 and free T4 should also be measured if there is clinical suspicion of an adverse event 
related to the endocrine system. 
10 Hepatitis B (HBV surface antigen [HBsAg]) and hepatitis C (HCV antibody) testing. Patients with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
11 Patients with previous history of bleeding and/or are taking anticoagulant medication may have a higher risk of subsequent bleeding. Monitor patients closely 
for possible bleeding. 
12 Pre-menopausal female subjects of childbearing potential only. 
13 Subjects with neurologic or other symptoms concerning for possible central nervous system (CNS) involvement should have a Brain MRI or Brain CT with 
contrast during the screening period. 
 


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14 Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or surgery. Formalin-Fixed Paraffin-Embedded (FFPE) block 
(preferred) or a minimum of 15 FFPE unstained sections of 5 micron thickness plus 1 H&E slide will be required. Procurement of tissue will be mandatory for 
enrollment. Submit tumor sample (block or slides) within 3 months of patient registration. See Section 13.1 and 13.3 for details. 
15 Research bloods are to be drawn prior to treatment on C1D1, prior to treatment on C2D1, and prior to treatment on C5D1 of concurrent therapy or at time of 
confirmed progression IF confirmed progression occurs before Cycle 5, Day 1. 
At each time point, collect one (1) 10 mL EDTA tube and two (2) 10 mL Streck tubes. EDTA tube must be collected before the Streck tubes. Details of 
blood specimen handling and shipping are provided in the lab manual. See Section 13.1 and 13.4 for details. 
16 Patients will receive durvalumab 1120 mg, pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (or carboplatin AUC 5) by IV infusion on days 1 of each 21 
day cycle (1 cycle=21 days). Up to 6 cycles (6 doses) of concurrent therapy will be administered. See Section 6.1 for administration and re-treatment guidelines 
and Section 6.3.1, Table 6-1 and Table 6-2 for dose modifications for durvalumab and Section 6.1 for administration and re-treatment guidelines and Section 
6.3.2 and Table 6-3 for dose modifications/reductions for pemetrexed and cisplatin (or carboplatin). Patients must have at least 2 cycles of pemetrexed/cisplatin 
(or carboplatin) with durvalumab in order to be eligible to proceed to maintenance durvalumab (Section 6.3.2 for additional guidelines). 
NOTE: Oral folic acid 350 to 1000 µg daily should be given starting 1 week prior to the first dose of pemetrexed, with at least 5 doses of folic acid administered 
in the 7 days prior to the first dose. Oral folic acid should be continued daily throughout the treatment with pemetrexed and for 21 days after the last 
dose of pemetrexed has been administered. Intramuscular (IM) injection of Vitamin B12 1000 µg should be given approximately one week prior to 
the first dose of pemetrexed and repeated on the day that the third and sixth pemetrexed treatment is administered. Oral folic acid and Vitamin B12 
injection may also be given per local standard of care. 
17 Palliative radiation may be given as clinically indicated and must start at least one week after dose of pemetrexed/cisplatin and durvalumab or must be 
completed one week before next dose of pemetrexed/cisplatin and durvalumab. 
18 Review of prior/concomitant medication taken 14 days prior to informed consent and continues until completion of study treatment. 
19 Beginning with Cycle 1 radiographic response will be assessed with imaging every 6 weeks until completion of concurrent phase of treatment. In the setting 
of progressive disease on a single tumor assessment, patients will be made aware of the potential benefits and risks of continuing the study regimen in the 
setting of PD by providing separate written informed consent (Section 9.1.5 for criteria for treatment beyond progression). 
20 If more than 4 weeks since last scan, repeat MRI and/or CT to confirm disease status/progression. If patient is removed from treatment for reason(s) other 
than progression, follow with regular tumor assessments per standard of care until progression or start of new treatment. 
21 Patients will be followed for adverse events related to cisplatin (or carboplatin) and/or pemetrexed for 30 days after their last dose of study therapy or for 90 
days after their last dose of durvalumab or until the initiation of alternative anticancer therapy. 
22 Every 3 months from treatment discontinuation until death or study closure. Initiation of any other anti-cancer therapies will also be documented. 


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Monotherapy with Durvalumab 
 
Procedures 
Each Cycle* 
1 Cycle = 21 Days 
Every 9 Weeks During 
Maintenance Phase* 
Off Treatment11 
Follow-Up13 
Day 1 
Day 8 
Day 15 
Day 21 
 
 
 
 
Written Informed Consent1 
 
 
 
 
 
 
 
 
Physical Exam including Weight2 
X 
 
 
 
 
X 
 
 
Vital Signs 
(Temperature, Pulse, Blood Pressure)3 
X 
 
 
 
 
X 
 
 
Body Surface Area (BSA) 
X 
 
 
 
 
 
 
 
Performance Status 
X 
 
 
 
 
X 
 
 
Electrocardiogram4 
As clinically indicated 
 
CBC/Differential/Platelets5 
X 
 
 
 
 
X 
 
 
Chemistry6 
X 
 
 
 
 
X 
 
 
TSH7 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
Chest CT with Contrast & MRI or CT of 
any other Disease Sites 
 
 
 
 
X10 
X11 
 
 
Treatment Administration8 
X 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
 
 
 
 
X 
 
 
Palliative Radiation Therapy9 
As clinically indicated 
 
Adverse Events Assessment 
X 
 
 
 
 
X12 
 
 
Survival Status 
 
 
 
 
 
 
X 
 


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* 
Scheduled Visits: +/- 3 day window for therapy/tests/visits during therapy. Delay due to holidays, weekends, bad weather or other unforeseen circumstances 
will be permitted. 
1 
Repeat Informed consent is required for patients continuing on treatment past initial RECIST progression (Section 9.1.5). 
2 
Full physical examination for first cycle of Maintenance therapy; targeted physical examination at other time points. 
3 
Patients will have Temperature, Pulse and Blood Pressure taken at each visit. In addition, patients will have their blood pressure and pulse measured before, 
during and after the durvalumab infusion at the following times (based on a 60-minute infusion): 
• 
At the beginning of the infusion (at 0 minutes) 
• 
At 30 minutes during the infusion (±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 
NOTE:  If the infusion takes longer than 60 minutes then blood pressure and pulse measurements should be collected every 30 minutes (±5 minutes) and 
as described above or more frequently if clinically indicated. 
4 
ECG as clinically indicated. Abnormal ECG at any time in triplicate (2-5 minutes apart); others single tracing. 
5 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hemoglobin, and Hematocrit required prior to each dose of treatment (Day 1 of 
each cycle), and results known prior to treatment administration. 
6 
Albumin, BUN/creatinine, uric acid, sodium, potassium, chloride, glucose, calcium, magnesium, alkaline phosphatase, AST, ALT, total bilirubin, LDH and total 
protein. GGT, amylase and lipase testing as clinically indicated. 
7 
Free T3 and free T4 will only be measured if TSH is abnormal. Free T3 and free T4 should also be measured if there is clinical suspicion of an adverse event 
related to the endocrine system. 
8 
Patients will receive durvalumab 1120 mg by IV infusion on days 1 of each 21 day cycle (1 cycle=21 days). Maximum duration of 12 months of durvalumab 
(starting from Cycle 1 of concurrent treatment) will be administered. See Section 6.1 for administration guidelines and Section 6.3.1, Table 6-1 and Table 6-2 
for dose modifications for durvalumab. 
9 
Palliative radiation may be given as clinically indicated and must start at least one week after dose of durvalumab or must be completed one week before next 
dose of durvalumab. 
10 During maintenance durvalumab tumor restaging will be once every 9 weeks. In the setting of progressive disease on a single tumor assessment, patients 
will be made aware of the potential benefits and risks of continuing the study regimen in the setting of PD by providing separate written informed consent 
(Section 9.1.5 for criteria for treatment beyond progression). 
11 If more than 4 weeks since last scan, repeat MRI and/or CT to confirm disease status/progression. If patient is removed from treatment for reason(s) other 
than progression, follow with regular tumor assessments per standard of care until progression or start of new treatment. 
12 Patients will be followed for adverse events for 90 days after their last dose of durvalumab or until the initiation of alternative anticancer therapy. 
13 Every 3 months from treatment discontinuation until death or study closure. Initiation of any other anti-cancer therapies will also be documented. 


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11. 
Drug Formulation and Procurement 
11.1 
Durvalumab 
11.1.1 Other Names 
Also known as MEDI4736. 
11.1.2 Classification 
Human IgG1κ monoclonal antibody. 
11.1.3 Mode of Action 
 
 
 
11.1.4 Storage 
Unopened vials of MEDI4736 lyophilized or liquid Drug Product must be stored at 2°C 
to 8°C (36°F to 46°F) and must not be frozen. 
11.1.5  Dose Specifics 
A fixed dose of 1120 mg q 3 weeks durvalumab will be used in this study. 
For patients weighing ≥ 30 kg, a fixed dose of 1120 mg Q3W durvalumab (equivalent 
to 15 mg/kg Q3W based on an average body weight of 75 kg) should be prepared. 
Patients <30 kg body weight should be discussed with PrECOG before considering 
patient for enrollment. 
Refer to Section 6.3.1 and Table 6-1 and Table 6-2 for Dose Delays and Modifications 
details. 
11.1.6 Preparation 
Durvalumab will be supplied by AstraZeneca as a 500 mg vial solution for infusion 
after dilution.
 
 
 The nominal fill volume is 10 mL Investigational 
product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Durvalumab must be used within the individually assigned expiry date on the label. 
Preparation of Durvalumab Doses for Administration with an IV Bag 
The dose of durvalumab for administration must be prepared using aseptic technique. 
Total time from needle puncture of the durvalumab vial to the start of administration 
should not exceed: 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
If in-use storage time exceeds these limits, a new dose must be prepared from new 
vials. Infusion solutions must be allowed to equilibrate to room temperature prior to 
commencement of administration. 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags 
have been observed. Dose of 1120 mg durvalumab for patient’s ≥ 30 kg will be 
administered using an IV bag containing 0.9% (w/v) saline with a final durvalumab 
concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration 
set with a 0.2- or 0.22-μm in-line filter. 


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Remove a volume of IV solution from the IV bag equal to the calculated volume of 
durvalumab to be added to the IV bag prior to addition of durvalumab. Next, the volume 
of durvalumab (i.e., 15.0 mL for 750 mg or 30.0 mL for 1500 mg of durvalumab) is 
added to the IV bag such that final concentration is within 1 to 20 mg/mL (IV bag 
volumes 100 to 1000 mL). Mix the bag by gently inverting to ensure homogeneity of 
the dose in the bag. 
11.1.7 Route of Administration 
Durvalumab will be administered at room temperature (approximately 25°C) by 
controlled infusion via an infusion pump into a peripheral or central vein. Following 
preparation of durvalumab, the entire contents of the IV bag should be administered 
as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm 
in-line filter. Less than 55 minutes is considered a deviation. 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the 
priming volume of the infusion set used after the contents of the IV bag are fully 
administered, or complete the infusion according to institutional policy to ensure the 
full dose is administered and document if the line was not flushed. 
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the 
total allowed time should not exceed 8 hours at room temperature. The table below 
summarizes time allowances and temperatures. 
Table 11-1 
Durvalumab Hold and Infusion Times 
Maximum time from needle puncture to 
start of administration 
4 hours at room temperature, 24 hours 
at 2°C to 8°C 
Maximum time for IV bag infusion, 
including interruptions 
8 hours at room temperature 
In the event that either preparation time or infusion time exceeds the time limits outlined 
above, a new dose must be prepared from new vials. Durvalumab does not contain 
preservatives, and any unused portion must be discarded. 
11.1.8 Monitoring of Dose Administration 
Subjects will be monitored before, during and after the infusion with assessment of 
vital signs at the times specified in Section 10. Subjects are monitored (pulse rate, 
blood pressure) every 30 minutes during the infusion period (including times where 
infusion rate is slowed or temporarily stopped). 
11.1.9 Management of Infusion Reaction 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of study drug 
may be decreased by 50% or interrupted until resolution of the event (up to 4 hours) 
and re-initiated at 50% of the initial rate until completion of the infusion. For subjects 
with a ≤ Grade 2 infusion related reaction, subsequent infusions may be administered 
at 50% of the initial rate. Acetaminophen and/or an antihistamine (e.g., 
diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the investigator. Steroids should not be used for 
routine premedication of ≤ Grade 2 infusion related reactions. 
If the infusion related reaction is Grade 3 or higher in severity, study drug will be 
discontinued. 
The standard infusion time is one hour, however if there are interruptions during 
infusion, the total allowed time from infusion start to completion of infusion should not 
exceed 4 hours at room temperature, with maximum total time at room temperature 
not exceeding 4 hours (otherwise requires new infusion preparation). 


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As with any antibody, allergic reactions to dose administration are possible. 
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must 
be immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. The study site must have immediate access to emergency resuscitation 
teams and equipment in addition to the ability to admit subjects to an intensive care 
unit if necessary. 
11.1.10 Availability 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution. 
The initial supply of durvalumab will be sent directly to the site upon site activation. As 
needed, durvalumab may be requested by the PI (or their authorized designees) at 
each participating institution. The investigator, or a responsible party designated by 
the investigator, must maintain a careful record of the receipt, disposition, and 
return/destruction (site’s drug destruction policy must be reviewed and approved by 
PrECOG before any study drug can be destroyed at a site) of durvalumab. 
11.1.11 Agent Ordering 
PrECOG will be responsible for ordering drug for re-supply to the site. Requests for 
shipments of durvalumab will be coordinated between PrECOG and AstraZeneca. 
11.1.12 Agent Accountability 
Durvalumab will be stored in a secure location. Only authorized pharmacy and study 
staff will have access to this agent. Drug accountability will be performed by PrECOG. 
11.2 
Pemetrexed [36] and Cisplatin [37] 
NOTE: 
Pemetrexed and Cisplatin (carboplatin may be substituted for cisplatin as 
described in Section 3.9 and Section 5.1) will be obtained by the individual study 
sites as standard of care treatments from commercial stock. Refer to commercial 
package inserts for full prescribing information. 
11.2.1 Other Names 
Pemetrexed - Alimta® 
Cisplatin – Platinol® 
Carboplatin [38] – Paraplatin® 
11.2.2 Classification 
Pemetrexed is a folate analog metabolic inhibitor indicated for the treatment of 
mesothelioma in combination with cisplatin. 
Cisplatin and Carboplatin are alkylating agents that appear to form intra- and inter-
strand crosslinks in cells which modifies DNA structure and inhibits DNA synthesis. 
11.2.3 Storage and Stability 
Please consult the prescribing information for Pemetrexed, Cisplatin and Carboplatin. 
11.2.4 Dose Specifics 
Recommended dose of pemetrexed is 500 mg/m2 IV on Day 1 of each 21-day cycle in 
combination with cisplatin 75 mg/m2 IV beginning 30 minutes after pemetrexed 
administration (or per investigator discretion and local standard-of-care). 
If carboplatin is substituted for cisplatin per Section 3.9 or Section 5.1, the recommend 
dose of Carboplatin is AUC of 5 on Day 1 of each 21-day cycle beginning 15-30 


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minutes after pemetrexed administration (or per investigator discretion and local 
standard-of-care).. 
11.2.5 Preparation 
Pemetrexed and cisplatin (or carboplatin) will be prepared as per the institutional 
standards. 
11.2.6 Route of Administration 
The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous 
infusion over 10 minutes (or per investigator discretion and local standard-of-care) on 
Day 1 of each 21-day cycle. 
During concurrent treatment days, pemetrexed infusion will begin approximately 
30 minutes after the infusion of durvalumab has finished (or per investigator 
discretion and local standard-of-care). 
The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning 
approximately 30 minutes after the end of pemetrexed administration (or per 
investigator discretion and local standard-of-care). Patients should receive appropriate 
hydration prior to and/or after receiving cisplatin. Hydration may commence prior to or 
concurrently with durvalumab. See cisplatin package insert for more information. 
If carboplatin is substituted for cisplatin per Section 3.9 or Section 5.1, the 
recommended dose of carboplatin is AUC 5 infused over 30 minutes beginning 
approximately 15-30 minutes after the end of the pemetrexed administration (or per 
investigator discretion and local standard-of-care). 
CALVERT FORMULA FOR CARBOPLATIN DOSING 
Total Dose (mg) = (target AUC) x (CrCL by Cockcroft-Gault [Appendix II] + 25) 
NOTE: 
With the Calvert formula, the total dose of PARAPLATIN is calculated in 
mg, not mg/m2. 
11.2.7 Incompatibilities 
Please consult the prescribing information for Pemetrexed, Cisplatin and Carboplatin. 
11.2.8 Premedication Regimen – Pemetrexed 
Oral corticosteroid should be given according to local standards at a dose equivalent 
to dexamethasone 4 mg BID on the day prior to, the day of, and the day after the 
administration of pemetrexed. Oral folic acid 350 to 1000 µg daily should be given 
starting 1 week prior to the first dose of pemetrexed, with at least 5 doses of folic acid 
administered in the 7 days prior to the first dose. Oral folic acid should be continued 
daily throughout the treatment with pemetrexed and for 21 days after the last dose of 
pemetrexed has been administered. Intramuscular (IM) injection of Vitamin B12 1000 
µg should be given approximately one week prior to the first dose of pemetrexed and 
repeated on the day that the third and sixth pemetrexed treatment is administered. 
Oral folic acid and Vitamin B12 injection may also be given per local standard of care. 
11.2.9 Premedication Regimen – Cisplatin 
Cisplatin will be administered to patients at least 30 minutes following the end of the 
pemetrexed infusion. Pretreatment hydration for cisplatin can follow local standard of 
care or use of 1 to 2 liters of fluid (per local standards) infused IV for 2-4 hours prior to 
cisplatin infusion is recommended. Adequate hydration and urinary output must be 
maintained for at least 24 hours following cisplatin administration. Administration and 
monitoring should be performed according to local standards. Use of mannitol 
following the cisplatin infusion should also follow local standard-of-care. 


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11.2.10 Premedication Regimen - Carboplatin 
If carboplatin has been substituted for cisplatin per Section 3.9 or Section 5.1, 
premedication should follow local standard-of-care. 
11.2.11 Antiemetics for use with Pemetrexed/Cisplatin (Carboplatin) 
Antiemetic premedication will be administered according to local standards. 
Recommended antiemetic treatments are dexamethasone (dosing according to local 
standards; an equivalent dose of another corticosteroid may be substituted) and a 5-
HT3 receptor antagonist (type per investigator discretion and local standard-of-care). 
Additional use of antiemetic premedications may be employed at the discretion of the 
Investigator. 


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12. 
Statistical Considerations 
12.1 
Study Design & Sample Size Considerations – Safety Run-In 
12.1.1 Study Design and Objectives – Initial Six Patients Enrolled 
It is planned to enroll a total of 55 patients (50 expected to receive treatment) on this 
study, the first six patients enrolled will be monitored for safety of the combination of 
durvalumab with pemetrexed/cisplatin (or carboplatin). Standard induction with 
pemetrexed/cisplatin (or carboplatin) will be given for six 3-week cycles with the 
addition of concurrent durvalumab dosed at 1120 mg every 3 weeks. After completion 
of Cycle 6 of concurrent therapy, patients with stable or responding disease per 
modified RECIST for malignant mesothelioma will continue on single agent 
durvalumab at the same dose every 3 weeks until disease progression or a maximum 
duration of 12 months of durvalumab starting from Cycle 1 of concurrent treatment. 
The initial 6 patients completed 2 cycles of concurrent therapy with no DLTs. 
12.1.2 Statistical Analysis Plan for Safety 
This study will initially enroll 6 patients (from the total of 50 patients expected to enroll 
and receive treatment) to the combination of pemetrexed/cisplatin (or carboplatin) with 
durvalumab. The combination will be declared intolerable if ≥ 2 of the 6 patients 
experience a DLT (defined as in Section 6.2) during the first 2 cycles of concurrent 
therapy. The table below summarizes the probability of declaring this combination safe 
for range of true but unknown DLT rates: 
True DLT rate 
10% 
20% 
30% 
40% 
50% 
Probability of <2 DLTs 
among 6 patients 
0.89 
0.66 
0.42 
0.23 
0.11 
Upon completion of the trial, we will summarize the total number of patients enrolled 
on the study, and provide summaries of toxicity rates. We will also review and tabulate 
the DLTs. 
12.1.3 Sample Size Considerations 
The study will proceed to enroll a total of 55 patients if <2 patients among the first 6 
patients enrolled experience a DLT. Depending on the rate of accrual and review of 
the data pertaining to DLT evaluation, accrual may be halted to ensure it is safe to 
continue patient enrollment. 
12.1.4 Monitoring Plan 
While the initial six patients are receiving treatment, the study team will meet via 
teleconference to review and discuss DLTs and the overall trial conduct. 
12.2 
Expansion Phase 
12.2.1 Expansion Study Design and Objectives 
The initial six patients were monitored for safety, without suspension to accrual and, 
the study will proceed with enrollment of a total of 55 patients of whom it is expected 
50 patients will receive treatment (ineligibility rate of 10%). This is a single arm phase 
II study evaluating the benefit of durvalumab in combination with pemetrexed/cisplatin 
(or carboplatin) for the treatment of first-line unresectable pleural mesothelioma. 
Durvalumab will be administered concurrently with Cycle 1-6 of first line pemetrexed 
and cisplatin (or carboplatin) followed by maintenance durvalumab until disease 
progression or a maximum duration of 12 months of durvalumab starting from Cycle 1 
of concurrent treatment. The primary objective of this phase II study is overall survival. 


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Secondary objectives include progression-free survival, objective response, immune-
related response, toxicity, and correlatives which will include association of PD-L1 
expression with clinical outcomes. 
12.2.2 Phase II Endpoints 
Overall survival (OS) is defined as the time from randomization to death from any 
cause. Patients that have not had an event reported at analysis will be censored at 
their date of last follow-up. 
Progression-free survival (PFS) is defined as the time from randomization to 
documented disease progression or death from any cause, whichever occurs first. 
Patients who have not experienced an event of interest by the time of analysis will be 
censored at the date they are last known to be alive and progression-free. 
Best objective response will be evaluated via RECIST Version 1.1 criteria modified for 
mesothelioma, as described in the Section 9. 
Immune-related response will be evaluated using the Wolchok criteria [51]. 
Toxicity will be determined using the CTCAE Version 4.03 criteria. 
12.2.3 Phase II Statistical Analysis Plan 
The primary and some secondary analyses will include all eligible patients who started 
assigned therapy including the first six patients evaluated for safety. 
OS and PFS distributions will be estimated using the Kaplan-Meier method, and Cox 
proportional hazards models will be used to estimate the hazard ratios among 
subgroups. The primary test for OS will be based on the Wald test for the log failure 
rate parameter and tested at a one-sided type I error rate of 10%. Any comparisons of 
subgroups will be made using the logrank test and Cox modeling. 
If toxicity rates are compared between subgroups, Fisher’s exact tests with a one-
sided type I error rate of 10% will be used; multivariable logistic regression modeling 
will be used to adjust for the effect of any covariates that are associated with these 
categorical outcomes. 
Point estimates of all endpoints will be accompanied by the corresponding 95% 
confidence intervals. 
In the event that there are missing data, no imputation of the missing data will be 
conducted. We will assume that data are missing at random and will conduct all 
analyses as originally planned because we do not anticipate an excess of missing 
data. 
Subset analyses are planned for known prognostic factors such as performance 
status, age, gender, etc. Subset analyses of all variables, including correlatives, are 
considered to be exploratory in nature. 
12.2.4 Phase II Sample Size Considerations 
The primary comparison will include all eligible patients who started protocol 
treatment, of whom 50 will be accrued. After inflating for an ineligibility rate of 10%, 
the total planned accrual is 55 patients. Based on the randomized phase III trial 
conducted by Vogelzang in this setting [39], we assume that the null hypothesis is that 
the median OS is 12 months with pemetrexed/cisplatin alone (refer to Section 1. for 
additional historical background information). Using a one-sided 0.10 level test, we will 
have 90% power to detect a 37% reduction in the OS hazard rate of 0.058 to 0.037 
(with an accrual period of 24 months for the 50 patients in the primary analysis, and 
an additional 18 months for treatment and follow-up); assuming exponential survival, 
this corresponds to a 58% improvement in the median OS of 12 months to 19 months. 


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The number of OS events needed to achieve this power is 32 events. 
12.2.5 Interim Toxicity Assessment 
Because this is the first time that durvalumab is being combined with pemetrexed/ 
cisplatin (or carboplatin) in this setting, close monitoring of toxicity is an important 
endpoint of the trial. We will collect data and conduct an interim safety analysis among 
the first 15 patients who have completed the first two cycles of tri-modal therapy 
without suspension to accrual. The safety analysis will be done based on the eCRF. 
This preliminary toxicity analysis will occur in addition to the twice yearly monitoring 
for toxicity for the purposes of interim reporting. The probability that 5 or more Grade 
4/5 events are observed among the first 15 patients is 0.03 if the true Grade 4/5 non-
hematologic toxicity rate is 12% as expected based on trials of pemetrexed/cisplatin 
in lung cancer and mesothelioma. This probability increases to 0.88 if the true rate of 
Grade 4/5 non-hematologic toxicity is 0.45. Therefore, we will suspend accrual for 
further review of non-hematologic toxicity if we observe at least 5 Grade 4/5 non-
hematologic events among the first 15 patients. 
Interim toxicity assessment was completed on the first 15 patients who completed the 
first two cycles of tri-modal therapy with no safety concerns noted. 
12.2.6 Phase II Projected Accrual 
It is estimated that the total accrual goal of 55 patients will be reached in approximately 
24 months, with a treatment and follow-up period of approximately 18 months, making 
the entire study duration (including safety and efficacy assessments) approximately 
50 months. 


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13. 
Laboratory and Pathology Correlative Studies 
13.1 
Correlative Studies: Mandatory Tumor and Peripheral Blood Samples 
13.1.1 Tumoral Assessments 
Pre-treatment, diagnostic pathology specimens obtained in the course of standard 
biopsy or surgery, FFPE block (preferred) or a minimum of 15 unstained sections of 5 
micron thickness plus 1 H&E slide. Sections should be cut with DNA precautions and 
mounted on plus charged slides. Analyses to be performed may include the following: 
• 
PD-L1 expression (Ventana SP263 assay) 
• 
Whole exome sequencing 
• 
T cell receptor sequencing 
• 
Gene expression by nanostring 
• 
CD8 and other immunologic correlates by IHC 
NOTE: 
Blocks must be less than 3 years old. If unstained slides are being submitted 
they must be less than 90 days old. 
Submitted tumor samples should follow the below guidelines: 
• 
Samples should be collected via a core needle of 18 gauge or larger or be 
collected as an excisional tumour biopsy sample. Where institutional practice in 
this setting uses a smaller gauge needle, samples should be submitted to ensure 
that availability of result can be achieved. 
• 
The tumour specimen submitted should be of sufficient quantity (i.e., >100 tumour 
cells) to allow for PD-L1 immunohistochemistry analyses. 
• 
When archival samples are used to assess PD-L1 status, the age of the sample / 
date of collection should be captured. 
• 
Samples submitted for PD-L1 testing must be formalin fixed and embedded in 
paraffin. 
• 
Samples from fine needle aspirates or bone metastasis are not appropriate for 
PD-L1 analysis. 
13.1.2 Peripheral Blood Assessments 
During Concurrent Therapy 
Research bloods are to be drawn prior to treatment on C1D1, prior to treatment on 
C2D1, and prior to treatment on C5D1 during concurrent therapy or at time of 
confirmed progression IF confirmed progression occurs before Cycle 5, Day 1. 
At each time point, collect one (1) 10 mL EDTA tube and two (2) 10 mL Streck tubes. 
EDTA tube must be collected before the Streck tubes. 
Peripheral blood samples will be obtained for: 
• 
Cytokine profiling (platform to be determined [TBD]) 
• 
ctDNA analysis 
• 
T cell receptor repertoire analysis 
13.1.3 Tumor Tissue and Peripheral Blood Analysis 
Tumor tissue samples and Streck tubes will be sent ambient to John Hopkins 
University and processed EDTA tubes will be sent frozen to the ECOG-ACRIN Central 
Biorepository and Pathology Facility (EA CBPF). 
Testing will be performed following receipt of accrued samples by John Hopkins 


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University. Any left-over samples will be stored for future analysis. 
13.2 
Assay Methodology 
13.2.1 Tumor Tissue Studies 
Baseline tumor will be obtained in all subjects. Archived tumor biopsies (core needle 
or excision) will be banked for future analysis.  
The following studies may be performed depending on tissue quality and availability. 
Immunohistochemical (IHC) staining. We will perform IHC of tumor samples to assess 
PD-L1 expression in tumor or tumor-infiltrating immune cells using the Ventana SP263 
assay. Markers for further characterization of immune cell subsets (CD3, CD4, CD8, 
CD20, CD68, CD45RO), T regulatory cells-Treg (FOXP3) as well as other immune 
checkpoints (LAG3, TIM3) will be assessed. These additional assessments may be 
performed using multiplex IHC. 
Whole exome sequencing to detect somatic genomic alterations. Using genome-wide 
methods we will perform whole-exome sequencing in pre-treatment tumors for 
identification of genomic correlates of response to durvalumab. Non-synonymous 
missense mutations identified will be used to predict mutant peptides and generate a 
neoantigen signature for each tumor using a computational pipeline we have 
developed. 
T cell receptor sequencing. A separate targeted capture and sequencing analysis of 
the T cell receptor will be performed to assess T cell clonality. 
Gene expression analyses. By nanostring or similar methods may also be performed. 
13.2.2 Peripheral Blood Studies 
Peripheral Blood Mononuclear Cells (PBMCs) will be obtained at time points indicated 
in Section 13.1.2. Samples will be banked for future analysis with plan to evaluate for 
immunologic markers of response and T cell receptor repertoire analysis. 
ctDNA analysis will be performed on Streck tube samples at time points indicated in 
Section 13.1.2. 
13.3 
Pathology Sample Processing and Shipment 
Sites should submit FFPE diagnosis tumor tissue block (preferred) or a minimum of 15 FFPE 
unstained, positively charged slides (2 sections per slide) plus H&E slide from a tumor tissue 
block within 3 months of patient registration. Thickness of the sections should be 5 micron and 
sections should be cut with DNA precautions. 
Blocks must be less than 3 years old. If unstained slides are being submitted they must be less 
than 90 days old.  
A copy of the pathology report from initial diagnosis should be sent when the sample is 
shipped. Samples should be shipped Monday-Thursday. Samples will be shipped ambient 
via overnight courier. 
All samples collected will be labeled with a unique numeric identifier that will be coded for 
patient privacy protection. 
Kits will be supplied. Instructions and shipping address will be provided. 
13.4 
Peripheral Blood Samples Processing and Shipment 
13.4.1 Streck Tubes Processing 
Fill tube completely. IMMEDIATELY mix the blood sample by gentle inversion 8-10 
times (do not shake). One inversion is a complete turn of the wrist (180 degrees and 
back). Store at ambient temperature (15-30 degrees Celsius). 


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Streck tube should be shipped to the lab within 72 hours of collection via overnight 
courier at room temperature (Do NOT freeze. Proper insulation may be required for 
shipment during extreme temperature conditions). NOTE: Samples may be shipped 
on Friday for Monday delivery. 
13.4.2 EDTA Tube Processing for Plasma and Buffy Coat 
**Process sample within 30 minutes of collection** 
• 
Gently mix blood sample by inversion 10 times (do not shake). 
• 
Place tube immediately on wet ice for 5 minutes. 
• 
Centrifuge at 1200 RPM for 15 minutes at 4°C. If a refrigerated centrifuge is not 
available, spin sample at room temperature (1200 RPM for 15 minutes). 
Immediately place the tube on wet ice after centrifugation. 
After centrifugation, the plasma layer will be at the top half of the tube. The nucleated 
cells (WBC) will be in a whitish layer, called the “buffy coat”, just under the plasma and 
above the red blood cells. 
Plasma Preparation: 
• 
Using a transfer pipette take the top two-thirds of the plasma and transfer plasma 
into a 15 ml conical centrifuge tube, be careful not to disturb the buffy coat layer 
in the EDTA tube (NOTE: see below for buffy coat processing instructions). 
Centrifuge the 15 ml conical tube at 1200 RPM for 15 minutes at 4°C. If a 
refrigerated centrifuge is not available, spin sample at room temperature (1200 
RPM for 15 minutes). Immediately place the conical tube on wet ice after 
centrifugation. 
• 
Transfer equal amounts of plasma into two (2) properly labeled polypropylene 
tubes for cryopreservation being careful not to disturb the small PBMC/pellet. 
• 
Store the two aliquots of plasma samples in the freezer at ≤ -70°C or colder until 
they are shipped to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (EA CBPF). 
Buffy Coat Preparation: 
• 
From the EDTA tube remove and aliquot the “buffy coat”; be careful not to disturb 
the layer of red blood cells. 
• 
Store the aliquot of cells in one (1) properly labeled polypropylene tube for 
cryopreservation. 
• 
Store the sample in the freezer at ≤ -70°C or colder until it is shipped to the ECOG-
ACRIN Central Biorepository and Pathology Facility (EA CBPF). 
Plasma and buffy coat samples should be batched together and shipped 
approximately every 4 months. Individual patients should only be included in the 
shipment if all of their samples have been completed. Samples should be shipped 
Monday-Thursday. Samples must be shipped on dry ice via overnight courier. 
Kits will be supplied. Instructions and shipping address will be provided. 
 


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87 
14. 
Administrative 
14.1 
Protocol Compliance 
The study shall be conducted as described in this protocol. All revisions to the protocol must 
be discussed with, and be prepared by PrECOG and/or representatives. The Investigator 
should not implement any deviation or change to the protocol or consent without prior review 
and documented approval from PrECOG and/or representatives and the Institutional Review 
Board (IRB) of an amendment, except where necessary to eliminate an immediate hazard(s) 
to study patients. 
If a deviation or change to the approved protocol is implemented to eliminate an immediate 
hazard(s) prior to obtaining IRB approval, notification will be submitted to the IRB for review 
and approval as soon as possible afterward. Documentation of approval signed by the 
chairperson or designee of the IRB(s) should be in the study records. If PrECOG and/or 
representatives provides an amendment that substantially alters the study design or increases 
the potential risk to the patient; the consent form must be revised and submitted to the IRB(s) 
for review and approval; the revised form must be used to obtain consent from patients 
currently enrolled in the study if they are affected by the Amendment; and the new form must 
be used to obtain consent from new patients prior to study entry. Information as to who 
investigators should send correspondence will be provided in additional study documents. 
14.2 
Institutional Review Board 
Before study initiation, the Investigator must have written and dated approval from their 
respective IRB for the protocol, consent form, patient recruitment materials/process and any 
other written information to be provided to patients. The Investigator should also provide the 
IRB with a copy of the Investigator Brochure or product labeling, and any updates. 
The Investigator should provide the IRB with reports, updates, and other information (e.g., 
Safety Updates, amendments, and administrative letters) according to regulatory 
requirements, IRB or study site procedures. 
14.3 
Informed Consent Procedures 
Investigators must ensure that patients who volunteer for clinical trials or their legally 
acceptable representative are clearly and fully informed about the purpose, potential risks and 
other information. 
A protocol specific informed consent form (ICF) template will be provided to sites. Preparation 
of the site-specific consent form is the responsibility of the site Investigator and must include 
all applicable regulatory and IRB requirements, and must adhere to Good Clinical Practices 
(GCP) and to the ethical principles that have their origin in the Declaration of Helsinki. All 
changes to the ICF template will be approved by PrECOG and/or their representatives prior to 
implementation. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
consent process will also include written authorization by patients to release medical 
information to allow PrECOG and/or its agents, regulatory authorities, and the IRB of record at 
the study site for access to patient records and medical information relevant to the study, 
including the medical history. This will be documented in the informed consent form or other 
approved form obtained at the time of informed consent per institutional policies. This form 
should also be submitted to PrECOG and/or its agents for review prior to its implementation. 
The Investigator must provide the patient or legally acceptable representative with a copy of 
the consent form and written information about the study in the language in which the patient 
is most proficient. The language must be non-technical and easily understood. The Investigator 
should allow time necessary for patient or patient's legally acceptable representative to inquire 
about the details of the study, then informed consent must be signed and personally dated by 
the patient or the patient's legally acceptable representative and by the person who conducted 


PrECOG Protocol Number: PrE0505 
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88 
the informed consent discussion. The patient or legally acceptable representative should 
receive a copy of the signed informed consent and any other written information provided to 
study patients prior to patient's participation in the trial. The investigator is responsible for 
assuring adequate documentation of this process and for storage and maintenance of the 
original signed consent form for each patient/subject. 
The informed consent and any other information provided to patients or the patient's legally 
acceptable representative, should be revised whenever important new information becomes 
available that is relevant to the patient's consent, and should receive IRB approval prior to use. 
The Investigator, or a person designated by the Investigator should inform the patient or the 
patient's legally acceptable representative of all pertinent aspects of the study and of any new 
information relevant to the patient's willingness to continue participation in the study. This 
communication should be documented in the patient record. During a patient's participation in 
the trial, any updates to the consent form and any updates to the written information will be 
provided to the patient. 
14.4 
Safety Communication 
Investigators will be notified of all AEs that are serious, unexpected, and definitely, probably, 
or possibly related to the investigational product. Upon receiving such notices, the Investigator 
must review and retain the notice with the Investigator Brochure and submit a copy of this 
information to the IRB according to local regulations. The Investigator and IRB will determine 
if the informed consent requires revision. The Investigator should also comply with the IRB 
procedures for reporting any other safety information. All revisions should be submitted to 
PrECOG and/or agents for review. 
14.5 
Monitoring 
Representatives and agents of PrECOG and, as applicable to the study, the manufacturer of 
investigational product must be allowed to visit all study site locations periodically to assess 
the data, quality and study integrity. The purpose of this visit is to review study records and 
directly compare them with source documents and discuss the conduct of the study with the 
Investigator, and verify that the facilities remain acceptable. Monitoring of drug accountability 
will also occur. 
The study may be evaluated by other auditors and government inspectors who must be 
allowed access to electronic Case Report Forms (eCRFs), source documents and other study 
files. The Investigator must notify PrECOG of any scheduled visits by regulatory authorities, 
and submit copies of all reports. Information as to who investigators should notify of an audit 
or where to address questions will be provided in additional study materials. 
14.6 
Study Records 
An Investigator is required to maintain adequate regulatory files with corresponding 
communication and approvals, accurate histories, observations and other data on each 
individual treated. Full details of required regulatory documents will be provided in additional 
study materials. Data reported on the eCRFs must be consistent with the source documents 
as part of the patient record. 
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
A study specific signature record will be maintained to document signatures and initials of all 
persons at a study site who are authorized to make entries and/or corrections on eCRFs as 
well as document other study-specific roles. 
 


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89 
14.7 
Electronic Case Report Form (eCRF) Information 
Additional information regarding eCRF instructions, timelines for data entry/submission and 
query completion can be found in supplemental materials provided to the site. Sites will be 
expected to complete eCRFs as per the schedule provided and submit all relevant data as per 
the specified timelines. All items recorded on eCRFs must be found in source documents. 
The completed eCRF must be promptly reviewed, electronically signed, and dated by the 
Principal Investigator. 
Instructions for management of patients who do not receive any protocol therapy: 
If a patient is registered and does not receive any assigned protocol treatment, baseline, 
Serious Adverse Event and follow-up data will still be entered and must be submitted according 
to the eCRF instructions. Document the reason for not starting protocol treatment on the 
appropriate electronic off treatment form. 
14.8 
Records Retention 
FDA Regulations (21CFR 312.62) require clinical investigators to retain all trial-related 
documentation, including source documents for the periods described below for studies 
performed under a US Investigational New Drug (IND): 
• two years after the FDA approves the marketing application, or 
• two years after the FDA disapproves the application for the indication being studied, or 
• two years after the FDA is notified by the sponsor of the discontinuation of trials and that an 
application will not be submitted. 
The Investigator must retain investigational product disposition records, copies of eCRFs (or 
electronic files), and source documents for the maximum period required by applicable 
regulations and guidelines, or Institution procedures, whichever is longer. The Investigator 
must contact PrECOG and/or representatives prior to destroying any records associated with 
the study. 
Information as to who investigators should contact for questions will be provided in additional 
study documents. PrECOG and/or representatives will notify the Investigator when the trial 
records for this study are no longer needed. 
 


PrECOG Protocol Number: PrE0505 
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90 
15. 
References 
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carcinogens. Am J Ind Med. 2005 Dec; 48(6):419-31. 
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3. Delgermaa V, Takahashi K, Park E-K, Le GV, Hara T, Sorahan T. 2011. Global mesothelioma 
deaths reported to the World Health Organization between 1994 and 2008. Bull. World Health 
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4. Hodgson JT, McElvenny DM, Darnton AJ et al. The expected burden of mesothelioma mortality in 
Great Britain from 2002 to 2050. Br J Cancer. 2005; 92(3):587. 
5. Murayama T, Takahashi K, Natori Y, Kurumatani N. 2006. Estimation of future mortality from 
pleural malignant mesothelioma in Japan based on an age-cohort model. Am. J. Ind. Med. 49(1):1–
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6. Curran D, Sahmoud T, Therasse P et al. Prognostic factors in patients with pleural mesothelioma: 
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Jan; 16(1):145-52. 
7. Cornelissen R, Heuvers ME, Maat AP et al. New roads open up for implementing immunotherapy 
in mesothelioma. Clin Dev Immunol. 2012; 2012: 927240. 
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9. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may 
contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating 
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10. Thompson RH, Gillett MD, Chevillem JC, Lohsem CM, Dong H, Webster WS, et al. Costimulatory 
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104(10):2084-91. 
11. Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is 
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Res. 2006; 66(7):3381-5. 
12. Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. Survivin and 
B7-H1 are collaborative predictors of survival and represent potential therapeutic targets for 
patients with renal cell carcinoma. Clin Cancer Res. 2007; 13(6):1749-56. 
13. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human 
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14. Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance and 
regulation of the costimulatory molecule B7-H1 in pancreatic adenocarcinoma. Cancer Lett. 2008; 
268(1):98-109. 
15. Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 expressions 
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16. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed cell 
death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human 
ovarian cancer. Proc Nat Acad Sci U S A. 2007; 104(9):3360-5. 
17. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, and Timmerman JM. Programmed death 
ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T 
cells. Clin Cancer Res. 2011. 17(13):4232-4244. 


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18. Brusa D, Serra S, Coscia M, Rossi D, D’Arena G, Laurenti L, et al. The PD-1/PD-L1 axis contributes 
to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013 Jun; 98(6):953-963. 
19. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu 
Rev Immunol. 2008; 26:677-704. 
20. Park J, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 
interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 
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21. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 
2008; 8(6):467-77. 
22. Currie AJ, Prosser A, McDonnell A, et al Dual control of antitumor CD8 T cells through the 
programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: 
regulation and counterregulation. J Immunol. 2009 Dec 15;183(12):7898-908. 
23. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med. 2012 Jun 28; 366(26):2443-54. 
24. Soria JC, Cruz C, Bahleda R, Delord JP, Horn L, Herbst RS, et al. Clinical activity, safety and 
biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): Additional analysis from a 
clinical study of the engineered antibody MPDL3280A (anti-PDL1). Presented at: 2013 European 
Cancer Conference; September 27-October 1, 2013, Amsterdam, The Netherlands. 
25. Garon EB, Balmanoukian A, Hamid O, Hui R, Gandhi L, Leighl N, et al. Preliminary Clinical Safety 
and Activity of MK-3475 monotherapy for the treatment of previously treated patients with non-
small-cell lung cancer (NSCLC). Presented at: 15th World Conference on Lung Cancer; October 
27-30, 2013, Sydney, Australia. 
26. Mansfield AS, Roden AC, Peikert T, et al. B7-H1 expression in malignant pleural mesothelioma is 
associated with sarcomatoid histology and poor prognosis. J Thorac Oncol. 2014 Jul; 9(7):1036-
40. 
27. Kindler HE, Zuo Z, Khatttri A, et al. T-cell inflamed phenotype and PDL1 expression in malignant 
mesothelioma. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts. Vol 32, No 
15_suppl (May 20 Supplement), 2014. 
28. Alley E, et al. Presented at: AACR Annual Meeting, Philadelphia, PA, 2015. 
29. www.clinicaltrials.gov Identifier: NCT02399371. 
30. MedImmune, LLC. MEDI4736 Investigator's Brochure, Edition 8; Date: 01Sep2015. 
31. Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in 
cancer patients based on population pharmacokinetic analysis. Pharm Res 2006;23(6):1275–84. 
32. Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009; 49(9):1012–24. 
33. Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol 2012; 52(1):18–28. 
34. Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an investigational 
anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus. Clin Pharmacokinet 
2013; 52:1017–27. 
35. Antonia S, Goldberg S, Balmanoukian A, Narwal R, Robbins P, D’Angelo G, et al. A Phase 1 open-
label study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell death-
ligand 1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced non-small 
cell lung cancer (NSCLC). Poster presented at European Society of Medical Oncology (ESMO) 
Meeting, 2014 Sep 26-30; Madrid, Spain. 
36. Alimta® Highlights of Prescribing Information, 10/2012; http://pi.lilly.com/us/alimta-pi.pdf; accessed 
11/17/2015. 


PrECOG Protocol Number: PrE0505 
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92 
37. Platinol® 
(cisplatin 
for 
injection, 
USP); 
http://www.accessdata.fda.gov/drugsatfda_ 
docs/label/2011/018057s080lbl.pdf; accessed 11/17/2015. 
38. Paraplatin® (carboplatin aqueous solution) Injection; http://www.fda.gov/ohrms/dockets/ac/ 
05/briefing/2005-4180b_03_05_Carboplatin% 
20label%201 
-9-04%20FDA.pdf; 
accessed 
11/17/2015. 
39. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination 
with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 
2003 Jul 15;21(14):2636-44. 
40. Buikhuisen WA, Hiddinga BI, Baas P, et al. Second line therapy in malignant pleural mesothelioma: 
A systematic review. Lung Cancer. 2015 Sep;89(3):223-31. 
41. www.clinicaltrials.gov Identifier: NCT01085630. 
42. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
43. ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking 
Antibody Side Effects.” Section on Lung, page 79. 
44. ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking 
Antibody Side Effects.” Section on Diarrhea/Colitis, page 77. 
45. ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking 
Antibody Side Effects.” Section on Hepatotoxicity, page 78. 
46. FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury-
Premarketing Clinical Evaluation. 
47. Callahan MK and Wolchok JD. CTLA-4 and PD-1 blocking antibodies in cancer immunotherapy. J 
Leukoc Biol. 2013; 94(1):41-53. 
48. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, 
and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28; 366(26):2443-
54. 
49. Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of 
anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28; 366(26):2455-
65. 
50. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural 
mesothelioma. Ann Oncol. 2004;1 5:257–60. 
51. Tsao AS, Garland L, Redman M, et al. A practical guide of the Southwest Oncology Group (SWOG) 
to measure malignant pleural mesothelioma (MPM) tumors by RECIST and modified RECIST 
criteria. J Thorac Oncol. 2011 Mar;6(3):598-601. 
52. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé, et al. Guidelines for the evaluation of 
immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 
2009;15: 7412-20. 
53. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH and Hodi FS. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria using 
unidimensional measurements. Clin Cancer Res. 2013 Jul; 19(14):3936-3943. 
54. European Medicines Agency’s “Guideline on the evaluation of anti-cancer medicinal products in 
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(EMA/CHMP/205/95/Rev.4); 
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Scientific_guideline/2013/01/WC500137128.pdf; accessed 11/16/2015. 
 


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93 
Appendix I: 
ECOG Performance Status 
 
PS 0 
Fully active, able to carry on all pre-disease performance 
without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature e.g. 
light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities. Up and about more than 50% of 
waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 


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Appendix II: Cockcroft-Gault Formula 
 
 
(140 - age [years]) (body wt [kg]) 
Creatinine clearance for males =  
————————————— 
(72) (serum creatinine [mg/dL]) 
 
 
 
(140 - age [years]) (body wt [kg]) 
Creatinine clearance for females =  ————————————— 
x 0.85 
(72) (serum creatinine [mg/dL]) 
 
Source: Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum 
creatinine (editorial). Nephron 1992; 62:249 
 


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Appendix III: Rule of Nines 
See the rule of nines as follows. Note that a patient's palm is approximately 1% total body surface area (TBSA) 
and can be used for estimating patchy areas. 
• 
Head/neck - 9% TBSA 
• 
Each arm - 9% TBSA 
• 
Anterior thorax - 18% TBSA 
• 
Posterior thorax - 18% TBSA 
• 
Each leg - 18% TBSA 
• 
Perineum - 1% TBSA 
 
Source: 
http://my.firefighternation.com/forum/topics/889755:Topic:2902596?q=forum/topics/889755:Topic:29
02596 


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96 
Appendix IV: Investigator’s Statement 
1. 
I have carefully read this protocol entitled “Open Label, Phase II Study of Anti-
Programmed Death-Ligand 1 Antibody, Durvalumab (MEDI4736), in Combination 
with Chemotherapy for the First-Line Treatment of Unresectable Mesothelioma”, 
Version 5.0 dated 3/19/2018 (Protocol Number PrE0505) and agree that it contains 
all the necessary information required to conduct the study. I agree to conduct the study 
as outlined in the protocol. 
2. 
I agree to conduct this study according to the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, the principles of 
Good Clinical Practice (GCP) as described in 21 Code of Federal Regulations (CFR) 
and any applicable local requirements. 
3. 
I understand that this trial and any subsequent changes to the trial will not be initiated 
without approval of the appropriate Institutional Review Board, and that all 
administrative requirements of the governing body of the institution will be complied 
with fully. 
4. 
Informed written consent will be obtained from all participating patients in accordance 
with institutional and Food and Drug Administration (FDA) requirements as specified in 
Title 21, CFR, Part 50. 
5. 
I understand that my signature on the electronic Case Report Form (eCRF) indicates 
that I have carefully reviewed each page and accept full responsibility for the contents 
thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from PrECOG, LLC unless this requirement is superseded by the 
FDA. 
Principal Investigator (PI): 
PI Name: 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
 
 
 
 
Signature of PI: 
 
 
 
 
 
 
 
 
 
Date of Signature: 
 
 
\ 
 
\ 
 
 
 
 
 
 
 
MM 
 
DD 
 
YYYY 
 

SAP_001.pdf: 
PrECOG Protocol Number: PrE0505 
Date: 5/23/2018 
 
1 
 
 
PrE0505 Statistical Analysis Plan (SAP) 
Open Label, Phase II Study of Anti - Programmed Death – 
Ligand 1 Antibody, Durvalumab (MEDI4736), in Combination 
with Chemotherapy for the First-Line Treatment of 
Unresectable Mesothelioma 
 
NCT #: 
NCT02899195 
Version Number: 
1.0 
Version Date: 
May 23, 2018 
 


Statistical Analysis Plan  
PrECOG/PrE0505 
Final/ 23 May 2018 
 
 
1 
 
 
 
 
 
Statistical Analysis Plan 
 
Study code 
PrE0505 
 
Version 
 Final V1.0 
 
Date 
 23 May 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Open Label, Phase II Study of Anti - Programmed Death –
Ligand 1 Antibody, Durvalumab (MEDI4736), in 
Combination with Chemotherapy for the First-Line 
Treatment of Unresectable Mesothelioma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
PrECOG/PrE0505 
Final/ 23 May 2018 
 
 
2 
 
 
 
 
 
DOCUMENT: 
 
Statistical Analysis Plan 
PROTOCOL 
 
 
Number: 
 
PrE0505 
Title: 
 
Open Label, Phase II Study of Anti ‐ Programmed Death – 
Ligand 1 Antibody, Durvalumab (MEDI4736), in Combination 
with Chemotherapy for the First‐Line Treatment of 
Unresectable Mesothelioma
       Version Date 
 
March 19, 2018, Version  5.0 
 
 
 
 
SAP STATUS 
 
Final 1.0 
SAP VERSION DATE 
 
23 May 2018  
SPONSOR: 
 
PrECOG    
PREPARED BY: 
 
 
Statistician 
Quality Data Services, Inc. 
 
 
 
 
 
 
 
 
 








Statistical Analysis Plan  
PrECOG/PrE0505 
Final/ 23 May 2018 
 
 
5 
 
 
 
 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................. 1 
1. LIST OF ABBREVIATIONS ........................................................................................... 7 
2. INTRODUCTION ........................................................................................................ 9 
2.1. Objective of the Statistical Analysis Plan ................................................................. 9 
3. STUDY OBJECTIVES ................................................................................................... 9 
3.1. Primary Objective .................................................................................................. 9 
3.2. Secondary Objectives ............................................................................................ 9 
3.3. Exploratory Objectives ......................................................................................... 10 
4. STUDY DESIGN ....................................................................................................... 10 
4.1. Overview ............................................................................................................ 10 
4.2. Patient Registration ............................................................................................. 10 
4.3. Dose Limiting Toxicity .......................................................................................... 11 
4.4. Duration of Therapy ............................................................................................ 11 
4.5. Duration of Follow‐Up ......................................................................................... 11 
4.6. Criteria for Removal from Study ........................................................................... 12 
5. MEASUREMENT OF EFFECT ..................................................................................... 12 
5.1. Solid Tumor Response Criteria (RECIST 1.1) ........................................................... 12 
5.1.1. Malignant Disease Evaluation ............................................................................. 12 
5.1.2. Definitions of Response ..................................................................................... 13 
5.1.3. Evaluation of New Lesions ................................................................................. 15 
5.1.4. Symptomatic Deterioration ................................................................................ 15 
5.2. Evaluation of Patient’s Best Overall Response ....................................................... 15 


Statistical Analysis Plan  
PrECOG/PrE0505 
Final/ 23 May 2018 
 
 
6 
 
 
 
 
6. STATISTICAL CONSIDERATIONS ................................................................................ 16 
6.1. Sample Size Considerations .................................................................................. 16 
6.2. General Methodology .......................................................................................... 16 
6.3. Handling of Dropouts or Missing Data ................................................................... 17 
6.4. Interim Analyses and Data Monitoring .................................................................. 17 
6.5. Endpoints ........................................................................................................... 17 
6.5.1. Primary Endpoint .............................................................................................. 17 
6.5.2. Secondary Endpoints ......................................................................................... 17 
6.6. Analysis Populations ............................................................................................ 17 
6.6.1. Full Analysis Set (FAS) ........................................................................................ 17 
6.6.2. Safety population .............................................................................................. 18 
6.7. Subgroup Analysis ............................................................................................... 18 
6.8. Analysis Methods ................................................................................................ 18 
6.8.1. Analysis of Primary Endpoint .............................................................................. 18 
6.8.2. Analysis of Secondary Endpoints ......................................................................... 18 
6.8.3. Analysis of Other Study Parameters .................................................................... 19 
7. SUMMARY OF CHANGES FROM PROTOCOL‐SPECIFIED ANALYSES .............................. 20 
8. REPORTING CONVENTIONS ..................................................................................... 20 
9. REFERENCES ........................................................................................................... 21 
10. TABLES, FIGURES, AND LISTINGS ............................................................................ 21 
 
 


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1.   LIST OF ABBREVIATIONS 
Abbreviation or special 
term 
Explanation 
AE(s) 
Adverse event(s) 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood pressure 
CR 
Complete response 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT 
computed tomography 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full analysis set 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
irAE 
Immune‐related adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
OS 
Overall survival 
PFS 
Progression free survival 
PR 
Partial response  
PD 
Progressive disease 
PFS 
Progression‐free survival 
QDS 
Quality Data Services, Inc. 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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Abbreviation or special 
term 
Explanation 
SD 
Stable Disease 
STD 
Standard deviation 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper limit of normal  
WHO‐DD 
World Health Organization Drug Dictionary 
 
 
 


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2.   INTRODUCTION 
2.1.   Objective of the Statistical Analysis Plan 
This statistical analysis plan (SAP) describes the planned analysis of the safety and efficacy data from the 
study.  A detailed description of the planned tables, figures and listings (TFLs) to be presented in the 
analysis is provided in the accompanying TFL template document. 
The intent of this document is to provide guidance for the analysis of data related to safety and efficacy 
to  describe  any  applicable  statistical  procedures.    In  general,  the  analyses  come  directly  from  the 
protocol, unless they have been modified by agreement between the Sponsor and Quality Data Services, 
Inc.  (QDS).    A  limited  amount  of  information  concerning  this  study  (e.g.,  objectives,  study  design)  is 
summarized to help the reader interpret the accompanying TFL templates.  That information is not a 
synopsis of the study and does not require review or approval because it is simply extracted from the 
protocol.  Attached signatures indicate approval of the statistical analysis sections of the SAP, as well as 
accompanying TFL templates.  These sections must be agreed upon prior to database lock.  When the 
SAP and TFL templates are agreed upon and finalized, they will serve as the template for a portion of 
this study’s report. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified.  If additional analyses are required to supplement the 
planned analyses described in this SAP, they may be performed and will be identified in the report. Any 
substantial deviations from this SAP will be agreed upon between the sponsor and QDS.  Deviations 
from this SAP, both substantial and non‐substantial, will be documented in the report.  Any updates to 
their respective analyses, study designs, and TFL presentations after this SAP is finalized and approved 
will be documented in a running Note to the SAP document. 
Various outputs may be required during the conduct of this trial which will necessitate the production of 
some but not all of the Figures, Summary Tables and Key Data Tabulations detailed in this document.  
The SAP will not be updated to reflect these potential changes. 
3.   STUDY OBJECTIVES 
3.1.   Primary Objective 
The primary objective of this phase II study is to demonstrate improved overall survival (OS) compared 
to  a  historic  control  with  the  addition  of  concurrent  and  maintenance  durvalumab  to  standard 
chemotherapy for unresectable pleural mesothelioma.  
3.2.   Secondary Objectives 
The secondary objectives of this study are:  
1)  To  evaluate  the  safety  and  tolerability  of  durvalumab  and  durvalumab  in  combination  with 
chemotherapy in subjects with malignant pleural mesothelioma.  


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2) Percentage of patients progression‐free at 24 weeks from the time of registration. Disease status 
at  24  weeks  will  be  compared  to  disease  status  at  the  time  of  registration,  and  response  coded 
based on modified RECIST 1.1 criteria.  
3)  Progression‐free  survival  (PFS)  will  be  measured  from  the  time  of  study  registration  until 
radiologic progression, clinical progression or death.  
4)  Best  Objective  Response  Rate  (ORR)  evaluation  will  continue  up  to  1  year  on  therapy  and 
response will be coded based on modified RECIST Version 1.1 criteria for mesothelioma.  
3.3.   Exploratory Objectives 
The exploratory objectives of this study are to study laboratory measurements that may correlate to 
response: 
1) Assessment of tumor baseline PD‐L1 expression may be performed.  
2) Assessment of the genomic and neoantigen landscape of baseline tumors may be performed.  
3) Assessment of dynamics of circulating cell free tumor DNA (ctDNA) may be performed.  
4) Serial assessment of soluble biomarkers may be performed. 
4.   STUDY DESIGN 
4.1.   Overview 
This is a single arm, unblinded, open‐label phase 2 study of durvalumab administered concurrently with 
pemetrexed/cisplatin chemotherapy as first‐line treatment for unresectable pleural mesothelioma. The 
first  6  patients  enrolled  will  be  monitored  for  safety  of  the  combination.  The combination will be 
declared intolerable if ≥ 2 of the 6 patients experience a dose limiting toxicity event occurring during the 
first 2 cycles of concurrent therapy phase, and the study will be stopped. Otherwise, the study will 
proceed with enrollment for a maximum of 55 patients (including the initial 6 patients) to receive up to 6 
three‐week  cycles  of  concurrent  durvalumab  with  chemotherapy.  Patients  with  responding  or  stable 
disease  after  six  cycles  of  concurrent  treatment  will  continue  on  durvalumab  as  a  single  agent 
administered once every 3 weeks. Maximum duration of durvalumab treatment is 12 months (inclusive 
of any treatment delays or missed treatments) starting from Cycle 1 of concurrent treatment.  
  
All subjects will be evaluated regularly and their clinical status classified according to RECIST guidelines 
Version 1.1 with modifications for pleural mesothelioma. Beginning with Cycle 1, radiographic response 
will be assessed with imaging every 6 weeks until completion of concurrent phase of treatment. Subjects 
will continue to receive treatment until disease progression or other discontinuation criteria are met. 
 
Following documentation of non‐fatal confirmed disease progression, all subjects will be followed for 
survival every 3 months until death or the close of the study. 
 
 
4.2.   Patient Registration 
Patients must not start protocol treatment prior to registration. 


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Patients must meet all of the eligibility requirements prior to registration. Treatment should begin ≤ 10 
working days from study entry (date of registration).  
Upon determination that a subject meets eligibility criteria, the subject will be registered in the study by 
site personnel via an electronic data capture (eDC) system. Confirmation of registration will be displayed 
in the eDC system.  
Mandatory tumor tissue samples are required to be available for enrollment. Mandatory peripheral 
blood samples will also be collected at protocol specified time points. 
4.3.   Dose Limiting Toxicity  
DLT will be evaluated for the first 2 cycles (2 doses, 42 days) of concurrent therapy with durvalumab, 
pemetrexed  and  cisplatin.  Toxicity  that  is  clearly  and  directly  related  to  the  primary  disease  or  to 
another etiology is excluded from this definition. The following will be DLTs:  
• Any Grade 4 immune‐related adverse event (irAE)  
• Any ≥ Grade 3 colitis  
• Any Grade 3 or 4 non‐infectious pneumonitis irrespective of duration  
• Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation of maximal 
supportive care  
• Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 within 3 days 
after onset of the event despite optimal medical management including systemic corticosteroids or does 
not downgrade to ≤ Grade 1 or baseline within 14 days  
• Liver transaminase elevation >8x ULN or total bilirubin >5x ULN  
 
DLTs occurring beyond the first 2 cycles window will be taken into account when determining whether 
to proceed to enroll the full planned cohort of 55. 
4.4.   Duration of Therapy 
Patients will receive protocol therapy unless:  
• 
Disease progression per modified RECIST Version.1.1 guidelines or clinical progression.  
• 
Toxicities  considered  unacceptable  by  either  the  patient  or  the  investigator,  despite  optimal 
supportive care and dose modifications.  
• 
Development of an inter‐current illness that prevents further administration of study treatment.  
• 
Extraordinary  Medical  Circumstances:  If  at  any  time  the  constraints  of  this  protocol  are 
detrimental to the patient's health, protocol treatment should be discontinued.  
• 
Patient withdraws consent or is unable to comply with study procedures.  
4.5.   Duration of Follow‐Up  
Patients  will  be  followed  for  adverse  events  for  90  days  after  their  last  dose  of  durvalumab  or  until 
initiation of alternative anticancer therapy.  
If a patient is removed from treatment for reason(s) other than progression, follow with regular tumor 
assessments per standard of care until progression or start of new treatment.  
Following documentation of non‐fatal confirmed disease progression, all subjects will be followed for 
survival every 3 months until death or the close of the study.  


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4.6.   Criteria for Removal from Study  
A genuine effort will be made to determine the reason(s) why a patient fails to return for the necessary 
visits or is discontinued from the trial, should this occur. It will be documented whether or not each 
patient  completed  the  clinical  study.  If  for  any  patient  study  treatment  or  observations  were 
discontinued, the reason will be recorded. 
Any patient who receives at least one dose of study drug, durvalumab, will be included in the safety 
analysis. Patients who discontinue study treatment early should be followed for response assessments, 
if possible. 
5.   MEASUREMENT OF EFFECT  
5.1.   Solid Tumor Response Criteria (RECIST 1.1)  
5.1.1.   Malignant Disease Evaluation  
Response and progression will be evaluated in  this study using  the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
Version 1.1 with modifications for pleural mesothelioma.  
To  assess  objective  response,  it  is  necessary  to  estimate  the  overall  tumor  burden  at 
baseline  to  which  subsequent  measurements  will  be  compared.  Measurable  disease  is 
defined by the presence of at least one measurable lesion.  
All measurements should be recorded in metric notation by use of a ruler or calipers. The 
same method of assessment and the same technique should be used to characterize each 
identified  lesion  at  baseline  and  during  follow‐up.  All  baseline  evaluations  should  be 
performed as closely as possible to the beginning of treatment and never more than four 
weeks before registration.  
The  term  evaluable  in  reference  to  measurability  will  not  be  used  because  it  does  not 
provide additional meaning or accuracy.  
At baseline, tumor lesions will be characterized as either measurable or non‐measurable.  
5.1.1.1.   Measurable  
Lesions that can be accurately measured in at least one dimension (longest diameter to be 
recorded) with a minimum size of: 
• ≥ 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm)  
• ≥ 10 mm caliper measurement by clinical exam (when superficial)  
• ≥ 20 mm by chest x‐ray (if clearly defined and surrounded by aerated lung)  
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.  


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5.1.1.2.   Malignant Lymph Nodes  
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm 
in short axis (perpendicular to longest diameter) when assessed by CT scan. 
5.1.1.3.   Non‐Measurable  
All  other  lesions  (or  sites  of  disease),  including  small  lesions  not  meeting  the  criteria  in 
5.1.1.1  and  5.1.1.2,  are  considered  non‐measurable  lesions.  This  includes  lymph  nodes 
measured at ≥ 10 to <15 mm in the short axis. Lymph nodes measured at <10 mm in the 
short axis are considered normal.  
Lesions considered to be non‐measurable include the following: leptomeningeal disease, 
ascites, 
pleural/pericardial 
effusions, 
inflammatory 
breast 
disease, 
lymphangitic 
involvement of the skin or lung, and abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques. 
Tumor lesions that are situated in a previously irradiated area, or in an area subjected to 
other loco‐regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  
5.1.2.   Definitions of Response  
5.1.2.1.   Target Lesions  
All  measurable  lesions  up  to  a  maximum  of  2  lesions  per  organ  and  5  lesions  in  total, 
representative of all involved organs are identified as target lesions. Target lesions should 
be selected on the basis of their size (those with the longest diameters), be representative 
of all involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements.  
The sum of the target lesions (longest diameter for non‐nodal lesions, short axis for nodal 
lesions)  will  be  calculated  and  reported  as  the  baseline  sum.  If  lymph  nodes  are  to  be 
included in the sum, then only the short axis is added into the sum. The baseline sum of the 
diameters/axes  will  be  used  as  reference  to  further  characterize  any  objective  tumor 
regression in the measurable dimension of the disease.  
Complete Response (CR)  
The disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non‐target) must have reduction in short axis to <10 mm (the sum may not be “0” if there 
are  target  nodes).  To  be  assigned  a  status  of  complete  response,  changes  in  tumor 
measurements must be confirmed by repeat assessments performed ≥ 4 weeks after the 
criteria for response are first met.  
Partial Response (PR)  


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At  least  a  30%  decrease  in  the  sum  of  the  diameters/axes  of  target  lesions,  taking  as 
reference the baseline sum diameters/axes. To be assigned a status of partial response, 
changes in tumor measurements must be confirmed by repeat assessments performed ≥ 4 
weeks after the criteria for response is met. 
Progressive Disease (PD)  
At  least  a  20%  increase  in  the  sum  of  the  diameters/axes  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 over the nadir. 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/axes while on study. A change of 20% or more 
that  does  not  increase  the  sum  of  the  diameters  by  5  mm  or  more  is  coded  as  stable 
disease.  
5.1.2.2.   Non‐Target Lesions  
All other lesions or sites of disease including any measurable lesions over and above the 5 
target lesions and lymph nodes measured at ≥ 10 to <15 mm in the short axis 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 unequivocal progression of 
each should be noted throughout follow‐up.  
Complete Response (CR)  
The disappearance of all non‐target lesions and normalization of tumor marker levels, if 
applicable. All lymph nodes must be non‐pathological in size (<10 mm short axis). To be 
assigned  a  status  of  complete  response,  changes  in  tumor  measurements  must  be 
confirmed by repeat assessments performed ≥ 4 weeks after the criteria for response are 
first met.  
Non‐CR/Non‐PD  
The  persistence  of  one  or  more  non‐target  lesion(s)  and/or  the  maintenance  of  tumor 
marker  levels  above  the  normal  limits.  To  be  assigned  a  status  of  Non‐CR/Non‐PD, 
measurements must have met the Non‐CR/Non‐PD criteria at least once after study entry 
at a minimum interval of ≥ 4 weeks.  
Progressive Disease (PD)  
The appearance of one or more new lesion(s) and/or unequivocal progression of existing 
non‐target  lesions.  Unequivocal  progression  should  not  normally  trump  target  lesion 


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status.  It  must  be  representative  of  overall  disease  status  change,  not  a  single  lesion 
increase.  
5.1.3.   Evaluation of New Lesions  
The appearance of new lesions constitutes Progressive Disease (PD). 
5.1.4.   Symptomatic Deterioration  
Patients with a global deterioration of health status requiring discontinuation of treatment 
without  objective  evidence  of  disease  progression  at  that  time  should  be  reported  as 
“symptomatic  deterioration”.  Every  effort  should  be  made  to  document  the  objective 
progression even after discontinuation of treatment. 
5.2.   Evaluation of Patient’s Best Overall Response  
The best overall response is the best response recorded from the start of the treatment until confirmed 
disease progression or non‐protocol therapy (taking as reference for progressive disease the smallest 
measurements  recorded  since  the  treatment  started).  The  patient's  best  response  assignment  will 
depend on the achievement of both measurement and confirmation criteria.  
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease  
 
To  be  assigned  a  status  of  complete  or  partial  response,  changes  in  tumor  measurements  must  be 
confirmed by repeat assessments performed ≥ 4 weeks after the criteria for response are first met.  
To be assigned a status of stable disease, measurements must have met the stable disease criteria at 
least once after study entry at a minimum interval of ≥ 4 weeks.  
Overall Response for all Possible Combinations of Tumor Response 
Target 
Lesions 
Non‐Target 
Lesions 
New Lesion 
Overall 
Response 
Remarks 
CR 
CR 
No 
CR 
Confirmation at ≥ 4 weeks 
CR 
Non‐CR/Non‐
PD 
No 
PR 
Confirmation at ≥ 4 weeks 
CR 
Not Evaluated 
No 
PR 
Confirmation at ≥ 4 weeks 
PR 
Non‐PD/Not 
Evaluated 
No 
PR 
Confirmation at ≥ 4 weeks 
SD 
Non‐PD/Not 
Evaluated 
No 
SD 
Documented at least once ≥ 
4 weeks from study entry 
Not All 
Evaluated 
Non‐PD 
No 
Not 
Evaluable 
 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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5.3.   Frequancy of Evaluation 
Response assessments will be performed every 6 weeks (2 doses of treatment) for the first 18 weeks. 
After  18  weeks  of  treatment,  response  assessments  will  be  performed  every  9  weeks  (3  doses  of 
treatment).  
Following documentation of non‐fatal confirmed disease progression, all subjects will be followed for 
survival (either routine clinic visit or telephone contact) every 3 months until death or the closure of the 
study. 
6.   STATISTICAL CONSIDERATIONS  
This  study  will  initially  enroll  6  patients  to  monitor  for  safety  and  tolerability  of  the  combination  of 
durvalumab with pemetrexed/cisplatin (or carboplatin). The study will proceed to the expansion phase 
to enroll a total of 55 patients (including the first 6 patients) if <2 patients among the first 6 patients 
enrolled experience a DLT during the first 2 cycles of concurrent therapy.  
The  statistical  analysis  described  in  this  section  applies  only  if  the  study  proceeds  to  the  expansion 
phase.  
6.1.   Sample Size Considerations 
The primary comparison is for overall survival and will include all eligible patients who started protocol 
treatment, of whom 50 will be accrued. After inflating for an ineligibility rate of 10%, the total planned 
accrual is 55 patients. Based on the randomized phase III trial conducted by Vogelzang in this setting, it 
is  assumed  that  the  null  hypothesis  is  that  the  median  overall  survival  (OS)  time  is  12  months  with 
pemetrexed/cisplatin  alone.  Using  a  one‐sided  0.10  level  test,  a  sample  size  of  50  will  achieve  90% 
power to detect a 37% reduction in the OS hazard rate of 0.058 to 0.037 (with an accrual period of 24 
months  for  the  50  patients  in  the  primary  analysis,  and  an  additional  18  months  for  treatment  and 
follow‐up); assuming exponential survival, this corresponds to a 58% improvement in the median OS of 
12 months to 19 months. The number of OS events needed to achieve this power is 32 events. 
6.2.   General Methodology 
Continuous data will be summarized with the following descriptive statistics: number of observations 
(n), mean, standard deviation (STD), median, minimum (min), and maximum (max). Categorical data will 
be summarized with frequencies and percentages. 
Kaplan‐Meier method will be used to analyze time‐to‐event variables. Cox proportional hazards models 
will be used to estimate the hazard ratios between subgroups. 
Baseline is defined as the last non‐missing measurement prior to the first dose of study treatment. 
The last record will be used for analysis if there are multiple records for a visit/time point. 
Statistical analysis and programming of tables, listings and figures will be conducted by QDS, using SAS® 
Release 9.4 or a later version (SAS Institute Inc., Cary, North Carolina, USA).     


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6.3.   Handling of Dropouts or Missing Data 
All  attempts  will  be  made  to  prevent  any  missing  values.    Missing  or  invalid  data  will  be  treated  as 
missing, not imputed. 
No data imputation will be done for missing data except for adverse events (AEs) with missing onset 
date.  If the AE onset date is completely missing, then the date of first study therapy will be used for 
classification of AEs that were experienced following administration of study therapy. 
6.4.   Interim Analyses and Data Monitoring 
There is no formal interim safety analysis planned for this study.  A toxicity assessment is planned when 
safety data are collected for the first 15 patients when they complete the first two cycles of concurrent 
therapy without suspension to accrual. The safety monitoring will be done based on the electronic case 
report form (eCRF) database. Accrual will be suspended for further review of non‐hematologic toxicity if 
at least 5 Grade 4/5 non‐hematologic events among the first 15 patients are observed. 
6.5.   Endpoints 
6.5.1.   Primary Endpoint 
The  primary  endpoint  is  overall  survival  (OS),  defined  as  the  time  from  registration  to 
death from any cause. Patients that have not had an event reported at time of analysis 
will be censored at their date of last follow‐up. 
6.5.2.   Secondary Endpoints 
• 
Progression‐free survival (PFS), defined as the time from registration to documented 
disease progression or death from any cause, whichever occurs first. Patients who 
have not experienced an event of interest by the time of analysis will be censored at 
the date they are last known to be alive and progression‐free. 
• 
Progression‐free survival (PFS) at 24 weeks from the time of registration. 
• 
Best objective response rate (ORR) 
• 
Dose limiting toxicity events and adverse events of the treatment regimen 
6.6.   Analysis Populations 
6.6.1.   Full Analysis Set (FAS)  
The Full Analysis Set is defined as all eligible patients who started study therapy. Primary 
and secondary endpoints analyses will be conducted for the FAS population.  


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6.6.2.   Safety population 
Safety  population  is  defined  as  all  patients  who  received  at  least  one  dose  of  study 
therapy. Safety analysis will be conducted for the safety population. 
6.7.   Subgroup Analysis 
Subset analyses are planned for known prognostic factors such as performance status, age, gender, etc. 
Subset analyses of all variables, including correlatives, are considered to be exploratory in nature. 
6.8.   Analysis Methods 
6.8.1.   Analysis of Primary Endpoint  
The primary test for Overall survival (OS) is based on Wald test for the log failure rate 
parameter  and  test  at  a  one‐side  type  I  error  rate  of  10%  by  using  Cox  proportional 
hazards model.   
Logrank test and Cox proportional hazards modeling will be used to assess the effect of 
gender,  baseline  ECOG  PS,  and  age  on  overall  survival  for  full  analysis  set.  OS  survival 
curve will be plotted.  
Point estimates and 95% confidence interval will be presented for median survival time 
and hazard ratio. 
6.8.2.   Analysis of Secondary Endpoints  
Analysis of progression free survival (PFS) will be performed in a similar way as for OS, 
without the comparison with historical control patients.  
Percentage  of  progression  free  patients  at  24  weeks  from  registration,  best  objective 
response  rate  (ORR)  will  be  summarized  for  the  FAS  population.  Point  estimate  of 
proportion and its 95% exact binomial confidence interval for each response category will 
be presented. 
Adverse events severity  will be graded according to the National Cancer Institute  (NCI) 
Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE V4.03). Analysis of 
AEs  will  be  on  treatment‐emergent  AEs  (TEAEs),  those  occur  or  worsening  after 
administration of the first study dose, for the safety population. In the case where the 
start date of the AE is unknown, it will be assumed to be treatment‐emergent. 
Treatment‐emergent AEs (TEAEs) will be summarized by system‐organ‐class and preferred 
term using the Medical Dictionary for Regulatory Activities (MedDRA®). The frequency of 
subjects  who  experience  TEAEs  will  be  summarized  along  with  95%  exact  binomial 
confidence interval for the proportion. Subjects having the same AE more than once will 
be  counted  once  at  maximum  intensity  for  each  preferred  term  and  once  within  each 
system  organ  class.  The  summary  AE  tables  will  display  the  number  of  subjects  with 
treatment‐emergent AEs by maximum intensity (CTCAE grading). 


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Additional  treatment‐emergent  AEs  by  strongest  relationship  to  Durvalumab  will  be 
presented by system organ class and preferred term.   
6.8.3.    Analysis of Other Study Parameters 
6.8.3.1.   Subject Accountability and Subject Disposition 
The number of subjects enrolled, completing the study, with protocol deviation, and study 
discontinuation  will  be  tabulated.  Protocol  deviations  will  be  categorized  by  deviation 
classification, and study discontinuation will be categorized by reason for discontinuation. 
Number of subjects in full analysis set  will also be summarized. 
6.8.3.2.   Demographics and Baseline Characteristics 
Demographic data (e.g age, sex, race, etc.) and disease characteristics will be summarized 
descriptively for FAS population.  
6.8.3.3.   Concomitant Medications  
The  use  of  concomitant  medications  will  be  recorded  and  coded  to  a  World  Health 
Organization Drug Dictionary (WHO‐ DD) term. 
The use of concomitant medications will be summarized. The number and percentage of 
subjects taking each medication will be presented by ATC Classification. 
6.8.3.4.   Lesion Assessments 
Lesion  assessments  (target  lesions,  non‐target  lesions)  are  used  for  tumor  overall 
response  at  each  assessment  (Protocol  Table  9‐1).  The  target  response,  non‐target 
response and overall response are collected in CRF page after every 2 doses treatment at 
first 18 weeks. After 18 weeks the response assessments are collected after every 3 doses 
treatment. 
6.8.3.5.   Response Assessment 
Disease response assessment (target, non‐target, overall, and best overall response) will 
be described using descriptive statistics by visit. 
6.8.3.6.   Treatment Cycles and Follow‐up Duration 
Number of cycles of treatment patients received will be summarized descriptively. Follow‐
up durations from time of registration to time of last patient contact will be calculated as 
last contact date – registration date +1, and be summarized descriptively.    
6.8.3.7.   Clinical Laboratory Data 
Clinical  laboratory  data  includes  hematology,  chemistry,  coagulation  and  urinalysis. 
Numeric laboratory tests at baseline will be summarized using descriptive statistics  


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Clinically significant worsening from baseline or new clinically significant laboratory test 
abnormalities that were considered AEs by the investigator will be presented in the AE 
analyses.  
7.   SUMMARY OF CHANGES FROM PROTOCOL‐SPECIFIED ANALYSES 
No changes are planned.  
8.   REPORTING CONVENTIONS 
The mean and median will be displayed to one decimal place greater than the original value and the 
standard deviation will be displayed to two decimal places greater than the original value. All statistical 
programming  and  analyses  will  be  performed  using  SAS®  Release  9.2  (SAS  Institute  Inc.,  Cary,  North 
Carolina, USA). 
The following standards will be used in the data presentation: 
• 
Section  10  tables  should  be  in  landscape  format.    Output  should  adhere  to  US  /  International 
Conference on Harmonization (ICH) margins and should not require changes for European page size.  
For item 10 tables, a blank row will separate the header from the content of the table listing.  For 
tables that have “n (%)”, the placement should be centered below “N=xx” in the column header.  
Frequency tables will be center justified.  Descriptive statistics will be decimal aligned.   
• 
Percentages presented in in‐text tables should be rounded to one decimal using the SAS rounding 
function.  If “%” is part of the column heading, do not repeat the “%” sign in the body of the table.  
Unless specified otherwise, “%” should reflect the total population of the treatment groups.  Any 
deviation  from  that  should  be  part  of  the  footnote.    For  0  counts,  leave  the  corresponding 
percentage blank. 
• 
The  format  for  minimum  and  maximum  should  be  “Min,  Max”.    STD  should  be  the  default  for 
representing  scale,  unless  standard  error  has  been  specified.    Standard  deviation  should  be 
abbreviated as “STD”, and presented next to the mean value, without any +/‐ sign.  The STD should 
have one additional decimal place beyond that of the mean (e.g. mean has one decimal place, STD 
should have two). 
• 
 “N” will represent the entire treatment group for the population group being analyzed, while “n” 
will represent a subset of the  treatment group.   For tables with population designated  as a row 
heading, “N” should be used (i.e. tables where all participant data is not available for every variable 
within  a  treatment  group).    As  a  guideline,  if  the  number  is  used  in  a  denominator  it  should  be 
presented as “N”.  If the number is used in the numerator, it should be presented as an “n”. 
• 
The heading should consist of four lines.  Line 1:  Sponsor identifier.  Line 2:  Protocol identifier.  Line 
3: blank line.  Line 4:  Table/Appendix number  Table Title – Population.  The title for in‐text tables 
should begin with the Table/Appendix number. 
• 
The date format for all dates is DDMMMYYYY.  


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A solid line should appear both above and below the column headings of a table.  A solid line should 
appear at the end of the table or at the bottom of each page if the table extends to more than one page.  
Footnotes should start after the bottom solid line. 
9.   REFERENCES 
References are provided in the protocol.  
10.   TABLES, FIGURES, AND LISTINGS 
See separate template document.


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DOCUMENT HISTORY 
 
Version 
Date 
Modified 
By 
Summary of Changes 
Draft 
03April2018 
 
Removed comparison column in primary efficacy tqable  
Draft 
18April2018 
 
Removed following tables and listing: 
Listing 16.2.2.1  Failed Inclusion Criteria  
Listing 16.2.2.2  Protocol Deviations        
Table 14.2.1.1  Summary of Lesion Assessments– Full Analysis Set               
Table 14.3.2.3  Summary of Coagulation Results at Baseline ‐ Full Analysis 
set        
Table 14.3.2.4  Summary of Numerical Urinalysis Results at Baseline ‐ Full 
Analysis set       
Final 
23May2018 
 
Reviewed and approved by 
, PhD and PrECOG