Conditions: Pancreatic Adenocarcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The standard or usual treatment for this disease consists of two chemotherapy drugs gemcitabine and nab-paclitaxel given together.

Detailed description:
Durvalumab is a new type of drug for many types of cancer. Laboratory tests show that it works by allowing the immune system to detect cancer and reactivate the immune response. This may halp to slow down the growth of cancer or may cause cancer cells to die. Durvalumab has been shown to shrink tumours in animals and has been studied in a few people and seems promising but it is not clear if it can offer better results than standard treatments alone.

Tremelimumab is a new type of drug for various types of cancers. It works in a similar way to durvalumab and may improve the effect of durvalumab. This may also help slow the growth of the cancer cells or may cause cancer cells to die. Tremelimumab has been shown to shrink tumours in animals and has been studied in a few people and seems promising but it is not clear if it can offer better results than standard treatment alone when used with durvalumab.

Combination of durvalumab and tremelimumab have also been studied and when combined have been shown to increase tumour shrinkage in animals compared to either drug alone and while the combination has been studied in a few people, it is not clear if it can offer better results than standard treatment.

Arms:
arm 1: Gemcitabine 1000 mg/m2 IV \& Nab-Paclitaxel 125 mg/m2 until unequivocal progression or unacceptable toxicity. Days 1, 8, 15 Q28 days. arm 2: Gemcitabine 1000 mg/m2 IV \& Nab-Paclitaxel 125 mg/m2 until unequivocal progression or unacceptable toxicity. Day 1, 8, 15 Q28 days.

plus Durvalumab 1500mg IV day 1 only Q28 days; and Tremelimumab 75 mg IV Days 1 cycles 1, 2, 3 and 4 only until unequivocal progression or unacceptable toxicity.

Interventions: intervention 1: Gemcitabine intervention 2: Nab-paclitaxel intervention 3: Durvalumab intervention 4: Tremelimumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_000.pdf: 
 
PROTOCOL DATE: 2016-JUL-20 
 
CCTG TRIAL: PA.7 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION 
 
 
AMENDMENT #2: 2018-MAR-20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A RANDOMIZED PHASE II TRIAL OF GEMCITABINE AND NAB-PACLITAXEL VS. 
GEMCITABINE, NAB-PACLITAXEL, DURVALUMAB AND TREMELIMUMAB AS 1ST LINE 
THERAPY IN METASTATIC PANCREATIC ADENOCARCINOMA 
 
CCTG Protocol Number: PA.7 
 
 
STUDY CHAIR: 
Daniel Renouf 
 
 
TRIAL COMMITTEE: 
Derek Jonker 
 
 
Petr Kavan 
 
 
Neesha Dhani 
 
 
SENIOR INVESTIGATOR: 
Chris O’Callaghan 
 
 
BIOSTATISTICIAN: 
Dongsheng Tu 
 
 
QUALITY OF LIFE COORDINATOR: 
Alice Wei 
 
 
PATHOLOGY COORDINATOR: 
David Schaeffer 
 
 
STUDY COORDINATORS: 
Barbara Graham 
 
 
Lisa Gallinaro 
 
 
REGULATORY SPONSOR: 
CCTG 
 
 
SUPPORTED BY: 
AstraZeneca 
 
(For contact information of study personnel see Final Page.) 
 


 
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AMEND #2: 2018-MAR-20 
TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) .................................................................................. 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 2 
 
1.0 
OBJECTIVES ......................................................................................................................................... 3 
1.1 
Primary Objective ................................................................................................................................... 3 
1.2 
Secondary Objectives .............................................................................................................................. 3 
1.3 
Tertiary Objectives .................................................................................................................................. 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 4 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION.......................................................................... 10 
3.1 
Durvalumab ........................................................................................................................................... 10 
3.2 
Tremelimumab ...................................................................................................................................... 11 
3.3  
Fixed Dosing in Durvalumab and Tremelimumab ................................................................................ 13 
3.4 
Gemcitabine .......................................................................................................................................... 14 
3.5 
Nab-Paclitaxel ....................................................................................................................................... 16 
 
4.0 
STUDY POPULATION ....................................................................................................................... 18 
4.1 
Eligibility Criteria ................................................................................................................................. 18 
4.2 
Ineligibility Criteria ............................................................................................................................... 21 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT....................................................................................................................................... 23 
5.1 
Follow-up for Ineligible Patients ........................................................................................................... 25 
 
6.0 
ENTRY/RANDOMIZATION PROCEDURES .................................................................................... 26 
6.1 
Entry Procedures ................................................................................................................................... 26 
6.2 
BSA Calculation .................................................................................................................................... 26 
6.3 
Stratification .......................................................................................................................................... 26 
6.4 
Registration / Randomization ................................................................................................................ 26 
 
7.0 
TREATMENT PLAN ........................................................................................................................... 28 
7.1 
Treatment Plan Overview...................................................................................................................... 28 
7.2 
Patient Treatment and Monitoring by Arm ........................................................................................... 29 
7.3 
Adverse Event Management and Dose Modification and Adjustments ................................................ 31 
7.4 
Duration of Therapy .............................................................................................................................. 39 
7.5 
Patient Compliance ............................................................................................................................... 40 
7.6 
Concomitant Therapy ............................................................................................................................ 40 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 42 
8.1 
Definitions ............................................................................................................................................. 42 
8.2 
RECIST 1.1 Response and Evaluation Endpoints ................................................................................. 42 
8.3 
Immune-Related (iRECIST) Response Assessment ............................................................................. 45 
8.4 
Response Duration (RECIST 1.1 and iRECIST) .................................................................................. 49 
8.5 
Stable Disease Duration ........................................................................................................................ 49 
8.6 
Methods of Measurement ...................................................................................................................... 49 
 
 
 


 
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9.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 51 
9.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 51 
9.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 54 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting............................ 54 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 56 
9.5 
CCTG Reporting Responsibility to AstraZeneca .................................................................................. 56 
9.6 
AstraZeneca Reporting Responsibilities ............................................................................................... 56 
9.7 
Reporting Safety Reports to Investigators ............................................................................................. 56 
 
10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 57 
10.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 57 
10.2 
Duration of Protocol Treatment ............................................................................................................ 57 
10.3 
Therapy After Protocol Treatment is Stopped ...................................................................................... 57 
10.4 
Follow-up Off Protocol Treatment ........................................................................................................ 57 
 
11.0 
CENTRAL REVIEW PROCEDURES ................................................................................................. 58 
11.1 
Central Radiology Review .................................................................................................................... 58 
11.2 
Central Pathology Review ..................................................................................................................... 58 
 
12.0 
CORRELATIVE STUDIES .................................................................................................................. 59 
12.1 
Protocol-Mandated Correlative Studies ................................................................................................ 59 
12.2 
Week 8 On-treatment Biopsy (Optional) .............................................................................................. 61 
12.3 
Blood, Serum and Plasma Collection (Mandatory) ............................................................................... 61 
12.4 
Optional Banking of Samples ............................................................................................................... 62 
 
13.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 63 
13.1 
Objectives and Design ........................................................................................................................... 63 
13.2 
Primary Endpoints and Analysis ........................................................................................................... 63 
13.3 
Sample Size and Duration of Study ...................................................................................................... 64 
13.4 
Safety Monitoring ................................................................................................................................. 64 
13.5 
Interim Analysis .................................................................................................................................... 64 
 
14.0 
PUBLICATION POLICY ..................................................................................................................... 65 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. ..................................................................................... 65 
14.2 
Responsibility for Publication ............................................................................................................... 65 
14.3 
Submission of Material for Presentation or Publication ........................................................................ 65 
 
15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 66 
15.1 
Regulatory Considerations .................................................................................................................... 66 
15.2 
Inclusivity in Research .......................................................................................................................... 66 
15.3 
Obtaining Informed Consent ................................................................................................................. 67 
15.4 
Discontinuation of the Trial .................................................................................................................. 68 
15.5 
Retention of Patient Records and Study Files ....................................................................................... 68 
15.6 
Centre Performance Monitoring ............................................................................................................ 68 
15.7 
On-Site Monitoring/Auditing ................................................................................................................ 69 
15.8 
Case Report Forms ................................................................................................................................ 69 
 
16.0 
REFERENCES ...................................................................................................................................... 70 
 
 


 
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APPENDIX I -  
PERFORMANCE STATUS SCALES/SCORES ................................................................ 72 
APPENDIX II -  DRUG DISTRIBUTION, SUPPLY AND CONTROL ....................................................... 73 
APPENDIX III -  DOSING MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED AND NON IMMUNE-MEDIATED 
REACTIONS  ...................................................................................................................... 74 
APPENDIX IV -  DOCUMENTATION FOR STUDY .................................................................................... 75 
APPENDIX V -  NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ...................... 77 
APPENDIX VI -  QUALITY OF LIFE ASSESSMENT .................................................................................. 78 
 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 


 
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AMEND #2: 2018-MAR-20 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG and 
AstraZeneca 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, in accordance with any modifications that may 
occur over the duration of the study, and according to Good Clinical Practice and any applicable local 
regulations. I will make a reasonable effort to complete the study within the time designated. I confirm that 
I and study personnel participating under my supervision have adequate resource to fulfill their 
responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG to study personnel 
under my supervision. I will discuss this material with them to ensure that they are fully informed about the 
investigational product and the study. 
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of AstraZeneca and CCTG. The foregoing shall not apply to 
disclosure required by governmental regulations or laws; however, I will give prompt notice to AstraZeneca 
and CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG or AstraZeneca with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
AstraZeneca and CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG PA.7 
 
CENTRE: ___________________________________________ 


 
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TREATMENT SCHEMA 
 
This is a multi-centre, phase II study of doublet immunotherapy (durvalumab + tremelimumab) in 
combination with standard chemotherapy regimens (gemcitabine and nab-paclitaxel) versus standard 
chemotherapy in patients with newly diagnosed, untreated, metastatic pancreatic adenocarcinoma. 
 
Patients with 
metastatic 
pancreatic cancer 
not previously 
treated 
 
Stratification: 
• ECOG PS (0 vs 1) 
• Prior Adjuvant 
Therapy (yes vs no) 
 Randomize 
2:1 
 
ARM 1: 
Gemcitabine + Nab-Paclitaxel N=60 
 
 
 ARM 2: 
Gemcitabine + Nab-Paclitaxel +  
Durvalumab + Tremelimumab* 
N=10** + 120 
Primary Endpoint: Overall Survival 
 
* Tremelimumab and Durvalumab q28 days for 4 cycles, followed by Durvalumab monotherapy until objective 
progression. 
** Prior to the randomized component, 10 patients will first be accrued to ensure safety and tolerability of the 
combination of gemcitabine + nab-paclitaxel + durvalumab + tremelimumab.  
 


 
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1.0 
OBJECTIVES 
 
Ten patients will be enrolled initially to Arm 2 to confirm the safety and tolerability of the 
combination of gemcitabine + nab-paclitaxel + durvalumab + tremelimumab. 
 
1.1 
Primary Objective 
 
The primary objective is to determine the effect on overall survival (OS), of the addition of a 
durvalumab + tremelimumab to standard 1st line chemotherapy with gemcitabine/nab-paclitaxel in 
patients with metastatic pancreatic cancer. 
 
1.2 
Secondary Objectives 
 
• 
To determine the effect on progression free survival (PFS) of the addition of durvalumab + 
tremelimumab to standard 1st line chemotherapy with gemcitabine/nab-paclitaxel in patients 
with metastatic pancreatic cancer. 
• 
To assess the toxicity and safety of durvalumab + tremelimumab in combination with 
gemcitabine/nab-paclitaxel in patients with metastatic pancreatic cancer. 
• 
To determine the effect on objective response rate (ORR) of the addition of durvalumab + 
tremelimumab to standard 1st line chemotherapy with gemcitabine/nab-paclitaxel in patients 
with metastatic pancreatic cancer. 
 
1.3 
Tertiary Objectives 
 
• 
To determine the effect on quality of life (QoL) of the addition of durvalumab + tremelimumab 
to standard 1st line chemotherapy with gemcitabine/nab-paclitaxel in patients with metastatic 
pancreatic cancer. 
• 
To determine the effect of tumour PD-L1 expression assessed by IHC on efficacy of the 
addition of durvalumab + tremelimumab to standard 1st line chemotherapy with 
gemcitabine/nab-paclitaxel in patients with metastatic pancreatic cancer. 
• 
To determine the effect of tumour hENT/SPARC expression assessed by IHC on efficacy of 
the addition of durvalumab + tremelimumab to standard 1st line chemotherapy with 
gemcitabine/nab-paclitaxel in patients with metastatic pancreatic cancer. 
• 
To investigate tumour gene expression signatures associated with the response to the addition 
of durvalumab + tremelimumab to standard 1st line chemotherapy with gemcitabine/nab-
paclitaxel in patients with metastatic pancreatic cancer. 
• 
To assess sequential circulating tumour DNA in patients with metastatic pancreatic cancer 
receiving standard 1st line chemotherapy with gemcitabine/nab-paclitaxel + durvalumab + 
tremelimumab. 
 


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Pancreatic Cancer 
 
Pancreatic cancer is the 4th leading cancer death (after lung, colorectal and breast), with 4800 new 
cases and 4600 deaths expected in Canada in 2015 [Canadian Cancer Society Statistics 2015]. This 96% 
case mortality ratio is the highest of any cancer. There are a number of causes of the high mortality 
rate of pancreatic cancer, including the lack of effective screening tests resulting in the majority of 
patients being diagnosed with advanced disease, and the general chemoresistance of this cancer. 
There has been recent progress in treatment options in the metastatic setting with data supporting 
the use of FOLFIRINOX or gemcitabine and nab-paclitaxel therapy as a 1st line treatment in 
patients with metastatic pancreatic cancer and a good performance status [Conroy 2011, Von Hoff 2013]. 
Despite these advances the majority of patients with metastatic pancreatic cancer will survive less 
than 1 year thus the development of more effective treatment strategies is a critical unmet need. 
 
One strategy to target cancer that has recently shown significant anti-tumour activity in multiple 
tumour types is through modulation of the immune system. There has been significant progress in 
this field over the past several years, with immunomodulatory strategies now becoming standard 
of care in melanoma, non-small cell lung cancer, and renal cell carcinoma. Clinical trials assessing 
immunomodulatory strategies are underway in multiple other cancer types. 
 
Immunotherapy & Immune Checkpoint Inhibitors 
 
Immune responses directed against tumours 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 
tumour types. In a number of these cancers, including lung [Mu 2011], renal [Thompson 2005; Thompson 
2006; Krambeck 2007], pancreatic [Nomi 2007; Loo 2008; Wang 2010], ovarian cancer [Hamanishi 2007], and 
hematologic malignancies [Andorsky 2011; Brusa 2013], tumour cell expression of PD-L1 is associated 
with reduced survival and an unfavourable prognosis. 
 
PD-L1 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 tumours to help evade detection and elimination by the host immune system tumour 
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 [Keir 2008; Park 2010]. This results in 
reduced T-cell activation and fewer activated T cells in circulation. In the tumour 
microenvironment, PD-L1 expressed on tumour cells binds to PD-1 and CD80 on activated T cells 
reaching the tumour. This delivers an inhibitory signal to those T cells, preventing them from killing 
target cancer cells and protecting the tumour from immune elimination [Zou 2008]. 


 
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Programmed death 1 (PD-1) protein is a co-inhibitory receptor known to be expressed on activated 
T cells, which when bound to its ligand PD-L1, limits T cell antitumour activity in the tumour 
microenvironment [Fife 2008]. Blockade of PD-1 engagement with its ligand PD-L1 induces immune 
responses in vitro and has been shown to mediate preclinical activity [Fife 2009]. Clinically, blockade 
of the PD-1 inhibitory checkpoint pathway by inhibiting PD-L1/ PD-1 engagement, has been shown 
to induce tumour regression across many cancer types, including melanoma and renal cell, colon 
and lung cancers [Pardoll 2012; Brahmer 2012]. Single agent immunotherapy with anti-PD-1 or anti-
PDL-1 antibodies across many tumour types has been generally well tolerated, with common drug 
related adverse events mainly limited to grade 1 or 2 fatigue, diarrhea, rash, pruritus, nausea and 
decreased appetite. Immune-related adverse events are uncommon (< 2%), and include 
pneumonitis, vitiligo, colitis, hepatitis and hypophysitis and thyroiditis [Antonia 2014b]. 
 
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) also known as CD152 (cluster of 
differentiation 152) is another protein involved in T-cell activation. Binding of CTLA-4 to its target 
ligands (B7-1 and B7-2) provides a negative regulatory signal, which limits T-cell activation. Anti-
CTLA-4 inhibitors antagonize the binding of CTLA-4 to B7 ligands and enhance human T-cell 
activation as demonstrated by increased cytokine (interleukin [IL]-2 and interferon [IFN] gamma) 
production in vitro in whole blood or peripheral blood mononuclear cell (PBMC) culture. 
 
Durvalumab 
 
Durvalumab is a novel IgG1-kappa PD-L1 inhibitor with potent and specific binding to PD-L1 
at picomolar concentrations and has directed mutations in the Fc region, limiting off-target 
cytotoxicity in PD-L1-expressing immune cells [Khleif 2013; Stewart 2011]. Surrogate anti-PD-LI 
antibodies have been shown to increase T-cell activation in vitro by blocking PD-L1/PD-1 
engagement and inducing antitumour responses in tumour-bearing mice, with corresponding 
changes in peripheral immune markers. Durvalumab has also been shown to inhibit tumour 
growth in vivo xenograft models 
 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect 
of PD-L1 on primary human T cells, resulting in their restored proliferation and release of interferon 
gamma (IFN-γ). Additionally, durvalumab demonstrated a lack of antibody-dependent cell-
mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based 
functional assays. In vivo studies show that durvalumab inhibits tumour growth in a xenograft 
model via a T lymphocyte (T-cell) dependent mechanism. Moreover, an anti-mouse PD-L1 
antibody demonstrated improved survival in a syngeneic tumour model when given as 
monotherapy and resulted in complete tumour regression in > 50% of treated mice when given in 
combination with chemotherapy. 


 
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Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid 
tumours. Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa 
(IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 
[B7-H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 
(B7-1). Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an 
overall molecular weight of approximately 149 kDa. Durvalumab contains a triple mutation in the 
constant domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement 
protein C1q and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector 
function. Durvalumab has potent and specific binding to PD-L1 at picomolar concentrations and 
has directed mutations in the Fc region, limiting off-target cytotoxicity in PD-L1-expressing 
immune cells [Khleif 2013; Stewart 2011]. Surrogate anti-PD-LI antibodies have been shown to increase 
T-cell activation in vitro by blocking PD-L1/PD-1 engagement and inducing antitumour responses 
in tumour-bearing mice, with corresponding changes in peripheral immune markers. Durvalumab 
has also been shown to inhibit tumour growth in vivo xenograft models. 
 
Tremelimumab 
 
Tremelimumab is a human IgG2 monoclonal antibody directed against the T-cell receptor protein 
cytotoxic T-lymphocyte-associated protein 4 (CTLA4) [Tarhini 2013]. CTLA-4 is a co-inhibitory 
receptor expressed on activated T cells and regulates early stage T cell activation, reducing the 
amplitude. Tremelimumab binds to CTLA4 and blocks the binding of the antigen-presenting cell 
ligands B7-1 and B7-2 to CTLA4, resulting in inhibition of B7-CTLA4-mediated downregulation 
of T-cell activation. 
 
Tremelimumab is an IgG 2 kappa isotype mAb directed against the cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152) this is an 
immunomodulatory therapy (IMT) that is being developed by AstraZeneca for use in the treatment 
of cancer. 
 
CTLA-4 binding to B7 by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation 
and anti-tumour activity in animal models, including killing of established murine solid tumours 
and induction of protective anti-tumour immunity. Therefore, it is expected that treatment with an 
anti-CTLA-4 antibody, such as tremelimumab, will lead to increased activation of the human 
immune system, increasing anti-tumour activity in patients with solid tumours. 
 
An extensive program of non-clinical and clinical studies has been conducted for tremelimumab 
both as monotherapy and combination therapy with conventional anticancer agents to support 
various cancer indications using different dose schedules. As of the data cut-off date of 
12 November 2014 (for all studies except D4190C00006, which has a cut-off date of 
4 December 2014), 973 patients have received tremelimumab monotherapy (not including 497 
patients who have been treated in the blinded phase IIb study, D4880C00003) and 208 patients 
have received tremelimumab in combination with other agents. Tremelimumab exhibited a biphasic 
PK profile with a long terminal phase half-life of 22 days. Overall, a low incidence of ADAs (< 6%) 
was observed for treatment with tremelimumab. 
 


 
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Combination of Durvalumab and Tremelimumab 
 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity because the 
mechanisms of action of CTLA-4 and PD-1 are non-redundant [Pardoll 2014]; therefore, the use of 
durvalumab + tremelimumab combination therapy for the treatment of cancer is under concurrent 
investigation. In fact, combining immunotherapy agents has been shown to result in improved 
response rates (RRs) relative to monotherapy. For example, the concurrent administration of 
nivolumab and ipilimumab to patients with advanced melanoma induced higher objective response 
rates (ORRs) than those obtained with single-agent therapy. Importantly, responses appeared to be 
deep and durable [Wolchok 2014]. Similar results have been observed in an ongoing study of 
durvalumab + tremelimumab in NSCLC [Antonia 2014a]. 
Study D4190C00006 is a phase Ib dose-escalation study to establish safety, PK/PDx, and 
preliminary anti-tumour activity of durvalumab + tremelimumab combination therapy in patients 
with advanced NSCLC. The dosing schedule utilized is durvalumab every 2 weeks (q2w) or every 
4 weeks (q4w) up to Week 50 and 48 (12 months), combined with tremelimumab q4w up to Week 
24 for 7 doses then every 12 weeks for 2 additional doses for up to 12 months. The study is ongoing 
and continues to accrue. 
 
As of 20 February 2015, ADA data were available from 60 subjects for durvalumab and 53 subjects 
for tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive for 
anti-durvalumab antibodies post treatment. One of 53 subjects was ADA positive for 
anti-tremelimumab antibodies post treatment. There was no clear relationship between ADA and 
the dose of either durvalumab or tremelimumab, and no obvious association between ADA and 
safety or efficacy. 
 
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were 
narrowed to 15 and 20 mg/kg durvalumab q4w. PK simulations from the durvalumab monotherapy 
data indicated that a similar area under the plasma drug concentration-time curve at steady state 
(AUCss; 4 weeks) was expected following both 10 mg/kg q2w and 20 mg/kg q4w durvalumab. 
The observed durvalumab PK data from the D4190C00006 study were well in line with the 
predicted monotherapy PK data developed preclinically. This demonstrates similar exposure of 
durvalumab 20 mg/kg q4w and 10 mg/kg q2w, with no alterations in PK when durvalumab and 
tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together. While the median Cmax at 
steady state (Cmax,ss) is expected to be higher with 20 mg/kg q4w (approximately 1.5 fold) and 
median trough concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg 
q2w (approximately 1.25 fold), this is not expected to impact the overall safety and efficacy profile, 
based on existing preclinical and clinical data. 
 
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab relative 
to the activity observed in patients treated with durvalumab monotherapy. There was evidence of 
augmented PDx activity relative to durvalumab monotherapy with combination doses containing 
1 mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab plus 1 mg/kg 
tremelimumab combinations. 


 
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Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 
10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohorts treated at the q2w schedule, the number of patients reporting any AE, Grade 
3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A similar 
pattern was noted in the q4w regimens, suggesting that, as the dose of tremelimumab increased 
above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, the SAEs 
frequently attributed to immunotherapy, pneumonitis and colitis, were more commonly seen in 
cohorts using either 3 or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts. 
Together, these data suggest that a combination using a tremelimumab dose of 1 mg/kg appeared 
to minimize the rate of toxicity when combined with durvalumab. As a result, all combination doses 
utilizing either the 3 or 10 mg/kg doses of tremelimumab were eliminated in the final dose selection. 
 
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab 
did not show an increase in the rate of AEs. The data suggested that increasing doses of durvalumab 
may not impact the safety of the combination as much as the tremelimumab dose. Further, safety 
data between the 10 mg/kg and 20 mg/kg cohorts were similar, with no change in safety events 
with increasing dose of durvalumab. 
 
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥ 3 AEs, SAEs, and 
treatment discontinuations due to AEs, but still showed strong evidence of clinical activity. This 
cohort had a lower number of treatment-related Grade ≥ 3 AEs or treatment-related SAEs. No dose-
limiting toxicities were reported. 
 
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to 
change with increasing doses of tremelimumab. The 15 and 20 mg/kg durvalumab q4w cohorts 
demonstrated objective responses at all doses of tremelimumab, and increasing doses of 
tremelimumab did not provide deeper or more rapid responses. 
 
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort may 
demonstrate equivalent clinical activity to other dose combinations. A total of 5 of 11 patients in 
the 20 mg/kg durvalumab + 1 mg/kg tremelimumab cohort were evaluable for efficacy with at least 
8 weeks of follow-up. Of these, there were 2 patients (40%) with partial response (PR), 1 patient 
(20%) with stable disease (SD), and 1 patient (20%) with progressive disease (PD). (The fifth 
patient had only a single scan, which was conducted outside the window for these evaluations.) 
 
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort had 
the fewest AEs, Grade ≥ 3 AEs, SAEs, and treatment discontinuations due to AEs, but still showed 
some evidence of clinical activity. Altogether, the data suggested that a 20 mg/kg durvalumab + 
1 mg/kg tremelimumab dose combination should be selected for further development. 
 
In summary, combinations of durvalumab and tremelimumab appear tolerable at doses of 
durvalumab 20 mg q4w and tremelimumab 1 mg/kg q4w. Higher doses did not result in greater 
antitumour activity but were generally associated with higher rates of AEs. Related Grade 3/4 
events were reported in 4/18 (22%) patients, while the most frequently reported events were 
diarrhea, pruritus, rash, and elevated AST/ALTs (11% for each AE). Only one patient discontinued 
study therapy due to drug-related AEs [Antonia 2015]. 


 
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Rationale for combined chemotherapy and immune checkpoint inhibition 
 
There is a significant degree of pre-clinical and early clinical data that immunomodulatory therapies 
may have activity in pancreatic adenocarcinoma. T-cell induction through CD40 agonists has 
shown promising activity in pre-clinical and early clinical studies [Beatty 2011]. A vaccine strategy 
of the GVAX vaccine in combination with CRS 207 (attenuated strain of Listeria expressing 
mesothelin) showed promising activity in a phase II study and a larger randomized phase II is 
currently underway [Le 2015].Regarding the efficacy of checkpoint inhibitors, there is a paucity of 
data up to this point, with only data from 14 patients demonstrating objective responses to single 
agent anti-PDL-1 therapy [Brahmer 2012]. 
 
One potential explanation for resistance to single agent PD-L1 inhibition may be related to the 
tumour microenvironment associated with pancreatic cancers, and specifically the role of cancer 
associated fibroblasts (CAFs). It is hypothesized that activity of single agent checkpoint inhibitor 
therapy in pancreatic cancer may be limited due to lack of epithelial activated T-cells, related to 
immune-inhibitory signals from the surrounding microenvironment, including signaling from 
CAFs. KPC mouse model studies have demonstrated that CAFs in the tumour stroma that are 
fibroblast associated protein expressing (FAP-positive) secrete CXCL12 leading to an 
immunosuppressive environment [Feig 2013; Garrido-Laguna 2015]. 
 
A potential strategy to improve the sensitivity of checkpoint inhibitor therapy in pancreatic cancer 
is through the depletion of CAFs. KPC mouse model experiments whereby FAP-positive CAFs 
were depleted demonstrated greater sensitivity to PDL-1 inhibition. Depletion of CAFs has also 
been demonstrated to increase sensitivity to CTLA-4 inhibition [Ozdemir 2014]. 
 
Gemcitabine and nab-paclitaxel is known to deplete stromal cells and CAFs [Hidalgo 2013; Feig 2013; 
Alvarez 2013], thus the combination of gemcitabine and nab-paclitaxel may induced greater 
sensitivity to PDL-1 and CTLA-4 inhibition. Another potential mechanism of chemotherapy 
induced immune sensitization is through the release of neoantigens with tumour cell death [Ma 
2013]. We hypothesize that the combination of chemotherapy with both anti-tumour and anti-
stromal activity with immune checkpoint inhibition with result in a significant improvement in 
progression free survival and overall survival in metastatic pancreatic cancer compared to 
chemotherapy alone. 


 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
Durvalumab 
 
3.1.1 
Name and Chemical Information 
 
Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1κ) subclass 
that inhibits binding of programmed cell death ligand (PD-L1) (B7 homolog 1[B7-H1], cluster of 
differentiation [CD]274 to programed cell death 1 (PD-1; CD279) and CD80 (B7). 
 
See the current durvalumab Investigator Brochure for additional details and the most up to date 
information. 
 
3.1.2 
Chemical Structure 
 
Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an overall 
molecular weight of approximately 149 kDa. Durvalumab contains a triple mutation in the constant 
domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein 
C1q and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
 
3.1.3 
Mechanism of Action 
 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect 
of PD-L1 on primary human T cells, resulting in their restored proliferation and release of interferon 
gamma (IFN-γ). 
 
3.1.4 
Experimental Antitumour Activity 
 
• 
In a xenograft model durvalumab inhibited human tumour growth via a T-cell-dependent 
mechanism. 
• 
An anti-mouse PD-L1 antibody demonstrated improved survival in a syngeneic tumour model 
when given as monotherapy and resulted in complete tumour regression in > 50% of treated 
mice when given in combination with chemotherapy. 
• 
Combination therapy (dual targeting of PD-L1 and CTLA-4) resulted in tumour regression in 
a mouse model of colorectal cancer. 
• 
Dual targeting of PD-1 and PD-L1 in a syngeneic model of sarcoma in mice demonstrated 
statistically significant mean tumour growth delay relative to the control group. 
 
3.1.5 
Animal Toxicology 
 
In general, treatment of cynomolgus monkeys with durvalumab was not associated with any 
durvalumab-related adverse effects that were considered to be of relevance to humans. 
 
 


 
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Data from the pivotal 3-month GLP toxicity study with durvalumab in cynomolgus monkeys 
showed that subchronic dosing of durvalumab was not associated with any adverse effects. 
Therefore, the NOAEL of durvalumab in all the general toxicity studies was considered to be 100 
mg/kg, the highest dose tested in these studies. In addition to the in vivo toxicology data, no 
unexpected membrane binding of durvalumab to human or cynomolgus monkey tissues was 
observed in GLP tissue cross-reactivity studies using normal human and cynomolgus monkey 
tissues. 
 
3.1.6 
Clinical Trials 
 
As of the most recent Investigator’s Brochure over 5000 subjects have been enrolled and treated in 
ongoing durvalumab clinical studies No studies have been terminated prematurely due to toxicity. 
 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
appears consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumour types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include diarrhea/colitis, and intestinal perforation, pneumonitis/ILD, ALT/AST 
increases/hepatitis/hepatotoxicity, 
neuropathy/neuromuscular 
toxicity 
(e.g. 
Guillain-Barré 
syndrome, and myasthenia gravis), endocrinopathies (i.e. hypophysitis, hypopituitarism, adrenal 
insufficiency, diabetes insipidus, hyper- and hypothyroidism and type I diabetes mellitus), 
rash/dermatitis, nephritis/blood creatinine increases, pancreatitis (or labs suggestive of 
pancreatititis – increased serum lipase, increase serum amylast), myocarditis and 
myocitis/polymositis. Other inflammatory responses that are rare with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, hematological and rheumatological events. It is possible that events with 
an inflammatory or immune mediated mechanism could occur in nearly all organs. 
 
3.1.7 
Pharmaceutical Data - Durvalumab 
 
Supplied: 
Supplied as a vialed liquid solution containing 500 mg (nominal) durvalumab. The solution 
contains 50 mg/mL durvalumab, 26 mM histidine/histidine-HCI, 275 mM trehalose dihydrate, 
0.02% (w/v) polysorbate 80, at pH 6.0. 
 
Storage: 
Durvalumab must be stored at 2°C to 8°C. 
 
Please refer to the PA.7 Pharmacy Manual for additional details. 
 
3.2 
Tremelimumab 
 
3.2.1 
Name and Chemical Information 
 
Tremelimumab is a human monoclonal antibody of the immunoglobulin G2 (IgG2) subclass that 
inhibits binding of B7 ligands (B7.1 (CD80) or B7.2 (CD86)) to cytotoxic T lymphocyte- 
associated antigen 4 (CTLA-4; cluster of differentiation [CD]152). 
 
See the current tremelimumab Investigator Brochure for additional details and the most up to date 
information. 
 
 


 
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3.2.2 
Chemical Structure 
 
Tremelimumab has an overall molecular weight of approximately 149 kDa including 
oligosaccharides. 
 
3.2.3 
Mechanism of Action 
 
Tremelimumab binds with high affinity and specificity to human CTLA-4, a cell surface receptor 
expressed primarily on activated T cells. Binding of CTLA-4 to its target ligands (B7.1 and B7.2) 
on antigen-presenting cells, provides a negative regulatory signal, which limits T-cell activation. 
Tremelimumab blocks this interaction of B7 ligands with CTLA-4, thus leading to prolongation 
and enhancement of T-cell activation and expansion. This mechanism is supported by in vitro 
studies where tremelimumab antagonizes binding of CTLA-4 to B7 ligands and enhances human 
T-cell activation as demonstrated by increased cytokine (IL-2, IFN-γ) production. 
 
3.2.4 
Experimental Antitumour Activity 
 
• 
In a mouse model of fibrosarcoma, an anti-mouse CTLA-4 antibody demonstrated dose-
dependent antitumour activity and, at the maximum dose tested, resulted in complete tumour 
regression in 4 of 5 treated animals. Also these animals were resistant to tumour rechallenge, 
demonstrating a durable antitumour immunity. Finding was corroborated in other mouse 
models of cancer. 
• 
In a mouse model of colon cancer, the combination of anti-mouse PD-L1 and anti-mouse 
CTLA-4 resulted in greatly increased activity with tumour regression observed in all mice 
treated relative to control. 
 
3.2.5 
Clinical Trials 
 
To date, 34 clinical studies have been conducted in over 1500 patients in both monotherapy and 
combination therapy clinical trials. Full details are described in the current tremelimumab 
Investigator Brochure. 
 
To date, no tumour type or stage appears to be associated with unique AEs (except for vitiligo that 
appears to be confined to subjects with melanoma). Treatment-related AEs were reported at similar 
rates in the 10 and 15 mg/kg groups, and were mostly Grade 1 or 2 in severity. The most frequent 
(in > 5% of subjects) treatment-related AEs (all grades) in patients with tremelimumab 
monotherapy were diarrhea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, headache, 
pyrexia, abdominal pain, and colitis. Please refer to the most recent version of the Investigator 
Brochure for incidence. 
 
Across clinical trials, a pattern of efficacy has emerged that is similar to the anti-CTLA-4 antibody, 
ipilimumab, which appears to be consistent across tumour types. Response rates to anti-CTLA-4 
antibodies are generally low, approximately 10%. However, in subjects who respond, the responses 
are generally durable, lasting several months even in subjects with aggressive tumours such as 
refractory metastatic melanoma. 
 
 


 
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3.2.6 
Pharmaceutical Data - Tremelimumab 
 
Supplied: 
Supplied as a vialed solution containing 400 mg (nominal) tremelimumab. The solution contains 
20 mg/mL tremelimumab, 20 mM histidine/histidine-HCI, 222 mM trehalose dihydrate, 0.02% 
(w/v) polysorbate 80, 0.27 mM disodium edetate dehydrate (EDTA), pH 5.5. 
 
Storage: 
Tremelimumab must be stored at 2°C to 8°C and must not be frozen. The product should be 
protected from light when not in use. 
 
Route of Administration: 
Intravenous. 
 
Please refer to the PA.7 Pharmacy Manual for additional details. 
 
3.3  
Fixed Dosing in Durvalumab and Tremelimumab 
 
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was selected 
to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 patients were 
simulated using body WT distribution of 40–120 kg. Simulation results demonstrate that body WT-
based and fixed dosing regimens yield similar median steady state PK concentrations with slightly 
less overall between-subject variability with fixed dosing regimen. 
 
Similarly, a population PK model was developed for tremelimumab using data from phase I 
through phase III (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) [Wang 
2014]. Population PK model indicated minor impact of body WT on PK of tremelimumab 
(coefficient of ≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on 
median body WT of ~75 kg) regimens were compared using predicted PK concentrations (5th, 
median and 95th percentiles) using population PK model in a simulated population of 1000 patients 
with body weight distribution of 40 to 120 kg. Similar to durvalumab, simulations indicated that 
both body WT-based and fixed dosing regimens of tremelimumab yield similar median steady state 
PK concentrations with slightly less between-subject variability with fixed dosing regimen. 
 
Similar findings have been reported by others [Ng 2006, Wang 2009, Zhang 2012, Narwal 2013]. 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. In addition, they 
investigated 18 therapeutic proteins and peptides and showed that fixed dosing performed better 
for 12 of 18 in terms of reducing the between-subject variability in pharmacokinetic / 
pharmacodynamics parameters [Zhang 2012]. 
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W and 75 mg 
tremelimumab (equivalent to 1 mg/kg) is planned. 
 
 


 
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Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with > 30 kg 
body weight due to endotoxin exposure. Patients with a body weight less than or equal to 30 kg 
should be dosed using a weight-based dosing schedule. This is not expected to be applicable to this 
trial in an adult patient population. 
 
3.4 
Gemcitabine 
 
3.4.1 
Name and Chemical Information 
 
Gemcitabine (difluorodeoyxcytidine) is a pyrimidine antimetabolite, which is an analogue of 
deoxycytidine. It was initially synthesized as a potential antiviral drug but selected for anticancer 
development because of its activity in in vivo and in vitro tumours. 
 
Chemical Name: 
2’-Deoxy-2, 2’-Difluorocytidine monohydrochloride 
Emperical Formula: 
C9H12CIF2N3O4 
Molecular weight: 
299.66 
Appearance: 
Crystalline powder 
Colour: 
White or off-white to translucent 
 
3.4.2 
Mechanism of Action 
 
Gemcitabine (2’-2’-difluorodeoxycytidine; dFdC) is an analogue of deoxycytidine which, like ara-
C (cytarabine), must be phosphorylated by cytidine deaminase into di- and tri-phosphate forms 
(dFdCDP and dFdCTP) to exert its cytotoxic effects of inhibition of DNA replication and repair. 
Gemcitabine was selected for clinical development because of the observation that, unlike ara-C, 
it exhibited marked antitumour effects in numerous murine and human xenograft solid tumour 
systems, including lung, breast, colon and ovarian cancer models. This differing spectrum of 
activity seems to be related to gemcitabine’s prolonged intracellular retention; a property related to 
several mechanisms. These include the drug’s ability to potentiate its own conversion into the 
phosphorylated form by decreasing intracellular deoxycytidine triphosphate (dCTP) levels with 
resulting enhanced kinase activity. The gemcitabine-induced fall in dCTP also decreases the 
activity of deoxycytidine monophosphate deaminase, which in turn helps maintain levels of 
phosphorylated drug. Thus the effect of the presence of activated gemcitabine (i.e. the 
phosphorylated form) is to decrease dCTP with resulting enhanced activity of those kinases 
responsible for gemcitabine activation and decreased activity of those deaminases responsible for 
elimination of the activated form of drug. These mechanisms are termed “self-potentiating”. 
 
3.4.3 
Experimental Antitumour Activity and Toxicity information 
 
Gemcitabine has been extensively evaluated in phase I, II, III studies and has a well characterized 
toxicity and efficacy profile. Gemcitabine has activity in a number of tumour types including 
pancreas, breast, bladder, lung, colon, head and neck and biliary tract cancer. It received FDA 
approval based on its activity and clinical benefit in pancreatic cancer [Burris 1997]. Preclinical 
studies show synergism with a number of drugs including 5-FU. 
 
 


 
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Pancreatic Cancer: 
 
Data from two clinical trials evaluated the use of gemcitabine in patients with locally advanced or 
metastatic pancreatic cancer. The first trial compared gemcitabine to 5-Fluorouracil (5-FU) in 
patients who had received no prior chemotherapy. A second trial studied the use of gemcitabine in 
pancreatic cancer patients previously treated with 5-FU or a 5-FU-containing regimen. In both 
studies, the first cycle of Gemcitabine was administered intravenously at a dose of 1000 mg/m2 
over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitated holding a dose) 
followed by a week of rest from treatment with gemcitabine. Subsequent cycles consisted of 
injections once weekly for 3 consecutive weeks out of every 4 weeks. 
 
It is generally a well-tolerated drug even when given to frail and elderly patients. The most common 
toxicity is short-lived myelosuppression. Weekly single agent doses between 800-1250 mg/m2 have 
been associated with the following grade 3, 4 hematologic toxicities (WHO classification): 
neutropenia 25%, anemia 8-11% and thrombocytopenia 5-7%. Discontinuation occurred in < 1% 
of patients (n=979). Non-hematologic toxicities are well tolerated and occur with the following 
frequencies: nausea and vomiting (mild to moderate with 17% requiring antiemetic therapy), 
diarrhea and stomatitis (mild, 13%), proteinuria and hematuria (mild, 33%). Hemolytic uremic 
syndrome has been reported in < 1%. A fine maculopapular rash has been reported in about 25% 
of patients; it is usually mild and responds to local therapy. Mild and transient elevations of 
transaminases (usually WHO grades 1 and 2) have been documented in about two thirds of patients 
with no evidence of increasing toxicity with longer treatment or cumulative dose. Fever is common 
(33% all grades); infection is not- 9% (grade 3 or 4: 1%). Flu-like symptoms regardless of cause 
occurred in about 19% of patients but discontinuation due to this cause is rare (< 1%). Serious 
cardiac toxicities are rarely reported and have tended to occur in patients with pre-existing 
cardiovascular disease. Pulmonary effects, sometimes severe (such as pulmonary edema, interstitial 
pneumonitis or adult respiratory distress syndrome (ARDS)), have been rarely reported and tend to 
occur in patients with underlying lung disease. 
 
In the setting of organ dysfunction (hepatic and renal), there is more toxicity, in particular transient 
hepatic dysfunction. A phase I trial of gemcitabine in patients with organ dysfunction demonstrated 
significant but transient hyperbilirubinemia in patients with baseline elevations in bilirubin levels 
[Venook 2000]. Baseline elevated transaminases did not appear to be predictive of toxicity. Patients 
with renal dysfunction had increased but unpredictable toxicity. Dose reductions were 
recommended in the setting of elevated bilirubin and caution with renal insufficiency. In the 
phase II trial which evaluated patients with stable hepatic function, the combination did not result 
in significant toxicity. 
 
3.4.4 
Pharmaceutical Data 
 
Supplied: 
Commercial supply of gemcitabine will be used in this study. See label/package insert for additional 
information. 
 
Route of Administration: 
Gemcitabine is administered intravenously. 
 
 


 
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3.5 
Nab-Paclitaxel 
 
3.5.1 
Name and Chemical Information 
 
Proper name: 
Paclitaxel 
Chemical name: 
5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 
4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-
phenylisoserine 
Molecular formula: 
C47H51NO14 
Molecular mass: 
853.91 
Physicochemical properties: 
Paclitaxel is a white to off-white crystalline powder. It is highly 
lipophilic, insoluble in water, and melts at approximately 216 to 
217°C. 
 
3.5.2 
Mechanism of Action 
 
Paclitaxel, the active pharmaceutical ingredient in nab-paclitaxel for Injectable Suspension 
(paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab®] paclitaxel), is 
an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and 
stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of 
the normal dynamic reorganization of the microtubule network that is essential for vital interphase 
and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules 
throughout the cell cycle and multiple asters of microtubules during mitosis. 
 
3.5.3 
Experimental Antitumour Activity 
 
Nab-paclitaxel has is indicated for the treatment of metastatic breast cancer and the first-line 
treatment of metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 
 
Metastatic Pancreatic Cancer 
 
A multicentre, multinational, randomized, open-label study was conducted in 861 patients to 
compare nab-paclitaxel /gemcitabine versus gemcitabine monotherapy as first-line treatment in 
patients with metastatic adenocarcinoma of the pancreas. Patients who received adjuvant 
chemotherapy were not eligible for enrollment. nab-paclitaxel E was administered to patients 
(N=431) as an intravenous infusion over 30-40 minutes at a dose of 125 mg/m2 followed by 
gemcitabine as an intravenous infusion over 30-40 minutes at a dose of 1000 mg/m2 given on Days 
1, 8 and 15 of each 28-day cycle. In the comparator treatment group, gemcitabine monotherapy 
was administered to patients (N=430) as 1000 mg/m2 given weekly for 7 weeks followed by a 
1 week rest period in Cycle 1 and in Cycle 2 and onwards was administered on Days 1, 8 and 15 
of a 28-day cycle (consistent with the label recommended dose and regimen). Treatment was 
administered until disease progression or development of an unacceptable toxicity. 
 
Evidence from the pivotal clinical study in metastatic pancreatic cancer suggest that patients 75 
years or older who received nab-paclitaxel in combination with gemcitabine had a higher risk of 
serious adverse reactions and adverse reactions that led to treatment discontinuation. No survival 
benefit for the combination treatment of nab-paclitaxel and gemcitabine has been demonstrated for 
patients 75 years and older, however, clinical studies did not include sufficient number of patients 
with metastatic pancreatic cancer in this age group to determine whether they respond differently 
from younger patients. 
 
 


 
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3.5.4 
Adverse Reaction Overview in Metastatic Pancreatic Cancer 
 
In the phase III study of metastatic pancreatic cancer, the most common treatment emergent adverse 
events (≥ 20%) in patients receiving nab-paclitaxel in combination with gemcitabine were: fatigue 
(59%), nausea (54%), peripheral neuropathy SMQ (54%), alopecia (50%), peripheral edema (46%), 
diarrhea (44%), anemia (42%), neutropenia (42%), pyrexia (41%), vomiting (36%), decreased 
appetite (36%), constipation (30%), thrombocytopenia (30%), rash (28%), abdominal pain (23%), 
and dehydration (21%). Approximately 50% of patients receiving nab-paclitaxel and gemcitabine 
experienced serious adverse events, including pyrexia, vomiting dehydration and pneumonia. 
Adverse reactions resulting in death within 30 days of the last dose of study drug were reported for 
4% of patients in the nab-paclitaxel and gemcitabine group and for 4% of patients in the 
gemcitabine group. 
 
3.5.5 
Pharmaceutical Data 
 
Supplied: 
Commercial supply of nab-paclitaxel will be used in this study. See label/package insert for 
additional information. 
 
Route of Administration: 
Nab-paclitaxel is administered intravenously. 


 
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4.0 
STUDY POPULATION 
 
Patients with metastatic ductal adenocarcinoma of the pancreas who are suitable candidates for 
first-line standard chemotherapy. 
 
Patients may have received prior adjuvant chemotherapy if last dose was given more than 6 months 
prior to recurrence. Patients may not have received adjuvant chemoradiotherapy. 
 
Prior treatment for borderline resectable or locally advanced disease is not permitted. 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
4.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed prior to randomization / registration. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfil all of the following criteria to be eligible for admission to the study: 
 
4.1.1 
Patients must have histologically or cytologically confirmed pancreatic ductal adenocarcinoma 
which is metastatic. 
 
4.1.2 
Must have presence of measurable or evaluable disease as defined by Response Evaluation Criteria 
in Solid Tumours (RECIST 1.1). 
 
4.1.3 
Patients must be considered suitable candidates for, and able to receive, first line chemotherapy for 
metastatic disease with gemcitabine and nab-paclitaxel. 
 
4.1.4 
Patient must consent to provision of, and investigator(s) must confirm access to and agree to submit 
within 4 weeks of randomization to the CCTG Central Tumour Bank, a representative formalin 
fixed paraffin block of tumour tissue of adequate amount and quality in order that the specific 
correlative marker assays proscribed in the protocol may be conducted. Cytospin and brushings are 
not considered to be sufficient. Sites undertaking genomic profiling may contact CCTG to discuss 
submission of tumour tissue sufficient for patient eligibility.  
 
Where adequate amount and quality of tissue exists but local centre regulations prohibit submission 
of blocks of tumour tissue, the approval of the CCTG must be sought prior to randomization of the 
first patient to allow cores (two 2 mm cores of tumour from the block) and a predetermined number 
of slides of representative tumour tissue to be substituted. Where tumour tissue is available, failure 
to submit any tissue samples will result in the patient being considered ineligible. Where no 
previously resected or biopsied tumour tissue exists or is found to be of inadequate amount or 
quality, additional biopsy of the primary or metastatic tumour will be required for the patient to be 
considered eligible for the study. Please refer to the PA.7 correlative tissue manual for details 
concerning adequacy of amount and quality of tumour tissue. 


 
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4.1.5 
Patient must consent to provision of samples of blood, serum and plasma in order that the specific 
correlative marker assays proscribed in Section 12.0 may be conducted. 
 
4.1.6 
Patients must be > 18 years of age. 
 
4.1.7 
Patients must have an ECOG performance status of 0 or 1 with a life expectancy of at least 
12 weeks. 
 
4.1.8 
No prior treatment for metastatic disease is permitted. Patients may have received prior adjuvant 
chemotherapy if the last dose was given more than 6 months prior to recurrence. Patients may not 
have received adjuvant chemoradiotherapy or adjuvant radiation therapy. Patient may not have 
received nab-paclitaxel as adjuvant therapy. Prior systemic treatment for borderline resectable or 
locally advanced disease is not permitted. Patients receiving a single dose of radiation (up to 8 Gy 
/ 800 RAD) with palliative intent for pain control are eligible provided a minimum of 14 days have 
elapsed between the radiation and the date of randomization. 
 
4.1.9 
Adequate normal organ and marrow function as defined below (must be done within 14 days prior 
to registration). 
 
Hematology 
Absolute neutrophils 
> 1.5 x 109/L 
Platelets 
> 100 x 109/L 
Hemoglobin 
> 90 g/L 
Biochemistry 
Bilirubin 
< 1.5 x ULN (upper limit of normal)* 
AST and ALT ** 
< 2.5 x ULN 
Serum creatinine 
or: 
Creatinine clearance*** 
< 1.25 x ULN 
 
> 40 mL/min 
* 
If confirmed Gilbert’s, eligible providing ≤ 3 x ULN. 
** < 3 x UNL in presence of liver metastases 
*** Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft and 
Gault equation below: 
Females: GFR  = 1.04 x (140-age) x weight in kg / serum creatinine in μmol/L 
Males: GFR 
= 1.23 x (140-age) x weight in kg / serum creatinine in μmol/L 
 
4.1.10 Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as necessary to 
document all sites of disease done within 28 days prior to randomization. 
 
4.1.11 Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in 
either English or French. The baseline assessment must be completed within required timelines, 
prior to registration/randomization. Inability (lack of comprehension in English or French, or other 
equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires 
will not make the patient ineligible for the study. However, ability but unwillingness to complete 
the questionnaires will make the patient ineligible. 
 
4.1.12 Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrolment in the trial to document 
their willingness to participate. A similar process must be followed for sites outside of Canada as 
per their respective cooperative group’s procedures. 
 
 


 
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4.1.13 Patients must be accessible for treatment and follow-up. Patients registered on this trial must be 
treated and followed at the participating centre. Patients must agree to return to the participating 
centre for management of any adverse events which may occur through the course of the trial. This 
implies there must be reasonable geographical limits placed on patients being considered for this 
trial. Sites are encouraged to contact CCTG (or their respective Cooperative Group for sites outside 
Canada) for any questions regarding the interpretation of this criterion. Investigators must assure 
themselves the patients registered on this trial will be available for complete documentation of the 
treatment, adverse events, and follow-up. 
 
4.1.14 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization. 
 
4.1.15 Women/men of childbearing potential must have agreed to use a highly effective contraceptive 
method. A woman is considered to be of "childbearing potential" if she has had menses at any time 
in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or 
with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously 
celibate patient chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive 
measures. 
 
Female patients of childbearing potential who are sexually active with a non sterilized male partner 
must use at least one highly effective method of contraception while on study and for 6 months 
after the last dose of durvalumab and tremelimumab or for 3 months after the last dose of 
durvalumab alone and consult product monograph for standard chemotherapy. Male partners of a 
female subject and non-sterilized male patients who are sexually active with a female partner of 
childbearing potential must use male condom plus spermicide while on study and for 6 months 
after the last dose of durvalumab and tremelimumab or for 3 months after the last dose of 
durvalumab alone and consult product monograph for standard chemotherapy. Female partners of 
a male subject must use a highly effective method of contraception throughout this period. 
Cessation of birth control after this point should be discussed with a responsible physician. See 
Section 9.3.1 for additional details. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Section 5.0); this may include an ultrasound to rule-out pregnancy if a 
false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and 
partner is vasectomized, it may be associated with tumour production of hCG, as seen with some 
cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
Male patients should also refrain from donating sperm during the study and for 6 months after the 
last dose of durvalumab and tremelimumab or for 3 months after the last dose of durvalumab alone. 
 
 


 
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4.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
4.2.1 
Patients with a history of other malignancies, except: adequately treated non-melanoma skin 
cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with 
no evidence of disease for > 5 years. Patients with a history of other malignancies detected at an 
early stage and whom the investigator believes have been curatively treated and are at a low risk of 
recurrence MAY be eligible. Contact CCTG to discuss eligibility prior to enrolling. 
 
4.2.2 
Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, 
including tremelimumab. 
 
4.2.3 
History of primary immunodeficiency, history of organ transplant that requires therapeutic 
immunosuppression or prior history of severe (grade 3 or 4) immune mediated toxicity from other 
immune therapy. 
 
4.2.4 
Current or prior use of immunosuppressive medication within 28 days before the first planned dose 
of study therapy, 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. 
 
4.2.5 
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel 
disease (e.g. colitis or Crohn’s disease), diverticulitis with the exception of diverticulosis, celiac 
disease or other serious gastrointestinal chronic conditions associated with diarrhea), systemic 
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with 
polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the 
start of treatment. The following are exceptions to this criterion: 
• 
Patients with alopecia. 
• 
Patients with Grave’s disease, vitiligo or psoriasis not requiring systemic treatment (within 
the last 2 years). 
• 
Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone 
replacement. 
 
NOTE: Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within 
the past 2 years) are not excluded. 
 
4.2.6 
Patients with active or uncontrolled intercurrent illness including, but not limited to: 
• 
cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia); 
• 
active peptic ulcer disease or gastritis; 
• 
active bleeding diatheses; 
• 
psychiatric illness/social situations that would limit compliance with study requirements or 
compromise the ability of the subject to give written informed consent; 
• 
known history of previous clinical diagnosis of tuberculosis; 
 
 


 
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• 
known human immunodeficiency virus infection (positive HIV 1/2 antibodies); 
• 
known active hepatitis B infection (positive HBV surface antigen (HBsAg)). Patients with a 
past or resolved HBV infection (defined as presence of hepatitis B core antibody (anti-HBc) 
and absence of HBsAg) are eligible; 
• 
known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA. 
 
4.2.7 
History of leptomeningeal carcinomatosis. 
 
4.2.8 
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not 
limited to surgery, radiation and/or corticosteroids. 
 
4.2.9 
Receipt of live attenuated vaccination (examples include, but are not limited to, vaccines for 
measles, mumps, and rubella, live attenuated influenza vaccine (nasal), chicken pox vaccine, oral 
polio vaccine, rotavirus vaccine, yellow fever vaccine, BCG vaccine, typhoid vaccine and typhus 
vaccine) within 30 days prior to randomization. 
 
4.2.10 Pregnant or lactating women. 
 
4.2.11 Any active disease condition which would render the protocol treatment dangerous or impair the 
ability of the patient to receive protocol therapy. 
 
4.2.12 Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the 
protocol. 
 
4.2.13 History of hypersensitivity to gemcitabine, nab-paclitaxel, durvalumab or tremelimumab or any 
excipient. 


 
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5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined below with 
documentation submitted according to the schedule in Appendix IV. 
 
Required Investigations 
Pre-study 
(≤14 days  
prior to 
randomization) 
During Protocol Treatment 
After Protocol 
Treatment1 
Day 1 each cycle, 
and as clinically 
indicated 
Day 8 each cycle, 
and as clinically 
indicated 
Day 15 each 
cycle 
4 weeks after 
end of last cycle 
date 
3 month 
follow-up 
History and Physical Exam2 
 
 
 
 
 
 
Including: height (baseline only), 
weight, BSA, ECOG performance 
status 
X 
X 
 
 
X 
X 
until 
objective 
progression 
Vital Signs (blood pressure, heart 
rate, temperature) 
X 
X3 
 
 
 
 
Concomitant Medications 
X 
X 
 
 
X 
 
Clinical tumour measurements (if 
applicable)4 
X 
Every 8 weeks from start of treatment  until  objective progression. 
Hematology2 
 
 
 
 
 
 
CBC, differential (including 
lymphocytes), platelets, 
X 
X 
X  
X 
X 
X5 
Coagulation2 
 
 
 
 
 
 
PTT, PT/INR 
X 
X 
X 
cycle 1 only 
and as clinically 
indicated 
as clinically 
indicated 
X 
X5 
Biochemistry2 
 
 
 
 
 
 
serum creatinine, chloride, sodium, 
potassium, calcium, magnesium, 
bilirubin, ALP, AST, and/or ALT17, 
LDH, Albumin, TSH6, Amylase, 
Lipase17 
X 
X7 
X8 
cycle 1 only 
and as clinically 
indicated 
as clinically 
indicated 
X 
X5 
Creatinine Clearance (calculated) 
X 
as clinically indicated 
 
 
Glucose 
X 
as clinically indicated 
 
 
Urea or BUN 
X 
as clinically indicated 
 
 
Radiology9 
 
 
 
 
 
 
Chest/abdomen/pelvis CT scan  
X 
≤ 28 days 
Every 8 weeks from start of treatment 4 until objective progression 
Other scans as necessary to 
document all measurable and non-
measurable disease 
X 
≤ 28 days 
Other Investigations 
 
 
 
 
 
 
Pregnancy Test10 
X 
 
 
 
 
 
Dipstick Urinalysis (including protein, 
specific gravity, glucose and blood) 
X 
as clinically indicated 
 
ECG 
X 
 
 
table continues on next page ... 
 
 


 
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Required Investigations 
Pre-study 
(≤14 days  
prior to 
randomization) 
During Protocol Treatment 
After Protocol Treatment1 
Day 1 each cycle, 
and as clinically 
indicated 
Day 8 each cycle, 
and as clinically 
indicated 
Day 15 each 
cycle 
4 weeks after 
end of last cycle 
date 
3 month 
follow-up 
Correlative Studies 
 
 
 
 
 
 
Archival Tissue Sample11 
Availability of 
sufficient tissue must 
be confirmed prior to 
randomization 
 
 
 
 
 
Tumour Biopsy (optional at 
participating sites for consenting 
patients only ) 
 
At 8 weeks on 
treatment 
 
 
 
 
Whole blood, plasma and serum 
After randomization 
but before first dose 
of study treatment 
At 8 weeks and at the time of progression12, if not already done 
See Section 12.0 and PA.7 Laboratory Manual for details. 
Adverse Events 
 
 
 
 
 
 
Adverse Event Assessment13 
≤ 14 days 
(To document 
residual adverse 
events form previous 
therapy and baseline 
symptoms) 
X7 
To be evaluated continuously for adverse 
events 
X 
X14 
Quality of Life 
 
 
 
 
 
 
EORTC QLQ C3015 
≤ 14 days 
At 4, 8, 12, 16 and 24 weeks after 
randomization, then every 12 weeks thereafter 
X 
X16 
 
footnotes on next page ... 
 
 


 
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1. 
All patients will be seen at 4 weeks after the end of the last cycle date. Thereafter, continued follow-up is not required for patients who go 
off protocol treatment with unequivocal progressive disease, except to document ongoing toxicities (until resolved to < grade 2) and late 
toxicities (including second malignancies) and for survival status. For patients who go off protocol treatment with CR, PR, or SD ongoing, 
follow-up will be required every 8 weeks until relapse (see Appendix I for investigations to be performed). Death Report will be required 
for all patients. Due within 2 weeks of knowledge of death (see Appendix IV - Documentation for Study). 
2. 
Timing of Assessments: Pre-treatment blood draws and physical exams may be done one working day prior to treatment if and when 
treatment is to begin on a Monday, may be done on the previous Friday (maximum 72 hours prior to treatment). In order to ensure that 
nadir counts are not missed, every effort should be made to do interim blood draws within 24 hours of the day specified in the protocol. If 
a patient shows an AST or ALT ≥ 3 x ULN together with total bilirubin ≥ 2 x ULN, refer to Appendix III for further instructions on cases 
of increases in liver biochemistry and evaluation of Hy’s Law. 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. Note: Labs do not need to be 
repeated D1C1. In order to ensure that nadir counts are not missed, every effort should be made to do interim blood draws within 24 hours 
prior to the day specified in the protocol. 
3. 
Patients will be monitored before, during infusion and after the infusion of tremelimumab and durvalumab with assessment of vital signs 
to be collected ≤ 30 minutes prior to start of infusion then every 30 ±5 minutes during infusion and observation periods. A 1-hour 
observation period is recommended after the tremelimumab, during which time durvalumab may be administered (see 7.2.4). A second 1-
hour observation period is recommended after the first infusion of durvalumab. If no clinically significant infusion reactions are observed 
during or after the first cycle of tremelimumab+durvalumab therapy, subsequent infusion observation periods can be at the investigator’s 
discretion but are recommended to be of 30 minutes (i.e. 30 minutes after tremelimumab infusion, during the durvalumab infusion and for 
30 minutes after the durvalumab infusion. For patients who receive only durvalumab, the recommended observation period is 30 minutes 
after the infusion. The standard chemotherapy (nab-paclitaxel followed by gemcitabine) may be administered during the observation 
period according to local practice. 
4. 
Lesion status assessment must be consistently performed every eight weeks counting from the first day of protocol treatment (i.e. day 1, 
cycle 1). Sites should adhere to this 8 week calendar based schedule regardless of any delays in treatment cycles. If a clinical lesion status 
assessment is done off schedule (e.g. early at 4 weeks), future protocol-required clinical lesion status assessments should still be performed 
based on the original schedule, i.e. every eight weeks counting from the first day of protocol treatment (not 6 weeks from the date of the 
off schedule assessment). For patients on Arm 2  (durvalumab + tremelimumab containing arm) who remains on protocol therapy after the 
RECIST 1.1 criteria for progression has been met must have imaging to for disease assessment done 4-8 weeks after PD by RECIST 1.1. 
Imaging is desirable 4- 8 weeks after progression is first documented by RECIST 1.1 for patients who receive further treatment.  No 
additional scans are required if patients commence second line treatment. 
5. 
Hematology, Coagulation and Biochemistry investigations to be done after objective progression ONLY if there are ongoing hematologic 
AEs that are related to protocol treatment. 
6. 
If abnormal, T3 and T4 must be measured. 
7. 
See Section 7 and Appendix III for additional monitoring of patients with toxicity. 
8. 
Amylase and lipase are required on Day 1 of each cycle only. 
9. 
To ensure comparability, baseline scans and subsequent scans to assess response must be performed using identical technique (i.e. scans 
performed immediately following bolus contrast administration using a standard volume of contrast, the identical contrast agent, and 
preferably the same scanner). 
10. For women of childbearing potential only. May be urine or serum. Pregnancy test (in women of childbearing potential), as part of Pre-
Study Evaluation, may include an ultrasound to rule-out pregnancy. 
11. Archival tissue, blood, plasma and serum samples mandatory. The tissue sample should be submitted within 4 weeks of 
registration/randomization. See Section 12.0 for details. 
12. Whole blood, plasma and serum should be obtained as close to the time of objective progression as possible and should be done within 28 
days (e.g. at the next clinic visit). Blood for correlatives done within 28 days PRIOR to date of progression does not need to be repeated. If 
patient has documented PD prior to 8 week assessment, addition bloodwork at 8 weeks is not required. See Correlative manual 
13. Adverse Events to be evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0) (see Appendix V). 
14. Only follow adverse events felt to be related to study therapy until resolved to ≤ grade 2. 
15. To be completed by patient in clinic 
16. QoL to be completed until PD, or the initiation of another anti-cancer treatment, or deterioration to ECOG PS 4 or hospitalization for end 
of life care; whichever comes first.  
17 It is preferable that both i) amylase and lipase and ii) AST and ALT parameters are assessed. For sites where only 1 of these parameters is 
routinely measured then either i) lipase or amylase or ii) AST or ALT is acceptable. 
 
5.1 
Follow-up for Ineligible Patients 
 
The follow-up requirements for ineligible patients who have received no protocol therapy include 
submission of the Baseline Report plus an annual short follow up form. Data submission for 
ineligible participants who have received at least one dose of protocol therapy (experimental or 
standard treatment, irrespective of allocation) should be followed according to the protocol to allow 
for treatment and adverse event assessment. 
 
NOTE: The dates of objective progression and death must be reported for ineligible patients. 


 
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6.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
6.1 
Entry Procedures 
 
All registration/randomizations will be done through the CCTG web-based, password-protected 
Electronic Data Capture (EDC) system. Complete details regarding obtaining a password, 
accessing the system and registering/randomizing patients will be provided at the time of study 
activation and will also be included in the “EDC Data Management Guidebook”, posted on the 
PA.7 trial specific web-site. If sites experience difficulties accessing the system and/or 
registering/randomizing patients please contact the help desk (link in EDC) or the PA.7 Study 
Coordinator. 
 
All eligible patients enrolled on the study by each participating centre will be assigned a serial 
number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required: 
• 
trial code (CCTG PA.7) 
• 
patient's initials (may be coded) 
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
tissue banking/optional consent version date 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
• 
BSA, height and weight 
• 
stratification factors 
 
6.2 
BSA Calculation 
 
In calculating surface areas, actual heights and weights should be used, that is, there will be no 
downward adjustment to “ideal” weight. This principle applies to individuals whose calculated 
surface area is 2.2 m2 or less. In those rare cases where a patient’s surface area is greater than 2.2, 
the actual surface area or 2.2 may be used CCTG BSA calculations are based on the Mosteller 
formula. Note: Where local standard of care is to utilize 2.0 m2 as maximum, this is also permitted. 
 
6.3 
Stratification 
 
Subjects will be stratified by: 
• 
ECOG performance status (0 vs 1) 
• 
prior adjuvant therapy (yes vs no) 
 
6.4 
Registration / Randomization 
 
Registration / Randomization will be provided electronically. 


 
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Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the patient withdraws from the trial and requests that data 
collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the treating physician to satisfy himself or herself that the patient is indeed eligible 
before requesting registration/randomization. 
 
All randomized patients are to be followed until death or until sites are informed by CCTG that 
further follow-up is no longer required. The follow-up requirements for ineligible patients are 
outlined in Section 5.1. 
 


 
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7.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for the treatment of patients rests with each individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization. 
 
One cycle will be defined as 28 days.  
 
All patients will receive standard chemotherapy with gemcitabine and nab-paclitaxel and the 
chemotherapy treatment plan is the same regardless of the arm of the trial they are allocated to. 
 
7.1 
Treatment Plan Overview 
 
7.1.1 
Safety Run-In 
 
Prior to the randomized component of this study, ten patients will be enrolled into Arm 2 at the 
doses outlined in the table below. Once the tenth patient has been registered the 10 patients will be 
observed for safety concerns until the end of the first cycle. If no safety concerns (i.e. unexpected 
severe toxicity) are identified the randomized component of the trial will be initiated. 
 
When durvalumab is given with tremelimumab, tremelimumab will be administered first. 
Durvalumab infusion will start immediately after the tremelimumab infusion (during the post-
tremelimumab observation period) and standard chemotherapy will start after the end of the 
durvalumab infusion. 
 
Safety Run-In 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
Arm 2 
Gemcitabine 
1000 mg/m2 
IV 
until 
unequivocal 
progression or 
unacceptable 
toxicity 
D1, D8, D15 
Q28 days  
Nab-Paclitaxel 
125 mg/m2 
IV 
Durvalumab  
1500 mg 
IV 
D1 only 
Q28 days 
Tremelimumab 
75 mg  
IV  
D1 cycles 1, 2, 3 
and 4 only 
 
See Sections 7.2.2 for patient monitoring and dose adjustments. 
 
7.1.2 
Phase II –Randomized to Standard Chemotherapy +/- Durvalumab AND Tremelimumab 
 
Following the analysis of safety run-in component of this study, patients will be randomized to 
receive either standard chemotherapy (ARM 1) or standard chemotherapy plus durvalumab and 
tremelimumab (ARM 2) at the doses outlined in the table below. Randomization will be 2:1 in 
favour of the investigational arm (ARM 2). 
 
 


 
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Arm 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
1 
Gemcitabine 
1000 mg/m2 
IV 
until 
unequivocal 
progression or 
unacceptable 
toxicity 
D1, D8, D15 
Q28 days  
Nab-Paclitaxel 
125 mg/m2 
IV 
2 
Gemcitabine 
1000 mg/m2 
IV 
until 
unequivocal 
progression or 
unacceptable 
toxicity 
D1, D8, D15 
Q28 days  
Nab-Paclitaxel 
125 mg/m2 
IV 
Durvalumab*  
1500 mg 
IV 
D1 only 
Q28 days 
Tremelimumab* 
75 mg  
IV 
D1 cycles 1, 2, 3  
and 4 only 
* When durvalumab is given with tremelimumab, tremelimumab will be administered first. Durvalumab infusion 
will start immediately after the tremelimumab infusion (during the post-tremelimumab observation period) and 
standard chemotherapy will start 15 minutes after the end of the durvalumab infusion. 
 
7.2 
Patient Treatment and Monitoring by Arm 
 
Consult the Pharmacy Information Manual for complete details 
 
7.2.1 
Patient Treatment and Monitoring for ARM 1 - Standard Chemotherapy (Gemcitabine +Nab-
Paclitaxel) 
 
Premedication: 
Patients should receive standard premedication according to the product monograph and local and 
provincial formulary guidelines. 
 
Premedication is not expected to be required, e.g. for nausea or prophylaxis for hypersensitivity. 
Management of symptoms should take place as necessary. Details of any premedication or 
concomitant medication given to manage or prevent adverse events should be recorded on the 
electronic case report form (eCRF). 
 
Order of Infusion: 
The nab-paclitaxel should be administered prior to the gemcitabine. 
 
The recommended dose of Nab-paclitaxel is 125 mg/m2 administered as an intravenous infusion 
over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. The recommended dose of 
gemcitabine is 1000 mg/m2 as an intravenous infusion over 30-40 minutes beginning immediately 
after the completion of Nab-paclitaxel administration on Days 1, 8 and 15 of each 28-day cycle. 
 
Patient Monitoring: 
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible 
infiltration during drug administration. Limiting the infusion of Nab-paclitaxel to 30 minutes, or as 
directed per the study protocol, reduces the likelihood of infusion-related reactions. 
 
 


 
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7.2.2 
Patient Treatment and Monitoring for ARM 2 - Standard Chemotherapy (Gemcitabine +Nab-
Paclitaxel) + Tremelimumab + Durvalumab 
 
Premedication: 
Patients should receive standard premedication according to the product monograph and local and 
provincial formulary guidelines. 
 
Premedication is not expected to be required, e.g. for nausea or prophylaxis for hypersensitivity. 
Management of symptoms related to the durvalumab and/or tremelimumab should take place as 
necessary (see Appendix III). See Sections 7.3.2 and 7.6 with respect to premedication of patients 
that have had a prior < Grade 2 infusion-related reaction. Details of any premedication or 
concomitant medication given to manage or prevent adverse events should be recorded on the 
electronic case report form (eCRF). 
 
Order of Infusion: 
When durvalumab is given with tremelimumab, tremelimumab will be administered first. 
Durvalumab infusion may start immediately after the tremelimumab infusion (during the post-
tremelimumab observation period) and standard chemotherapy will start 15 minutes after the end 
of the durvalumab infusion. The nab-paclitaxel should be administered prior to the gemcitabine. 
 
Patient Monitoring: 
Patients will be monitored before, during infusion and after the infusion of tremelimumab and 
durvalumab or durvalumab alone with assessment of vital signs as specified in Section 5.0. A 
1-hour observation period is recommended after the first durvalumab or tremelimumab infusion 
period which may run concurrently. After the first cycle, subsequent observation periods can be at 
the discretion of the investigator (30 minutes is suggested). 
 
Patients should be monitored for signs and symptoms of immune related AEs (see Appendix III). 
In the absence of an alternate etiology (e.g. infection or relapse), signs or symptoms of events with 
a potential inflammatory or immune-mediate mechanism should be considered to be immune- 
related. Guidelines for management of infusion-related reaction are summarized below and in 
Appendix III. 
 
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible 
infiltration during drug administration. Limiting the infusion of Nab-paclitaxel to 30 minutes, or as 
directed per the study protocol, reduces the likelihood of infusion-related reactions. 
 
Management of Infusion Reactions: 
 
Guidelines for management of infusion-related reaction are summarized in Appendix III. The 
standard infusion times for both durvalumab and tremelimumab are 1 hour. However, if there are 
interruptions during infusion, the total allowed time should not exceed 8 hours at room temperature. 
 
Study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to appropriate drugs and medical equipment to treat acute anaphylactic reactions, 
emergency resuscitation teams and equipment in addition to the ability to admit patients to an 
intensive care unit if necessary. 


 
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AMEND #2: 2018-MAR-20 
Drug Administration and Patient Monitoring/Vitals for ARM 2: 
 
Drug 
administration 
Infusion 
duration 
Vital signs and Monitoring* 
Tremelimumab 
60 min 
First infusion: Vital signs ≤ 30 
minutes prior to start of infusion 
then every 30 ±5 minutes during 
infusion and observation periods 
Subsequent infusions: At 
Investigator’s discretion 
First infusion: 60 min observation 
period after administration of 1st 
cycle of durvalumab/tremelimumab 
Subsequent infusions: At 
Investigator’s discretion (30 min 
recommended) 
Durvalumab 
60 min 
Nab-Paclitaxel 
30-40 
min** 
Infusion may begin 15 minutes after end of durvalumab and may continue 
through the observation period for the durvalumab. 
Gemcitabine 
30-40 
min** 
* 
Guidelines for management of infusion-related reaction are summarized below and in Appendix III. 
** Duration of infusion should be according to local protocol. 
 
Management of Infusion Reactions: 
Guidelines for management of infusion-related reaction are summarized in Appendix III. The 
standard infusion times for both durvalumab and tremelimumab are 1 hour. However, if there are 
interruptions during infusion, the total allowed time should not exceed 8 hours at room temperature. 
 
Study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to appropriate drugs and medical equipment to treat acute anaphylactic reactions, 
emergency resuscitation teams and equipment in addition to the ability to admit patients to an 
intensive care unit if necessary. 
 
7.3 
Adverse Event Management and Dose Modification and Adjustments 
 
7.3.1 
Overview (BOTH Arms) 
 
Doses will be reduced for adverse events. Dose adjustments are to be made according to the system 
showing the greatest degree of toxicity. Adverse events will be graded using the NCI Common 
Toxicity Criteria Version 4.0 (see Appendix V). The guidelines which follow outline dose 
adjustments for several of the potential adverse events related to gemcitabine and nab-paclitaxel 
and durvalumab + tremelimumab as referenced in the sections below. If a patient experiences 
several toxicities and there are conflicting recommendations, please use the recommended dose 
adjustment that reduces the dose to the lowest level. 
 
The maximum delay in the start of the next scheduled cycle should not normally be longer than 
21 days. Day 1 of the next planned cycle may be delayed up to 21 days not including any Day 8 or 
Day 15 omitted doses during the preceding cycle. Day 1 of a cycle should only delayed due to 
AEs related to the gemcitabine and/or nab-paclitaxel. If AEs are related to durvalumab and/or 
tremelimumab the standard chemotherapy should be maintained and the investigational agent 
omitted for that cycle (see Section 7.3.2 for additional information).  
 
 


 
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AMEND #2: 2018-MAR-20 
In the situation where a delay in the start of the next scheduled cycles of nab-paclitaxel or 
gemcitabine dosing of > 21 days has occurred due to management of toxicities considered 
potentially associated with both chemotherapy and immune therapy study agents, if it is the opinion 
of the investigator that the patient would benefit from resumption of gemcitabine and nab-
paclitaxel, the CCTG should be contacted for prior approval. 
 
The overarching principle of adverse event management is that dose modifications or adjustments 
should be made for those study agents considered to be associated with the corresponding adverse 
events as illustrated in the following diagram:  
 
Flowchart for Dose Modifications 
 
 
 
* If there are conflicting recommendations, use the recommended dose adjustment that reduces the does to 
the lowest level. 
 
The recommended dose of Nab-paclitaxel is 125 mg/m2 administered as an intravenous infusion 
over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. The recommended dose of 
gemcitabine is 1000 mg/m2 as an intravenous infusion over 30-40 minutes beginning immediately 
after the completion of Nab-paclitaxel administration on Days 1, 8 and 15 of each 28-day cycle. 
 
 
 
Treatment-Related Adverse Event 
Requiring Dose Adjustment 
What agent(s) is/are 
the AE(s) related to?  
Standard chemotherapy 
ONLY (gemcitabine 
and/or nab-paclitaxel) 
Durvalumab and/or 
Tremelimumab ONLY 
Both standard chemotherapy and 
durvalumab or tremelimumab, or 
unable to determine relation 
See Protocol Section 7.3.3 
and Appendix III 
See Protocol Section 7.3.2 
See Protocol Sections 7.3.2, 
7.3.3 and Appendix III* 


 
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7.3.2 
Dose Modifications for Gemcitabine and Nab-Paclitaxel (Standard Treatment – BOTH Arms) 
 
Dose Level Reductions for Gemcitabine and Nab-Paclitaxel 
 
Dose Level 
Nab-Paclitaxel Dose (mg/m2) 
Gemcitabine Dose (mg/m2) 
Full dose  
125 
1000 
1st dose level reduction  
100 
800 
2nd dose level reduction  
75 
600 
If additional dose reduction required  
Discontinue treatment 
Discontinue treatment 
 
Rules for Gemcitabine or Nab-Paclitaxel Dose Omissions and Modified Schedules 
 
One cycle is considered to be 28 days. Day 1 of a cycle is defined as the date nab-paclitaxel and 
gemcitabine are given. Day 1 of a cycle should only delayed due to AEs related to the gemcitabine 
and/or nab-paclitaxel. If AEs are related to durvalumab and tremelimumab the standard 
chemotherapy should be maintained and the investigational agent omitted for that cycle (see 
Section 7.3.2 for additional information). 
 
When a dose reduction is required for either gemcitabine or nab-paclitaxel, no dose reescalation 
will be permitted for the duration of study treatment (with the exception of Day 15, where re-
escalation with granulocyte-colony stimulating factor (G-CSF) support is permitted, after a 
previous dose reduction on Day 8 of the same cycle). 
 
Day 1 dose delayed: 
If the dose held or missed was to be given on Day 1 of the next cycle, that next cycle will not be 
considered to start until the day the first dose is actually administered to the patient (i.e. 1-2-3-Rest, 
X-1-2-3-Rest, etc.). If patient was randomized to the investigational arm, the durvalumab + 
tremelimumab (cycles 1 through 4) should also be delayed until patient is able to resume the 
gemcitabine/nab-paclitaxel and start the next cycle. 
 
Day 8 dose is missed: 
Cycle continues per protocol, with one dose not given (i.e. 1-2-3-Rest, 1-X-3-Rest, 1-2-3-Rest, 
etc.). Day 8 is administered as per cycle calendar if counts and chemistries permit. 
 
Day 15 dose missed: 
Cycle continues per protocol, with the dose not given (i.e. 1-2-3-Rest, 1-2-X- Rest, 1-X-X-Rest, 
etc.) The 28 day cycle should be maintained and the day 15 dose omitted.  Investigators should 
consider the use of G-CSF for patients who are unable to receive Day 15 or have isolated grade 3 
neutropenia and received day 15, in order to ensure the next cycle is given on time. 
 
The maximum delay in the start of the next scheduled cycle should not normally be longer than 
21 days. Day 1 of the next planned cycle may be delayed up to 21, days not including any Day 8 
or Day 15 omitted doses during the preceding cycle.   
 
In the event that patients must have treatment delayed within a treatment cycle due to toxicities, 
those doses held during a cycle will not be made up. Omitted doses are not considered to be 
treatment delays. 
 
 


 
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AMEND #2: 2018-MAR-20 
Arm 1 (standard chemotherapy): Specific Information for Dose Modifications and Adjustments 
to Gemcitabine and/or Nab-paclitaxel: 
 
Patients enrolled to ARM 1 (standard treatment with gemcitabine and nab-paclitaxel) experiencing 
study drug-related toxicities that require a delay in the start of the next scheduled cycle of treatment 
with nab-paclitaxel or gemcitabine dosing for > 21 days for unresolved adverse events related to 
either nab-paclitaxel or gemcitabine (except for peripheral neuropathy) should normally be 
discontinued from further treatment in this study. In the situation where it is the opinion of the 
investigator that the patient would benefit from resumption of study therapy beyond this interval, 
the CCTG should be contacted for prior approval. 
 
Arm 2 (standard chemotherapy with addition of durvalumab + tremelimumab): Specific 
Information for Dose Modifications and Adjustments to Gemcitabine and/or Nab-paclitaxel: 
 
Important: For patients randomized the investigational arms (ARM 2), if Day 1 of a cycle is 
delayed due to AEs related to the gemcitabine and/or nab-paclitaxel, the infusion of durvalumab 
+/- tremelimumab should also be delayed until the Day 1 treatment may be given. If the patient 
permanently discontinues treatment with gemcitabine and/or nab-paclitaxel he/she may continue 
to receive treatment with durvalumab +/- tremelimumab. 
 
If the AEs requiring treatment modifications are only related to durvalumab and/or tremelimumab 
(see Section 7.3.2), the administration of the gemcitabine and nab-paclitaxel should not be delayed 
if patient meets the requirements for their administration.  
 
For patients enrolled to ARM 2 experiencing gemcitabine or nab-paclitaxel related toxicities that 
require a delay in the start of the next scheduled cycle (Day 1) with nab-paclitaxel or gemcitabine 
dosing for > 21 days for unresolved adverse events (except for peripheral neuropathy), 
consideration should be given to discontinuation of further gemcitabine and nab-paclitaxel therapy. 
 
Patients on Arm 2 are unable to tolerate gemcitabine or nab-paclitaxel therapy may continue to 
receive immune therapy study agents.  
 
In the situation where a delay in the start of the next scheduled cycle of nab-paclitaxel or 
gemcitabine dosing of > 21 days has occurred due to management of toxicities considered 
potentially associated with both chemotherapy and immune therapy study agents, if it is the opinion 
of the investigator that the patient would benefit from resumption of gemcitabine and nab-
paclitaxel, the CCTG should be contacted for prior approval.  
 
Management of Gemcitabine and Nab-Paclitaxel Related Toxicities 
 
The major toxic effects of gemcitabine and nab-paclitaxel which limit dose are hematologic 
(neutropenia with or without fever, and thrombocytopenia), peripheral neuropathy, gastrointestinal 
toxicity (mucositis and diarrhea) and infusion site reactions. The guidelines which follow outline 
dose adjustments for several of these toxic effects. If a patient experiences several adverse events 
and there are conflicting recommendations, please use the recommended dose adjustment that 
reduces the dose to the lowest level. 
 
 


 
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AMEND #2: 2018-MAR-20 
Hematologic Adverse Events at the Start of a Cycle or Within a Cycle for Gemcitabine and Nab-
paclitaxel 
 
Cycle Day 
Absolute 
Neutrophils 
(x 109/L) 
 
Platelets 
(x 109/L) 
Nab-paclitaxel and Gemcitabine dose 
Day 1 
≥ 1.5 
and 
> 100 
Treat on time at current dose levels  
< 1.5 
or 
< 100 
Delay doses until recovery 
Day 8 
≥ 1.0 
and 
≥ 75 
Treat on time at current dose levels  
≥ 0.5 but < 1.0 
or 
≥ 50 but < 75 Treat on time, but reduce doses 1 dose level  
< 0.5 
or 
< 50 
Withhold doses 
Day 15: IF Day 8 doses were given without modification: 
Day 15 
≥ 1.0 
and 
≥ 75 
Treat on time at current dose levels  
≥ 0.5 but < 1.0 
or 
≥ 50 but < 75 
Treat on time at current dose levels and follow with 
WBC Growth factors1,2 
< 0.5 
or 
< 50 
Withhold doses 
Day 15: IF Day 8 doses were reduced: 
 
≥ 1.0 
and 
≥ 75 
Treat on time, but return to Day 1 dose level and 
follow with WBC Growth factors1,2 
Day 15 
≥ 0.5 but < 1.0 
or 
≥ 50 but < 75 
Treat on time with Day 8 dose level and follow with 
WBC Growth factors1,2 
< 0.5 
or 
< 50 
Withhold doses 
Day 15: IF Day 8 doses were withheld: 
Day 15 
≥ 1.0 
and 
≥ 75 
Treat on time, but return to Day 1 dose level and 
follow with WBC Growth factors1,2 
≥ 0.5 but < 1.0 
or 
≥ 50 but < 75 
Treat on time, but reduce 1 dose level and follow 
with WBC Growth Factors 1,2 
< 0.5 
or 
< 50 
Withhold doses 
1  G-CSF optional if descent only affected platelets 
2  If G-CSF is not available, a reduction in dose levels is recommended. 
 
Non-hematologic Adverse Events for Gemcitabine and Nab-paclitaxel 
 
Adverse Drug Reaction 
Grade 
Nab-paclitaxel Dose 
Gemcitabine dose 
Febrile Neutropenia 
Grade 3 or 4 Withhold doses until fever resolves and ANC ≥ 1.5; resume at 
reduced dose levels  
Peripheral Neuropathy 
Grade 3 or 4 Withhold dose until improves to 
≤ Grade 1; resume at reduced dose level  Treat with same dose 
Cutaneous Toxicity 
Grade 2 or 3 Treat on time, but reduce doses 1 level; discontinue treatment if 
adverse event persists 
Gastrointestinal 
Toxicity: 
mucositis or diarrhea 
Grade 3 
Withhold doses until improves to ≤ Grade 1; resume at reduced 
dose levels 
 
 


 
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AMEND #2: 2018-MAR-20 
Abnormal Hepatic Function 
Gemcitabine and nab-Paclitaxel should only be administered if hepatic function is within the 
parameters established in the eligibility criteria, specifically bilirubin ≤ 1.5 x upper limit of normal  
(ULN) and  AST and ALT ≤ 2.5 ULN (<3 x ULN in the presence of liver metastases). Hepatic 
toxicity from taxanes may occur but it is uncommon. Therefore, hepatic dysfunction that occurs 
while the patient is on study should prompt an evaluation to determine the cause, including the 
possibility of progressive metastatic disease and hepatotoxicity from concurrent medications, or in 
the case of patients enrolled to the investigational arm (Arm 2), from durvalumab +/- 
tremelimumab. 
 
Pulmonary Embolism 
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular-weight 
heparin without interruption of therapy. Moderate to severe pulmonary embolism will require 
permanent discontinuation of treatment. 
 
Interstitial Pneumonitis 
During study participation, patients should be carefully monitored for signs and symptoms of 
pneumonitis (i.e. episodes of transient or repeated dyspnea with unproductive persistent cough or 
fever) and, if observed, immediate clinical evaluation and timely institution of appropriate 
management (emphasizing the need for corticosteroids if an infectious process has been ruled out 
as well as appropriate ventilation and oxygen support when required).  
 
Other (Non-hematologic) Adverse Events considered related to Gemcitabine or Nab-paclitaxel 
 
Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity) 
 
Non Hematologic Toxicity and/or Dose Hold with Previous Cycle 
Toxicity/dose held 
Nab-paclitaxel and Gemcitabine Dose (this cycle) 
Grade 0, 1 or 2 toxicity 
Same as Day 1 of previous cycle (except for Grade 2 cutaneous toxicity where 
doses of gemcitabine and nab-paclitaxel should both be reduced to next lower 
dose level) 
Grade 3 toxicity1  
Decrease gemcitabine and nab-paclitaxel to next lower dose level1 
Grade 4 toxicity1,2 
Off protocol treatment2 
1 
If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced. 
2 
Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or a symptomatic, will be exempt from this 
requirement. 
 
7.3.3 
Dose Modifications for Durvalumab with Tremelimumab (Arm 2)  
 
The major toxic effects of durvalumab or tremelimumab which are anticipated to limit dosing are 
hypersensitivity/ infusion related reactions and possible class related immune related AEs, based 
on the mechanism of action of durvalumab and tremelimumab leading to T-cell activation and 
proliferation. These AEs are inflammatory in nature and can affect any organ. With anti-PD-L1 
and anti-CTLA-4 combination therapy, the occurrence of overlapping or increasing cumulative 
toxicities that include immune related AEs could potentially occur at higher frequencies than with 
either durvalumab or tremelimumab monotherapy.  
 
 


 
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AMEND #2: 2018-MAR-20 
Immune-related AEs (irAEs), which are important risks of immune checkpoint inhibitors, have 
been observed with durvalumab and include diarrhea/colitis, and intestinal perforation, 
pneumonitis/ILD, 
ALT/AST 
increases/hepatitis/hepatotoxicity, 
neuropathy/neuromuscular 
toxicities (e.g. Guillain-Barré syndrome, and myasthenia gravis), endocrinopathies (i.e. 
hypophysitis, 
hypopituitarism, 
adrenal 
insufficiency, 
diabetes 
insipidus, 
hyper- 
and 
hypothyroidism and type I diabetes mellitus), rash/dermatitis, nephritis/blood creatinine increases, 
pancreatitis (or labs suggestive of pancreatitis - increased serum lipase , increased serum amylase), 
myocarditis, and myocitis/polymyositis. Other inflammatory responses that are rare with a potential 
immune-mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eye, skin, hematological and rheumatological events. It is possible that 
events with an inflammatory or immune mediated mechanism could occur in nearly all organs.  
Please refer to the most recent version of the Investigator Brochure for incidence. 
 
Patients should be monitored for signs and symptoms of immune related AEs. In the absence of an 
alternate etiology (e.g. infection or relapse), signs or symptoms of enterocolitis, dermatitis, 
hepatitis, and endocrinopathy should be considered to be immune- related. 
 
Adverse events that are suspect to be immune mediated AND that require intervention with high 
doses of steroids are considered to be medically important events that require intervention to 
prevent a fatal, life-threatening or hospitalization event. They should be reported as expedited 
SAEs. See Section 9.1.2 for additional information.  
 
Guidelines for durvalumab and/or tremelimumab dose modification and toxicity 
management of immune related and non-immune related events are described in detail in 
Appendix III. 
 
Centres must contact CCTG in the event of severe immune related adverse event(s), especially 
when the use of drugs such as infliximab is considered. 
 
If a patient experiences several adverse events and there are conflicting recommendations, please 
use the recommended dose adjustment that requires the greatest dose hold or discontinuation. 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (see Appendix V). 
 
Dose reductions are not permitted to the durvalumab and/or tremelimumab. Dose 
adjustments (slowing/interruption of infusion rate, omission of a dose, or permanent 
discontinuation) will be made for hematologic and other adverse events that are related to only to 
durvalumab or tremelimumab. 
 
Dose delays are not permitted for AEs related ONLY to the durvalumab and/or 
tremelimumab. 
 
Patients on Arms 2 who are unable to tolerate durvalumab and/or tremelimumab therapy may 
continue to receive standard chemotherapy on study.  
 
 


 
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AMEND #2: 2018-MAR-20 
If a patient has received high dose steroids for management of AEs related to durvalumab +/- 
tremelimumab, treatment with durvalumab +/- tremelimumab should only be resumed at the next 
scheduled dose after the event has stabilized to grade ≤ grade 1 and 5-7 days has passed since the 
completion of the steroid taper. The treatment schedule of the standard chemotherapy (gemcitabine 
and nab-paclitaxel) should remain unchanged provided the patient meets the requirement for 
treatment outlined in Section 7.3.1. In other words, the start of a cycle should NOT be delayed due 
to AEs related only to durvalumab and/or tremelimumab, nor should the start of a cycle be delayed 
to allow for completion of steroid tapers and wash out periods.  
 
In the situation where a delay in the start of the next scheduled cycles of nab-paclitaxel or 
gemcitabine dosing of > 21 days has occurred due to management of toxicities considered 
potentially associated with both chemotherapy and immune therapy study agents, if it is the opinion 
of the investigator that the patient would benefit from resumption of gemcitabine and nab-
paclitaxel, the CCTG should be contacted for prior approval. 
 
The next cycle should not be given until the laboratory criteria in Section 7.3.1 are met and 
resolution of all drug related toxicity to < grade 2. Discuss with CCTG if asymptomatic/not felt to 
be clinically significant. 
 
Important: If the infusion cannot be administered, it should be omitted until the next planned 
infusion. The gemcitabine and nab-paclitaxel schedule should NOT be adjusted if AEs are related 
only to durvalumab or tremelimumab. Explicitly, start of the next cycle should not be delayed for 
adverse events related to either durvalumab or tremelimumab, rather Day 1 treatment with the 
standard chemotherapy (gemcitabine and nab-paclitaxel) should be given on schedule if possible 
and treatment with durvalumab or tremelimumab omitted until related adverse events have resolved 
to permit resumption of durvalumab or tremelimumab therapy with subsequent cycles. 
 
For patients enrolled to ARM 2 (addition of durvalumab and tremelimumab), where a dose of 
tremelimumab is omitted from one or more of the first four cycles of therapy as planned, then the 
investigator may exercise discretion in adding tremelimumab to subsequent cycles beyond the first 
4 with a maximum of 4 doses of tremelimumab administered. 
 
If durvalumab or tremelimumab are omitted for ≥ 2 consecutive cycles due to unresolved adverse 
events related to durvalumab or tremelimumab, consideration should be given to discontinuing 
further therapy with durvalumab and/or tremelimumab. However, if it is the investigator’s 
assessment that the patient would benefit from the resumption of durvalumab or tremelimumab 
therapy, then CCTG should be contacted for prior approval.  
 
Important: For patients randomized to the investigational arms (Arm 2), if Day 1 of a cycle is 
delayed due to AEs related to the gemcitabine or nab-paclitaxel, the infusion of durvalumab +/- 
tremelimumab should also be delayed until the Day 1 treatment may be given. If the patient 
permanently discontinues treatment with gemcitabine and/or nab-paclitaxel he/she may continue 
to receive treatment with durvalumab +/- tremelimumab. 
 
For patients enrolled to ARM 2 (addition of durvalumab and tremelimumab) experiencing 
gemcitabine or nab-paclitaxel related toxicities that require a delay in the start of the next scheduled 
cycles of nab-paclitaxel or gemcitabine dosing for > 21 days for unresolved adverse events (except 
for peripheral neuropathy), consideration should be given to discontinuation of further gemcitabine 
and nab-paclitaxel therapy. Patients that are unable to tolerate gemcitabine or nab-paclitaxel 
therapy may continue to receive immune therapy study agents.  
 
 


 
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AMEND #2: 2018-MAR-20 
In the situation where a delay in the start of the next scheduled cycle of nab-paclitaxel or 
gemcitabine dosing of > 21 days has occurred due to management of toxicities considered 
potentially associated with both chemotherapy and immune therapy study agents, if it is the opinion 
of the investigator that the patient would benefit from resumption of gemcitabine and nab-
paclitaxel, the CCTG should be contacted for prior approval.  
 
Management of Toxicity for Durvalumab +/- Tremelimumab: 
 
The following general guidance should be followed for management of toxicities: 
1. Treat each of the toxicities with maximum supportive care (including slowing / interrupting / 
omitting the agent suspected of causing the toxicity where required). 
2. If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab ± tremelimumab along with appropriate continuing 
supportive care. 
3. All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
 
In addition to the dose adjustments shown in Appendix III, the following are recommended: 
• 
Patient evaluation to identify any alternative etiology. 
• 
In the absence of a clear alternative etiology, all events of an inflammatory nature should be 
considered to be immune-related. 
• 
Symptomatic and topical therapy should be considered for low-grade events. 
• 
For persistent (greater than 3 to 5 days) low-grade (Grade 2) or severe (Grade ≥ 3) events 
promptly start prednisone PO 1-2 mg/kg/day or IV equivalent. 
• 
If symptoms recur or worsen during corticosteroid tapering (> 4 weeks of taper), increase the 
corticosteroid dose (prednisone dose [e.g. up to 2-4 mg/kg/day or IV equivalent]) until 
stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate. 
• 
More potent immunosuppressive therapy (refer to individual sections of the immune related 
adverse event for specific type of immunosuppressive agents) should be considered for events 
not responding to systemic steroids. 
• 
Discontinuation of study drug is not mandated for Grade 3 / Grade 4 inflammatory reactions 
attributed to local tumour 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 and be discussed with CCTG. 
 
7.4 
Duration of Therapy 
 
Protocol treatment will continue until confirmed disease progression as defined in Section 8 or 
intolerable toxicity. However, a maximum of 4 doses of tremelimumab may be given to patient 
randomized to the dual immunotherapy arms (Arm 2).  
 
 


 
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If, in the opinion of the Investigator, a patient is deriving clinical benefit from study therapy despite 
the documentation of objective disease progression per RECIST 1.1 criteria, then provided the 
patient does not have any significant, unacceptable, or irreversible toxicities that indicate that 
continuing treatment will not further benefit the patient, the patient may remain on study therapy 
pending their next disease assessment. However, appropriate imaging studies must be repeated 
within 4-8 weeks to re-assess treatment response. A patient with objective disease progression 
confirmed on subsequent assessment by either RECIST 1.1 criteria or iRECIST criteria as 
appropriate, should be discontinued from the study. Patients should also be discontinued from the 
study if objective disease progression occurs in a target lesion that has previously shown a 
confirmed response. 
 
For a complete list of general criteria for stopping study treatment, please see Section 10.0. 
 
7.5 
Patient Compliance 
 
Treatment compliance will be monitored by drug accountability, as well as recording drug 
administration in the patient’s medical record and case report form (CRF). 
 
7.6 
Concomitant Therapy 
 
The Investigator must be informed as soon as possible about any medication taken from the time 
of screening until the end of the clinical phase of the study (final study visit). Any concomitant 
medication(s), including herbal preparations, taken during the study are to be recorded in the eCRF. 
 
7.6.1 
Permitted 
 
Investigators may prescribe concomitant medications or treatments deemed necessary to provide 
adequate prophylactic or supportive care except for those medications identified as “not permitted” 
below. In addition, the following medications or treatments are permitted during the study: 
• 
Growth factors may be used according to centre policy to treat life threatening toxicity but 
cannot be used in place of protocol defined dose adjustments. Please consult CCTG in the case 
of patients experiencing multiple delays as exceptions may be made for patients who are 
benefitting from protocol therapy. 
• 
Other best supportive and palliative care (e.g. pain control) as required throughout the study. 
• 
Anti-emetics or anti-diarrheal agents as required. 
 
7.6.2 
Not Permitted 
• 
Cytokines 
• 
Other anti-cancer treatment 
• 
Other investigational therapy 
• 
Concurrent radiation treatment; Note: local radiation treatment of isolated lesions for palliative 
intent is acceptable. Protocol therapy should be held prior to and during the radiation (Consult 
CCTG in these cases). 
• 
Corticosteroids IV or PO (except for the treatment of ≥ grade 3 infusion reaction and nausea 
prophylaxis for chemotherapy). Note: Topical applications (e.g. rash), inhaled sprays (e.g. 
obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed, as 
are oral dose of steroids equivalent to 10 mg or less of prednisone. 
 
 


 
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AMEND #2: 2018-MAR-20 
• 
Other immunosuppressive medications including methotrexate, azathioprine, and TNF-α 
blockers. Use of immunosuppressive medications for the management of investigational 
product-related AEs is acceptable. 
• 
Live attenuated vaccines (examples include, but are not limited to, vaccines for measles, 
mumps, and rubella, live attenuated influenza vaccine (nasal), chicken pox vaccine, oral polio 
vaccine, rotavirus vaccine, yellow fever vaccine, BCG vaccine, typhoid vaccine and typhus 
vaccine) within 30 days of durvalumab and tremelimumab dosing (i.e. 30 days prior to the first 
dose, during treatment with durvalumab and tremelimumab and for 30 days post 
discontinuation of durvalumab and tremelimumab). Inactivated vaccines, such as the injectable 
influenza vaccine, are permitted. 
 
7.6.3 
Steroid Tapering Guidelines 
 
IMPORTANT: Adverse events that are suspected to be immune mediated AND that require 
intervention with high doses of steroids as described in Appendix III are considered to be medically 
important events that require intervention to prevent a fatal, life-threatening or hospitalization event 
should be reported as expedited events using the SAEs reporting system (see Section 9). 
 
If the patient experiences immune-mediated toxicity, they may receive moderate to high-dose 
steroid therapy for multiple weeks. During the time frame the patient is receiving the steroid, 
treatment with durvalumab +/- tremelimumab should be omitted and treatment with standard 
chemotherapy should continue if patient is well enough, in the investigator’s opinion, to receive 
the gemcitabine and nab- paclitaxel. Per guidelines contained in Appendix III, durvalumab 
+/- tremelimumab may resume once event stabilizes to Grade ≤1 after completion of steroid taper. 
 
Length of steroid tapering is usually dictated by the severity of the immune mediated adverse event 
and regular monitoring during tapering is strongly recommended, as there is an increased risk of 
recurrence of the immune mediated adverse event. Local protocols for tapering schedules maybe 
be followed. 
 
More potent immunosuppressive therapy (refer to individual sections of the immune related 
adverse event for specific type of immunosuppressive agents in Appendix III) should be considered 
for events not responding to systemic steroids. 
 
If symptoms recur or worsen during corticosteroid tapering, increase the corticosteroid dose until 
stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate 
 
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/study regimen should normally require the patient to 
discontinue durvalumab and/or tremelimumab.  
 
If a patient has received high dose steroids for management of AEs related to durvalumab +/- 
tremelimumab, treatment with durvalumab +/- tremelimumab should only be resumed at the next 
scheduled dose after the event has stabilized to grade ≤ grade 1 and 5-7 days has passed since the 
completion of the steroid taper. The treatment schedule of the standard chemotherapy (gemcitabine 
and nab-paclitaxel) should remain unchanged provided the patient meets the requirement for 
treatment outlined in Section 7.3.1. In other words, the start of a cycle should NOT be delayed due 
to AEs related only to durvalumab and/or tremelimumab, nor should the start of a cycle be delayed 
to allow for completion of steroid tapers and wash out periods. 


 
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8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
8.1 
Definitions 
 
8.1.1 
Evaluable for Adverse Events 
 
All patients will be evaluable for adverse event evaluation from the time of their first treatment. 
 
8.1.2 
Evaluable for Response 
 
All patients who have received at least one cycle of therapy and have their disease re-evaluated will 
be considered evaluable for response (exceptions will be those who exhibit objective disease 
progression prior to the end of cycle 1 who will also be considered evaluable). Patients on therapy 
for at least this period and who meet the other listed criteria will have their response classified 
according to the definitions set out below [Seymour 2017]. 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee as well 
as the modified iRECIST guidelines [Seymour 2017]. Investigators should note the different 
requirements for confirmatory scans as well as follow up for the two criteria. 
 
See Section 10 for criteria for continuing treatment past RECIST 1.1 disease progression. 
 
8.1.3 
Evaluable for Quality of Life Assessment 
 
All patients who have completed the quality of life questionnaire are evaluable for quality of life. 
 
8.2 
RECIST 1.1 Response and Evaluation Endpoints 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee as well 
as the Immune-Related modified Response Criteria (iRECIST)).  
 
Investigators should continue treatment, as appropriate, in the absence of unacceptable toxicity, 
until unequivocal disease progression. This is particularly important for patients in whom 
pseudoprogression may have occurred. Follow up response assessments must be continued until 
unequivocal disease progression has occurred. 
 
8.2.1 
Measurable Disease 
 
Measurable tumour lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray and as > 10 mm with CT 
scan or clinical examination. Bone lesions are considered measurable only if assessed by CT scan 
and have an identifiable soft tissue component that meets these requirements (soft tissue component 
≥ 10 mm by CT scan). Malignant lymph nodes must be ≥ 15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumour measurements must be 
recorded in millimetres (or decimal fractions of centimetres). Previously irradiated lesions are not 
considered measurable unless progression has been documented in the lesion. 
 
 


 
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8.2.2 
Non-measurable Disease 
 
All other lesions (or sites of disease), including small lesions are considered non-measurable 
disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
lymphangitic involvement of lung or skin and abdominal masses followed by clinical examination 
are all non-measurable. Lesions in previously irradiated areas are non-measurable, unless 
progression has been demonstrated. 
 
8.2.3 
Target Lesions 
 
When more than one measurable tumour lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the criterion of a short axis of ≥ 15 mm by 
CT scan and only the short axis of these nodes will contribute to the baseline sum. All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target 
lesions. Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed (see 10.2.4). At baseline, the sum of the target lesions (longest diameter of 
tumour lesions plus short axis of lymph nodes: overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately measured 
but are deemed to be present, a default value of 5 mm may be used. If lesions are too small to 
measure and indeed are believed to be absent, a default value of 0 mm may be used. 
 
8.2.4 
Non-target Lesions 
 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above those 
listed as target lesions are considered non-target lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present” or “absent”. 
 
8.2.5 
RECIST 1.1 Response 
 
8.2.5.1 RECIST 1.1 - Patients With Measurable Disease 
 
RECIST 1.1 response will be classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target lesions and normalization of 
tumour markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: 
continue to record the measurement even if < 10 mm and considered CR). Residual lesions (other 
than nodes < 10 mm) thought to be non-malignant should be further investigated (by cytology 
specialized imaging or other techniques as appropriate for individual cases [Eisenhauer 2009]) before 
CR can be accepted. 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumour 
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non target lesions must be non-PD. 


 
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND an 
absolute increase of ≥ 5 mm. Appearance of new lesions will also constitute progressive disease 
(including lesions in previously unassessed areas). In exceptional circumstances, unequivocal 
progression of non-target disease may be accepted as evidence of disease progression, where the 
overall tumour burden has increased sufficiently to merit discontinuation of treatment or where the 
tumour burden appears to have increased by at least 73% in volume. Modest increases in the size 
of one or more non-target lesions are NOT considered unequivocal progression. If the evidence of 
PD is equivocal (target or non-target), treatment may continue until the next assessment, but if 
confirmed, the earlier date must be used. 
 
Table 1: Integration of Target, non-Target and New Lesions into Response Assessment for patients 
with measurable disease: 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes < 10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
Documented at least once ≥ 4 weeks 
from baseline  
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes < 10 mm 
No Target 
Non-CR/non-PD 
No 
Non-
CR/non-
PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note: 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”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 


 
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8.2.5.2 RECIST 1.1 - Patients With Non-Measurable Disease Only 
 
Patients with only non-measurable (but evaluable) disease, may only have an overall RECIST 1.1 
response or SD or PD as follows: 
 
Complete Response (CR): disappearance of non-target lesions. Residual lesions thought to be non-
malignant should be further investigated (by cytology specialized imaging or other techniques as 
appropriate for individual cases [Eisenhauer 2009] before CR can be accepted. 
 
Stable Disease (SD): steady state of disease. No new lesions and not sufficient progression of non-
target lesions to qualify for PD. 
 
Progressive Disease (PD): the appearance of new lesions and/or unequivocal progression of non-
target lesions. 
 
Table 2: Integration of Target, non-Target and New Lesions into Response Assessment for patients 
with only non-measurable, evaluable, lesions: 
 
Non-Measurable Lesions* 
New Lesions 
Overall 
Response 
Best Overall Response for this 
category also requires 
Complete disappearance 
No 
CR 
 
Non-PD 
No 
SD 
Documented at least once > 4 weeks 
from baseline 
PD** 
No 
PD 
No prior SD 
Any 
Yes 
PD 
* 
Note that these lesions should be recorded under the "Non-Target" lesions table on the CRFs. 
** 
Unequivocal progression in non-measurable lesions will be accepted as disease progression. 
Note: 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”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
8.3 
Immune-Related (iRECIST) Response Assessment 
 
Overall response will also be assessed using iRECIST [Seymour 2017]. Immunotherapeutics may 
result in infiltration of immune cells leading to transient increase in the size in malignant lesions, 
or undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumour burden, 
or the appearance of new lesions, does not reflect true tumour progression. 
 
Key differences are described below. All responses defined using iRECIST criteria are designated 
with a prefix. iRECIST time-point and best overall responses will be recorded separately. 
 
8.3.1 
Confirming Progression 
 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
 


 
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iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is seen as 
evidenced by one or more of the following: 
• 
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
− 
Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum 
− 
Continued unequivocal progression in non-target disease with an increase in tumour burden 
− 
Increase in size of previously identified new lesion (s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions. 
• 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). As can be seen in table 2, the prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response (BOR) 
providing that iCPD is not documented at the next assessment after iUPD. 
 
8.3.2 
New Lesions 
 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum 
of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short axis for nodal 
lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to allow 
clear differentiation from baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of target lesions should NOT be included in the sum of measures of original target 
lesions identified at baseline. Rather, these measurements will be collected on a separate table in 
the case report form. 
 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 
weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with either 
an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but not 
necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of additional new 
lesions 
 
 


 
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Table 3: Time-point (TP) iResponse 
 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non-
iUPD 
No 
iSD 
iSD 
iUPD with 
no change 
OR 
decrease 
from last 
TP 
iUPD with no 
change OR 
decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously identified 
and increase in size (≥5 mm in SOM for NLT or any 
increase for NLNT) or number. If no change in NLs 
(size or number) from last TP, remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in further 
increase in size of NT disease (need not meet RECIST 
1.1 criteria for unequivocal PD) 
iUPD 
Non-iCR/Non-
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
• further increase in SOM of at least 5 mm, otherwise 
remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further 
increase in: 
• previously identified T lesion iUPD SOM ≥5 mm 
and / or 
• NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on further 
increase in: 
• previously identified T lesion iUPD ≥5 mm and / or 
• previously identified NT lesion iUPD (need not be 
unequivocal) and /or 
• size or number of new lesions previously identified 
Non-
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
• increase in size or number of new lesions previously 
identified 
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and 
SD would be the same.  
** in any lesion category.  
*** previously identified in assessment immediately prior to this TP. 
 
 


 
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Table 4: iRECIST Best Overall Response (iBOR) 
 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR, iPR, 
iUPD, NE 
iCR, iPR, iUPD, 
NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, 
NE 
iCR 
iCR, iPR, iSD, iUPD, 
NE 
iCR, iPR, iSD, iUPD, 
iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, 
NE 
iPR, iSD, iUPD, NE, 
iCPD 
iPR, iSD, iUPD, NE, 
iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, iCPD, 
NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, NE 
iSD, iUPD, ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
• 
Table assumes a randomised study where confirmation of CR or PR is not required. 
• 
NE = not evaluable that cycle. 
• 
Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation. 
• 
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each TPR 
but is not shown in the table for ease of presentation. 
 
All patients will have their iBOR from the start of study treatment until the end of treatment classified as 
outlined below. 
 
8.3.3 
iRECIST - Patients With Non-Measurable Disease Only 
 
Table 5: Immune-Related RECIST Criteria (iRECIST) for patients with only non-measurable, 
evaluable lesions: 
 
Response 
Description of Response 
Confirmation by 
Complete remission: iCR  
Complete disappearance of all non-
measurable lesions (and no new 
lesions). Patient may have had prior 
iuPD by RECIST 1.1 criteria.  
Repeat, consecutive assessment 
no less than 4 weeks from the 
date first documented 
Stable Disease: iSD 
Not meeting criteria for iCR in 
absence of iPD. Patient may have had 
prior iuPD by RECIST 1.1 criteria 
 
Progressive disease: iPD 
 Unequivocal increase in tumour 
burden 
Confirmation by a repeat, 
consecutive assessment no less 
than 4 weeks from the date first 
documented is required  
New measurable lesions 
(i.e. ≥ 10 mm in long axis) 
Measured but not incorporated into 
overall assessment of target lesions. 
 
New, non-measurable 
lesions 
Recorded 
 
 
 
 


 
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8.4 
Response Duration (RECIST 1.1 and iRECIST) 
 
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(whichever is first recorded) are first met until the first date that recurrent or progressive disease is 
objectively documented, taking as reference the smallest measurements recorded on study 
(including baseline). 
 
8.5 
Stable Disease Duration 
 
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
 
8.6 
Methods of Measurement 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
8.6.1 
Clinical Lesions 
 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm as 
assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is recommended. If feasible, imaging 
is preferred. 
 
8.6.2 
Chest X-ray 
 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions > 
20 mm on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
 
8.6.3 
CT, MRI 
 
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). Other specialized imaging or other 
techniques may also be appropriate for individual case. For example, while PET scans are not 
considered adequate to measure lesions, PET-CT scans may be used providing that the measures 
are obtained from the CT scan and the CT scan is of identical diagnostic quality to a diagnostic CT 
(with IV and oral contrast). 
 
 


 
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8.6.4 
Ultrasound 
 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 
 
8.6.5 
Endoscopy, Laparoscopy 
 
The utilization of these techniques for objective tumour evaluation is not advised. However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response or surgical resection is an endpoint. 
 
8.6.6 
Tumour Markers 
 
Tumour markers alone cannot be used to assess objective tumour response. If markers are initially 
above the upper normal limit, however, they must normalize for a patient to be considered in 
complete response. 
 
8.6.7 
Cytology, Histology 
 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumour types such as germ cell tumours, where known 
residual benign tumours can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when 
the measurable tumour has met criteria for response or stable disease is advised to differentiate 
between response or stable disease and progressive disease. 


 
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9.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site : 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG. 
 
9.1 
Definition of a Reportable Serious Adverse Event 
 
9.1.1 
ARM 1 - Standard Treatment (Gemcitabine + Nab-Paclitaxel) 
 
Arm 1 (Standard Treatment with gemcitabine and nab-paclitaxel) does not contain investigational 
agents, and adverse events occurring as a result of this commercially available treatment should be 
reported to CCTG in the manner described below. In addition, your local Research Ethics Board 
(REB) should be notified. 
 
• 
All serious adverse events which are unexpected and related to protocol treatment must be 
reported in an expedited manner (see Section 9.2 for reporting instructions). These include 
events occurring during the treatment period (until 30 days after last protocol treatment 
administration) and at any time afterwards. 
• 
Unexpected adverse events are those which are not consistent in either nature or severity with 
information contained in the product monograph or package insert. 
• 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol agent cannot reasonably be ruled out. 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
 


 
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9.1.2 
ARM 2 (including Safety Run-In) - Investigational Treatment (Gemcitabine + Nab-Paclitaxel + 
Durvalumab + Tremelimumab) 
 
• 
All serious adverse events, regardless of whether they are unexpected or related to protocol 
treatment, occurring during the treatment period and within 30 days after the last protocol 
treatment administration, must be reported in an expedited manner. Any late serious adverse 
event occurring after this 30-day period which is unexpected and related to protocol treatment 
must also be reported in an expedited manner (see Section 9.3 for reporting instructions). 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
IMPORTANT NOTES:  
 
Adverse events that are suspect to be immune mediated AND that require intervention with high 
doses of steroids are considered to be medically important events. They should be reported as 
expedited events using the SAEs reporting system. 
 
If a patient shows an AST or ALT ≥ 3 x ULN together with total bilirubin ≥ 2 x ULN, refer to 
Appendix III for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s Law. 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. 
 
9.1.3 
Durvalumab + Tremelimumab Adverse Events of Special Interest 
 
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 An AESI may be 
serious or non-serious.  
 
AESIs for durvalumab ± tremelimumab 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 may require close monitoring in the treatment arms with durvalumab =/- 
tremelimumab. 
 
 


 
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An immune-mediated adverse event (imAE) is defined as an AESI 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 event being an imAE, the Investigator should 
promptly contact the CCTG.  
 
AESIs observed with durvalumab ±tremelimumab include: 
• 
Diarrhea / Colitis, and intestinal perforation; 
• 
Pneumonitis / ILD; 
• 
ALT/AST increases / hepatitis / hepatotoxicity; 
• 
Neuropathy / neuromuscular toxicities (e.g. Guillain-Barré syndrome, and myasthenia gravis); 
• 
Endocrinopathies (i.e. events of hypophysitis, hypopituitarism adrenal insufficiency, diabetes 
insipidus, hyper- and hypothyroidism and type I diabetes mellitus); 
• 
Rash / Dermatitis; 
• 
Nephritis / Blood creatinine increases; 
• 
Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase); 
• 
Myocarditis; 
• 
Myocitis/polymyositis; 
• 
Other inflammatory responses that are rare with a potential immune-mediated aetiology 
include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events involving the 
eye, skin, hematological and rheumatological events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab and tremelimumab Investigator’s Brochures. More specific guidelines for their 
evaluation and treatment are described in detail in Appendix III. 
 
9.1.4 
Events Not to be Treated as SAEs (Both Treatment Arms and Safety Run-in) 
 
Serious adverse events which are unequivocally related to the underlying malignancy or disease 
progression do NOT require expedited reporting. These include such adverse events as admission 
for pain control, palliative care or paracentesis of malignant effusions. 
 
• 
In addition, the following events will NOT be recorded as AEs (or SAEs): 
− 
lack of efficacy /disease progression (will be recorded separately on CRF); 
− 
laboratory abnormalities for protocol specified tests (these are derived electronically from 
actual values supplied and need not be reported separately in adverse event tables on 
CRFs); 
 
 


 
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− 
elective hospitalization for medical, radiological or surgical procedures for treatment of 
disease or to simplify treatment for study procedures (will be recorded separately on CRF); 
− 
hospitalization for palliative care or pain control. 
 
9.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the PA.7 section of the CCTG website (www.ctg.queensu.ca). 
 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
PA.7 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2941 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application. 
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the PA.7 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application. 
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430). 
 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting 
 
9.3.1 
Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 4.1.15. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy. 
 
 


 
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A highly effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. Highly effective methods of 
contraception are described in the table below. Note that some contraception methods are not 
considered highly effective (e.g. male or female condom with or without spermicide; female cap, 
diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; 
progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary 
mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and 
triphasic combined oral contraceptive pills). 
 
9.3.2 
Pregnancy Reporting 
 
If a patient becomes pregnant during the course of the study, the investigational agent should be 
discontinued immediately. 
 
Pregnancy itself - occurring in female participants, and female partners of male participants - is not 
regarded as an AE unless there is a suspicion that the IP under study may have interfered with the 
effectiveness of a contraceptive medication. 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. 
 
The investigator is required to report to Canadian Cancer Trials Group (CCTG) any pregnancy 
occurring in female participants, and female partners of male participants. Pregnancies occurring 
up to 6 months after the last dose of study treatment must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage. 
 
Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca). 
 
 
Highly Effective* Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing 
intrauterine system (e.g. 
Mirena®)** 
• 
Etonogestrel implants: e.g. Implanon or Norplan 
• 
Intravaginal device: e.g. ethinylestradiol and 
etonogestrel 
• 
Medroxyprogesterone injection: e.g. Depo-Provera 
• 
Normal and low dose combined oral contraceptive 
pill 
• 
Norelgestromin/ethinylestradiol transdermal system 
• 
Cerazette (desogestrel) 
* 
Highly effective (i.e. failure rate of <1% per year). 
** This is also considered a hormonal method. 


 
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If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada for those events which meet 
regulatory requirements for expedited reporting, i.e. events which are BOTH serious AND 
unexpected, AND which are thought to be related to protocol treatment (or for which a causal 
relationship with protocol treatment can not be ruled out). 
 
9.5 
CCTG Reporting Responsibility to AstraZeneca 
 
AstraZeneca will be notified of all protocol reportable serious adverse events (as defined in Section 
9.1) within one working day of receipt of report at CCTG. CCTG, as sponsor, will determine 
regulatory re-portability in Canada. 
 
AstraZeneca will be notified of all pregnancies and outcomes of pregnancies within 30 days of 
receipt of the report at CCTG. 
 
9.6 
AstraZeneca Reporting Responsibilities 
 
AstraZeneca will report all regulatory reportable serious adverse events from non-CCTG trials 
(Safety Updates) with durvalumab and tremelimumab to CCTG within the timelines outlined in the 
contract. CCTG will review these events to determine which meet the criteria (serious, unexpected, 
drug related) for reporting to PA.7 investigators. AstraZeneca will report these events to Health 
Canada. 
 
9.7 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory authorities 
in Canada as reported to the CCTG. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment. The reports will be posted to the CCTG 
trial PA.7 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial 
PA.7 web based safety monitoring utility and documentation of REB submission must be retained 
in the study binder on site. The REB submission template provided by CCTG can be used to assist 
with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 


 
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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
10.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 7.0 and Appendix III. 
• 
Tumour progression or disease recurrence as defined in Section 8.0. 
• 
Request by the patient. 
 
Efforts should be made to maintain the investigations schedule and continue follow-up, even if 
patients discontinue protocol treatment prematurely and/or no longer attend the participating 
institution. 
 
10.2 
Duration of Protocol Treatment 
 
Investigators are encouraged to continue therapy, as appropriate in the absence of unacceptable 
toxicity, until disease progression has been unequivocally documented. 
 
For patients randomized to the gemcitabine + nab-paclitaxel + durvalumab + tremelimumab arm 
ONLY, study therapy may be continued beyond the first documentation of objective disease 
progression (i.e. per RECIST 1.1 criteria) on the basis of clinical benefit; continued follow-up 
assessments per protocol must also be continued until disease progression has been unequivocally 
confirmed, either through RECIST 1.1 or Immune-Related Response Criteria (iRECIST) (i.e. 
treatment failure), at which time study therapy should cease. 
 
10.3 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 
 
10.4 
Follow-up Off Protocol Treatment 
 
All patients will be seen at 4 weeks after completion of protocol therapy. Thereafter, continued 
follow-up is not required for patients who go off protocol treatment with progressive disease, except 
to document ongoing toxicities (until resolved to ≤ Grade 2) and late toxicities (including second 
malignancies) and for survival status. For patients who go off protocol treatment with CR, PR, or 
SD ongoing, follow-up will be required every 8 weeks until relapse (see Section 5 for investigations 
to be performed). Final report (Form 6) will be required for ALL patients, due within 2 weeks of 
knowledge of death (see Appendix IV - Documentation for Study). 
 
For patients randomized to the gemcitabine + nab-paclitaxel + durvalumab + tremelimumab arm 
(Arm 2) study therapy may be continued beyond the first documentation of objective disease 
progression (i.e. per RECIST 1.1 criteria) on the basis of clinical benefit; and the possibility of 
pseudoprogression. Continued follow-up assessments per protocol must also be continued until 
disease progression has been unequivocally confirmed, either through RECIST 1.1 or Immune-
Related Response Criteria (iRECIST) (i.e. treatment failure), at which time study therapy should 
cease. 


 
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11.0 
CENTRAL REVIEW PROCEDURES 
 
11.1 
Central Radiology Review 
 
There will be no central radiology review for this study. 
 
11.2 
Central Pathology Review 
 
There will be no upfront central pathology review for this study, however, per Section 4.1.4 patients 
must consent to provision of, and investigator(s) must confirm access to and agree to submit within 
4 weeks of randomization to the CCTG Central Tumour Bank, a representative formalin fixed 
paraffin block of tumour tissue of adequate amount and quality in order that the specific correlative 
marker assays proscribed in the protocol may be conducted. Cytospin and brushings are not 
considered to be sufficient. Where adequate amount and quality of tissue exists but local centre 
regulations prohibit submission of blocks of tumour tissue, the approval of the CCTG must be 
sought prior to randomization of the first patient to allow cores (two 2 mm cores of tumour from 
the block) and a predetermined number of slides of representative tumour tissue to be substituted. 
Where tumour tissue is available, failure to submit any tissue samples will result in the patient being 
considered ineligible. Where no previously resected or biopsied tumour tissue exists or is found to 
be of inadequate amount or quality, additional biopsy of the primary or metastatic tumour will be 
required for the patient to be considered eligible for the study. Please refer to the PA.7 correlative 
tissue manual for details concerning adequacy of amount and quality of tumour tissue. 


 
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12.0 
CORRELATIVE STUDIES 
 
A detailed Correlative Studies Manual is provided on the PA.7 trial specific website, which will 
include details regarding sample collection, preparation, handling and shipping. 
 
Tissue samples collected on this trial may be used by researchers now or in the future to better 
understand the nature of pancreas cancer and how patients respond to treatment. Samples will be 
used for research purposes only and will not be sold. Patients will not be identified by name. The 
only identification of tissue will be by a tumour banking code assigned at the time of sample receipt. 
Material issued to researchers will be anonymized and identified by tumour banking coded number. 
 
Future use of the banked samples (optional) will undergo a scientific review process of any 
proposals to use the tissue and any proposals approved will have undergone ethics approval. 
 
Specific samples to be collected and priority assays are as follows: 
 
12.1 
Protocol-Mandated Correlative Studies 
 
Tissue Submission (Mandatory) 
 
Archival Tumour Block/Slides: 
The submission of a representative block of the diagnostic tumour tissue  is an important part of 
this trial and is mandatory for participation in this trial. Submitted tissue samples will be carefully 
stored as part of the CCTG Tumour Tissue Data Repository at Queen’s University in Kingston, 
Ontario, and the only assays done will be as part of this study.  
 
All patients must consent to provision of, and investigators must confirm access to and agree to 
submit, within 4 weeks of randomization to the CCTG Central Tumour Bank, a representative 
formalin fixed paraffin block of tumour tissue of adequate amount and quality in order that the 
specific correlative marker assays proscribed in the protocol may be conducted. Cytospin and 
brushings are not considered to be sufficient. 
 
Tumour tissue may be from a prior primary resection or a sample of metastatic tissue may be 
submitted, but the preferred tumour sample for the determination of a patient’s PD-L1 status is the 
one taken following the completion of adjuvant therapy (if applicable). 
 
Note: One block of adjacent normal tissue is also requested if available, but is not mandated. 
 
Sites undertaking genomic profiling may contact CCTG to discuss submission of tumour tissue 
sufficient for patient eligibility.  
 
Blocks are the preferred material to collect, as it is well known that tissue materials (including 
protein and nucleic acid integrity) on unstained sections deteriorate rapidly within 3-6 months after 
preparation. This will optimize the amount of tissue available to investigators and permit the 
preservation of the block submitted. If, at any time, the submitting hospital requires the block to be 
returned for medical or legal concerns, it will be returned by courier on request. 
 
 


 
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Where adequate amount and quality of tissue exists but local centre regulations prohibit submission 
of blocks of tumour tissue, the approval of the CCTG must be sought prior to randomization of the 
first patient to allow cores (two 2 mm cores of tumour from the block) and a predetermined number 
of slides of representative tumour tissue to be substituted. Where tumour tissue is available, failure 
to submit any tissue samples will result in the patient being considered ineligible.  
 
Where no previously resected or biopsied tumour tissue exists or is found to be of inadequate 
amount or quality, additional biopsy of the primary or metastatic tumour will be required for the 
patient to be considered eligible for the study. 
 
Samples will be used for research purposes only and will not be sold. Patients will not be identified 
by name. The only identification of tissue will be by a patient study number assigned at the time of 
registration to the trial the surgical/ histology number and/or patient initials. Material issued to 
researchers will be anonymized and only identified by a coded number. 
 
Testing specifically for hereditary genetic defects predisposing to malignant disease will not be 
carried out without the expressed consent of the patient. 
 
Detailed instructions for FFPE sample acquisition, preparation, and shipping are found in the PA.7 
Lab Manual. 
 
Planned priority assays on archival tumour tissue include: 
a. Immunohistochemistry for PD-L1 and CTLA-4 expression; 
b. Immunohistochemistry for tumour infiltrating lymphocytes (CD8+ T cells); 
c. Other exploratory analysis by IHC and/or flow cytometry for more detailed characterization of 
immune cell population subsets / additional immune markers (e.g. IDO, CD4, CD3, FOXP3); 
d. Immunohistochemistry for mismatch repair (MMR) proteins, SPARC and hENT1 expression; 
e. Immunohistochemistry for MCT4 to determine correlation with immune marker expression 
and prognosis; 
f. Tumour gene expression subtyping by RNA sequencing of laser capture microdissected biopsy 
tumour component; 
g. Gene expression analysis (NanoString nCounter gene expression system) of immune-related 
genes; 
h. Genomic instability measured by MSI assays or using SNP arrays. 
 
Directions: 
 
Within 4 weeks of randomization of the patient, an original tumour block should be sent to the 
CCTG Pathology Coordinator. Centres should contact the CCTG Study Coordinator and/or the 
Pathology Coordinator if they are unable to submit a tumour block, as sufficient tissue is required 
for the assays described below. 
 
 


 
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Complete the EDC Archival Tumour Tissue Submission Form. Print a copy of the completed form 
and ship tumour blocks/slides along with a Request for Payment form to: 
 
Shakeel Virk 
Pathology Coordinator Canadian Cancer Trials Group 
Richardson Labs Bldg, 4th Floor 
88 Stuart St. 
Queen’s University 
Kingston, ON  K7L 3N6 
Tel: 613-533-2906 / Fax: 613-548-2486 
Email: virks@queensu.ca 
 
12.2 
Week 8 On-treatment Biopsy (Optional) 
 
The collection of additional biopsy to tissue collection at 8 weeks after start of treatment is optional 
for sites. Participating sites should present the option of the additional to all patient for whom 
participation is also optional. 
 
Planned priority assays on biopsied tumour tissue include: 
a. Immunohistochemistry for PD-L1 and CTLA-4 expression 
b. Immunohistochemistry for tumour infiltrating lymphocytes (CD8+ T cells) 
c. Other exploratory analysis by IHC and/or flow cytometry for more detailed characterization of 
immune cell population subsets / additional immune markers (e.g. IDO, CD4, CD3, FOXP3) 
d. Immunohistochemistry for MMR, SPARC and hENT1 expression 
 
Detailed instructions for FFPE sample acquisition, preparation, and shipping are found in the PA.7 
Lab Manual. 
 
12.3 
Blood, Serum and Plasma Collection (Mandatory) 
 
The CCTG is interested in exploring the use of surrogate tissues such as serum and plasma in 
evaluating potential prognostic or predictive biomarkers. Blood, serum and plasma samples will be 
collected and banked for planned studies from all patients after randomization but before the first 
dose of study treatment, at 8 weeks after randomization and at progression (if not already done). 
 
Planned priority assays on blood, serum and plasma include: 
• 
Circulating tumour DNA; 
 
Detailed instructions for blood, serum and plasma sample acquisition, preparation, and shipping 
are found in the PA.7 Lab Manual. 
 
 


 
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12.4 
Optional Banking of Samples  
 
Banking of Tumour Tissue:  
 
Mandatory submission of tumour tissue has been described above. The subsequent banking of 
collected diagnostic tissue is not mandatory for participation in the study, but the participation of 
all centres is strongly encouraged. Blocks and blood will be carefully banked as part of the CCTG 
tissue/tumour bank at Queen’s University in Kingston, Ontario.  
 
After patient consent, collection of paraffin tumour blocks will preferred, as one of the objectives 
will be to create tissue micro arrays. These will optimize the amount of tissue available to 
investigators and permit the preservation of the tumour block submitted. If tumour blocks are 
unavailable, then two x 2 mm cores of tumour from the block and 30 specimen slides are preferred. 
If, at any time, the submitting hospital requires the block to be returned for medical or legal 
concerns, it will be returned by courier on request.  
 
Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval.  
 
Banking of Blood, Serum, and Plasma:  
 
Mandatory submission of whole blood, serum, and plasma has been described above. The 
subsequent banking of collected samples is not mandatory for participation in the study, but the 
participation of all centres is strongly encouraged. Samples will be carefully banked as part of the 
CCTG tissue/tumour bank at Queen’s University in Kingston, Ontario.  
 
Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval. 


 
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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Objectives and Design 
 
The primary objective of this phase II randomized study is to assess the effect of the addition of 
durvalumab + tremelimumab to standard 1st line chemotherapy with gemcitabine/nab-paclitaxel 
on the Overall Survival in patients with metastatic pancreatic cancer. Secondary objectives include 
assessments of Progression Free Survival, Objective Response Rate, and Adverse Events. 
 
Prior to starting the randomized component of the study, 10 additional patients will be accrued to 
Arm 2 (gemcitabine + nab-paclitaxel+ durvalumab + tremelimumab) in a safety run-in to evaluate 
the safety and tolerability of the combination. Provided that Arm 2 is deemed safe and tolerable 
after the review of data from the safety run-in, then after stratification by ECOG performance status 
(0 versus 1) and receipt of prior adjuvant therapy (yes versus no), patients will be randomized in a 
2:1 ratio to the following two arms: addition of durvalumab + tremelimumab to the standard 1st 
line chemotherapy with gemcitabine/nab-paclitaxel (Arm 2), and standard 1st line chemotherapy 
with gemcitabine + nab-paclitaxel (Arm 1). 
 
13.2 
Primary Endpoints and Analysis 
 
Overall Survival 
 
Overall Survival, the primary endpoint of this study, is defined as the time from randomization to 
death from any cause. Patients who are alive at the time of the final analysis or who have become 
lost to follow-up will be censored at their last date known to be alive. Patients will be analyzed in 
the arm to which they are randomized regardless of the treatment they received (intent-to-treat 
analysis). The survival experience of patients in three treatment groups will be summarized by the 
Kaplan-Meier method and compared primarily by a stratified log-rank test adjusting for the 
stratification variables (ECOG performance status and receipt of prior adjuvant therapy) at 
randomization. Secondary analyses based on stratified Cox proportional hazards model will also 
be performed. ECOG performance status (0 versus 1) and receipt of prior adjuvant therapy (yes 
versus no) will be the stratification factor to define the stratified Cox proportional hazards model. 
Besides the treatment factor (combination of durvalumab and tremelimumab + BSC versus BSC 
alone), the following factors at patient entry will be included in the stratified Cox proportional 
hazards model: 
• 
Age (< 65 versus ≥ 65); 
• 
Sex (male versus female); 
• 
Number of organ sites involved at baseline (≤ 2 versus > 2). 
 
A formal pre-planned subset analysis for the primary endpoint (OS) will be conducted to address 
the benefit of addition of durvalumab + tremelimumab to standard 1st line chemotherapy with 
gemcitabine/nab-paclitaxel between the groups defined by the above factors and the following: 
• 
ECOG Performance Status (0 versus 1); 
• 
Race (white, black, Asian, other). 


 
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Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the time from randomization to the first objective 
documentation of disease progression or death due to any cause. If a patient has not progressed or 
died at the time of final analysis, PFS will be censored on the date of the last tumour assessment. 
This includes patients who are lost to follow-up or have withdrawn consent. All analyses for OS 
will also be performed for PFS, using similar methodology. A sensitivity analysis of PFS will also 
be performed where PFS is defined as the time from randomization to the second documentation 
of unequivocal disease progression in those patients who continued study therapy beyond the first 
objective documentation of disease progression and with interim CR, PR or SD documented. 
 
Objective Response Rate 
 
Objective Response Rate (ORR) is defined as the proportion of patients with a documented 
complete response and partial response based on RECIST 1.1. The primary estimate of ORR will 
be based on all patients randomized. A Cochran-Mantel-Haenszel test adjusting for the 
stratification factor (ECOG performance status) at the time of randomization will be used as the 
primary method to compare the objective response rates. A sensitivity analysis of ORR will also 
be performed where response is defined as the proportion of patients with a documented complete 
response and partial response based on RECIST 1.1 and/or Immune-Related Response Criteria 
(irRECIST) . 
 
Safety Analysis 
 
All patients who have received at least one dose of protocol treatment will be included in the safety 
analysis. The incidence of adverse events will be summarized by type of adverse event and severity 
using the NCI Common Terminology Criteria for Adverse Events. A Fisher’s exact test will be 
used to compare adverse events between the two arms if required. 
 
13.3 
Sample Size and Duration of Study 
 
The 10 patients registered in the safety-run in will not be included in the overall sample size. 
 
The study is designed to have a power of 80% and a two-sided alpha of 10% to detect a 35% 
reduction in the continuous risk of death (HR 0.65, which corresponds to an increase of median 
survival from 8.5 to 13.1 months). It is estimated that 150 events will be required to detect this 
reduction. The final analysis will be performed when 150 events are observed. Assuming an 
average accrual rate of 10 patients per month, the required number of events would be observed by 
accruing a total of 180 patients and following them for an additional 17 months. The estimated total 
duration of the study would be 35 months. 
 
13.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators' meetings. 
 
13.5 
Interim Analysis 
 
No interim analysis will be performed. 


 
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14.0 
PUBLICATION POLICY 
 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
14.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group (CCTG) may be 
credited as authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
 
14.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
14.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following the analysis of study results the 
draft is not substantially complete, the central office reserves the right to make other arrangements 
to ensure timely publication. 
 
14.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by the CCTG 
Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair. 
Individual participating centres may not present outcome results from their own centres separately. 
Supporting groups and agencies will be acknowledged. 


 
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15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
15.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
15.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion. 
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs. 
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately. 
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs. 
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable). 
 
Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation. 


 
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15.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in a CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study. 
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial. 
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject. 
 
15.3.1 Obtaining Consent for Pregnancy 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them. If the 
main consent form adequately addresses the collection of information regarding the outcome of a 
pregnancy of a trial participant, a “Pregnancy Follow-up consent form will not be required by 
CCTG. 
 
Trial-specific consent forms for “Pregnancy Follow-up” can be found on the trial webpage. The 
appropriate consent form must be used to obtain consent from any non-trial participant (such as the 
pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy. Similarly, male participants will not be 
withdrawn from the main study should their partner refuse/withdraw permission. 


 
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Obtaining Consent for Research on Children 
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/guardian. 
 
15.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at anytime by the centre (prior to closure of the trial by the CCTG), it is 
the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why. 
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
15.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP. 
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site. 
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CCTG that documents no longer need to be retained. 
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access. 
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained. 
 
15.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI). 
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 


 
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15.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
AstraZeneca has reserved the right to audit participating centres. Audits may only be conducted 
after consultation with CCTG. 
 
15.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For 
details of accessing the EDC system and completing the on-line Case Report Forms please refer to 
the “Registration/Randomization and Data Management Guidebook” posted on the PA.7 area of 
the CCTG web-site (http://www.ctg.queensu.ca/trials/gi/PA7/PA7.html). 


 
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AMEND #2: 2018-MAR-20 
16.0 
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Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, Yao S, Tsushima F, Narazaki H, 
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Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line 
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Seymour L, Bogaerts J, Perrone A et al. iRECIST: Guidelines for response criteria for use in trials testing 
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Stewart RA, Morrow M, Chodorge M et al. Abstract LB-158. MEDI4736: Delivering effective blockade of 
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Thompson RH, Webster WS, Cheville JC, Lohse CM, Dong H, Leibovich BC, Kuntz SM, Sengupta S, Kwon 
ED, Blute ML. B7-H1 glycoprotein blockade: A novel strategy to enhance immunotherapy in patients with renal 
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Thompson RH, Kwon ED. Significance of B7-H1 Overexpression in Kidney Cancer. Clinical Genitourinary 
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Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab 
in advanced melanoma. N Engl J Med 2013;369(2):122-33. 
Venook AP, Egorin MJ, Rosner GL, et al. Phase I and pharmacokinetic trial of gemcitabine in patients with 
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2008; 8.6:467-477. 


 
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APPENDIX I - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 


 
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APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Details of Drug Distribution, Supply and Control/Accountability are provided in the PA.7 Drug Supply 
Manual, available on the PA.7 website (http://www.ctg.queensu.ca/trials/gi/PA7/PA7.html). 
 
Distribution 
 
Durvalumab and tremelimumab will be supplied by AstraZeneca to the distributor, Bay Area Research 
Logistics (BARL), and distributed by BARL to participating centres in Canada. 
 
Nab-paclitaxel and Gemcitabine are commercially available and will not be supplied. 
 
Initial Supply 
 
BARL will ship durvalumab and tremelimumab directly to the site pharmacy. Sites should follow 
instruction RE initial supply in the PA.7 Drug Supply Manual. Sites should allow 5 working days for initial 
drug shipments to arrive. 
 
Resupply 
For re-supply of durvalumab and tremelimumab, sites should follow instruction in the PA.7 Drug Supply 
Manual. Sites should allow 5 working days for re-supply shipments to arrive. 
 
Drug Accountability 
 
The investigational products are to be prescribed only by the Qualified Investigator or Sub-Investigators 
having this delegated duty on the participants list. Under no circumstances will the investigator allow the 
drug to be used other than as directed by the protocol. Accurate records must be maintained accounting for 
the receipt, dispensation, return and/or destruction of the investigational product and for the disposition of 
the 
product 
(Drug 
Accountability 
Log, 
available 
on 
the 
PA.7 
website 
(http://www.ctg.queensu.ca/trials/gi/PA7/PA7.html). At the end of the study, it must be possible to 
reconcile shipment records with records of usage/returned stock by completion of the study drug 
accountability form. Any discrepancies must be accounted for and documented. 
 
Drug Destruction of Expired Medication 
 
The CCTG Study Coordinator must be contacted prior to destruction of expired medication to ensure an 
extension of expiry date is not expected. Expired trial medication may be destroyed per local policy, AFTER 
accountability and reconciliation has been completed and documented by the site. Documentation of 
destruction must be kept on file in the site pharmacy and is subject to on site monitoring/audit.  
 
Drug Destruction of Unused Medication (End of Trial) 
Instructions for return or destruction of unused drug will be supplied at the time of expiry and at trial closure. 
 
** PLEASE NOTE ** 
DRUG FROM THIS SUPPLY IS TO BE USED 
ONLY FOR PATIENTS REGISTERED ON THIS STUDY 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a satellite 
pharmacy, provided separate drug accountability records are maintained in each pharmacy and appropriate 
storage is available. Investigational agent may NOT however, be transferred to pharmacies or physicians 
outside the participating centre. 


 
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APPENDIX III - DOSING MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED AND NON IMMUNE-MEDIATED REACTIONS  
(MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or Tremelimumab Monotherapy) 1Nov2017 Version 
 
The Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion Related 
and Non Immune-Mediated Reactions can be downloaded at: 
 
https://www.ctg.queensu.ca/docs/trials/generic_forms/DoseMod-ToxMngmtGuidelines/DoseMod-
ToxicityMgmntGuidelines_01Nov2017.pdf 


 
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APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of randomization and will apply to all eligible patients. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For details of 
accessing the EDC system and completing the on-line Case Report Forms please refer to the “CCTG EDC 
Generic Data Management Guidebook” posted on the tool box area of the CCTG web-site 
(www.ctg.queensu.ca). 
 
The ELECTRONIC CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Required at 
To be completed electronically 
Supporting Documentation Required1 
Eligibility Checklist 
Prior to 
randomization 
At the time of randomization 
Consent form2 
Pathology/cytology report(s) 
Operative report(s) 
Radiology reports (including CT 
chest/abdomen/pelvis) 
Tumour Measurement Worksheet 
Baseline Report 
At the time of 
randomization 
Within 2 week of randomization 
Correlative Studies 
Report 
(Tumour and Blood) 
Continuous running-
log folder 
 
See Sections 6.0 and 
12.0 
Information pertaining to tumour tissue 
submission must be completed as soon 
as possible after randomization, and 
tissue submitted within 4 weeks of 
randomization 
Information pertaining to 
baseline/pretreatment (i.e. tumour 
specimen information and blood collection 
for correlative studies) must be completed 
within 2 weeks of randomization. 
Information pertaining to post 
randomization blood collection 
samples (i.e. whole blood, plasma, and 
serum) for correlative studies and banking 
should be completed within 2 weeks after 
collection of final blood specimen. 
Information pertaining to the optional 
tumour biopsy (at 8 weeks, for 
consenting patients) must be completed 
as soon as possible at tissue submitted 
within 4 weeks of biopsy. 
Consent form2 
Diagnostic pathology report (for 
tumour tissue only) 
Concomitant 
Medication Report 
Continuous running-
log folder 
 
 
Treatment Report 
Every cycle (28 
days) while patient is 
on protocol treatment 
Within 2 weeks of the end of each cycle 
If applicable: 
CT chest/abdomen/pelvis report(s) 
Other radiology reports 
Tumour Measurement Worksheet 
ECG report  
End of Treatment 
Report 
To be completed 
once when the 
patient goes off all 
protocol treatment 
permanently 
Within 2 weeks of the end of treatment 
 
Post Treatment 
Follow-up Report 
To be completed 
once on all patients, 
4 weeks post-
protocol treatment 
discontinuation 
Within 2 weeks of the 4 week post-
treatment visit 
If applicable: 
CT chest/abdomen/pelvis report(s) 
Other radiology reports 
Tumour Measurement Worksheet 
 
table continued on next page ... 
 
 


 
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Electronic Folder 
Required at 
To be completed electronically 
Supporting Documentation Required1 
Follow-up Report 
Every 3 months after 
the 4-week post-
treatment visit, until 
PD 
Within 2 weeks of follow-up visit 
CT chest/abdomen/pelvis report(s) 
Other radiology reports 
Tumour Measurement Worksheet 
Relapse/Progression 
Report 
Upon the patient’s 
objective disease 
progression 
Within 4 weeks of disease progression 
Relevant radiology, operative and 
pathology reports 
Short Follow-up 
Report 
Every 3 months after 
the 4-week post-
treatment visit, after 
PD 
Within 2 weeks of follow-up visit 
 
Death Report 
When patient dies 
Within 4 weeks of patient’s death 
Autopsy/post-mortem report, if done 
SAE Report3 
At the time of the 
event 
Within 1 working day3 
 
1 
Please scan and upload all required source documentation into the EDC Supporting Document Upload Tool. Ensure the 
patient’s identifiers (e.g. name) are blacked-out on all source documentation. 
2 
For Canadian centres, it is acceptable to submit only the signature page(s) of the main consent and only the check box 
page(s)/signature page(s) of the optional consent provided that the version date of the consent form is indicated. 
3 
See section 11.0 Serious Adverse Event Reporting for details. 
 


 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


 
PROTOCOL DATE: 2016-JUL-20 
 
CCTG TRIAL: PA.7 
 
 
CONFIDENTIAL 
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CONFIDENTIAL 
APPENDIX VI - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as 
a guide for the administration of the Quality of Life questionnaire. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must 
be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization or pre-registration (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 


 
PROTOCOL DATE: 2016-JUL-20 
 
CCTG TRIAL: PA.7 
 
 
CONFIDENTIAL 
79 
CONFIDENTIAL 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient 
does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, s/he should still complete the questionnaire prior to 
treatment. 
 
4. Assessments During Follow-up 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel 
unwell. In that case, you may express sympathy that things are below par, but state that this 
is exactly the information we require if we are to understand more about how quality of 
life is affected. You may also remind them that it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better! 
 
5. What If . . . 
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient. 


 
PROTOCOL DATE: 2016-JUL-20 
 
CCTG TRIAL: PA.7 
 
 
CONFIDENTIAL 
80 
CONFIDENTIAL 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over 
the phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 
 
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible. 
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and 
failing to comply with the patient's wishes is likely to result in the questionnaire not being completed 
at all, then the patient may take the questionnaire home with instructions that it is to be completed the 
same day. When the questionnaire is returned, the date on which the questionnaire was completed 
should be noted and a comment made on the questionnaire as to why the patient took it away from the 
clinic before completion. 
 
6. Waiving the Quality of Life Component 
 
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he 
cannot comprehend either English or French (or other languages that the questionnaire may be available 
in). In other words, if the assistance of a translator is required to comprehend the questions and reply, 
the questionnaires should not be completed. Translation of the questions is not acceptable. Please 
indicate on questionnaire. 
 
7. Unwillingness to Complete Quality of Life Questionnaire 
 
If a patient speaks and reads English or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should 
NOT be put on study. 
 


 
PROTOCOL DATE: 2016-JUL-20 
 
CCTG TRIAL: PA.7 
 
 
CONFIDENTIAL 
81 
CONFIDENTIAL 
8. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire 
should be read to them and the answers recorded by a health care professional (e.g. preferably the 
clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who 
is familiar with the instructions for administering the questionnaires would be acceptable). If the patient 
is completing the questionnaire at home, and a telephone interview by the clinical research associate is 
not possible, then a spouse or friend may read the questions to the patient and record the answers. 
However, this method should be a last resort, and the spouse or friend should be instructed to not coach 
or suggest answers to the patient. Whichever method is used, it should be recorded on the questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 


 
 
Quality of Life Questionnaire – ENGLISH 
 
CCTG Trial: PA.7 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to randomization (with 14 days prior to randomization) 
During protocol treatment: 
 4 weeks      8 weeks      12 weeks      16 weeks      24 weeks 
Then every 3 months until PD or the initiation of another chemotherapy treatment 
 3 months      6 months      9 months      12 months      15 months      18 months      21 months 
 24 months      ___ months 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home    clinic    another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed: __ __ __ __ - __ __ __ - __ __ 
 
       yyyy           mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 


This box to be completed by the clinical research associate:   Pt. Serial #: _____________   Pt. Initials: ____ ____ ____ 
 
CCTG Trial PA.7 
Page 1 of 3 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (PA.7) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:   Pt. Serial #: _____________   Pt. Initials: ____ ____ ____ 
 
CCTG Trial PA.7. EORTC QLQ-C30 
Page 2 of 3 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:   Pt. Serial #: _____________   Pt. Initials: ____ ____ ____ 
 
CCTG Trial PA.7. EORTC QLQ-C30 
Page 3 of 3 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
 
Please check to make sure you have answered all the questions. 
 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
 
Today's date (Year, Month, Day): ________________________________ 
 
 
Thank you. 
 
 


 
PROTOCOL DATE: 2016-JUL-20 
 
CCTG TRIAL: PA.7 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
AMEND #2: 2018-MAR-20 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
ELIGIBILITY CHECKLIST 
Must be completed prior to 
allocation. 
Julia Baran or Vicki Classen 
Clinical Trials Assistants, CCTG 
Email: 
jbaran@ctg.queensu.ca 
vclassen@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Barbara Graham or 
Lisa Gallinaro 
Study Coordinators, CCTG 
Email: 
bgraham@ctg.queensu.ca 
lgallinaro@ctg.queensu.ca 
or: 
Dr. Chris O’Callaghan 
Senior Investigator, CCTG 
Email: 
cocallaghan@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr.Dan Renouf 
Study Chair 
Email: drenouf@bccancer.bc.ca 
 
 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for 
details of reportable events. 
Dr. Chris O’Callaghan 
Senior Investigator, CCTG 
or: 
Barbara Graham 
Study Coordinator, CCTG 
613-533-6430 
613-533-2941 
DRUG ORDERING 
See Appendix II for full details. 
See Appendix II and trial website: 
http://www.ctg.queensu.ca/trials/gi/PA7/PA7.html 
for details and contact information 
ELECTRONIC DATA 
CAPTURE (EDC) AND RIPPLE 
(technical support) 
CCTG Home Page (Toolbox): 
https://scooby.ctg.queensu.ca 
Email Support Staff at: support@ctg.queensu.ca 
 

SAP_001.pdf: 
PA7_SAP_draft.docx 
1 
 
STATISTICAL ANALYSIS PLAN  
 
A RANDOMIZED PHASE II TRIAL OF GEMCITABINE AND NAB-
PACLITAXEL VS. GEMCITABINE, NAB-PACLITAXEL, DURVALUMAB 
AND TREMELIMUMAB AS 1ST LINE THERAPY IN METASTATIC 
PANCREATIC ADENOCARCINOMA  
 
 
Protocol CCTG PA.7 
 
Prepared by: 
Signature 
Date 
 
CCTG/Queen’s Statistician              
 
 
            
 
 
 
 
 
Dongsheng Tu 
 
 
 
Reviewed by:  
 
 
Signature 
 
 
Date 
 
CCTG/Queen’s 
Senior Investigator       
 
 
 
 
            
 
 
 
 
 
 
 
Chris O’Callaghan 
 
 
 
August 9, 2019 
 


PA7_SAP_draft.docx 
2 
ABBREVIATIONS 
 
AE 
 
Adverse Event 
ALP 
 
Alkaline phosphatase 
ALT 
 
Alanine Aminotransferase 
AST 
 
Serum Glutamic Oxaloacetic Transaminase  
BSA 
 
Body Surface Area 
BUN  
Blood urea nitrogen 
CCTG  
Canadian Cancer Trials Group  
C. I. 
 
Confidence Interval 
CMH  
Cochran-Mantel-Haenszel 
CR 
 
Complete Response 
CRF 
 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
DSMC  
Data and Safety Monitoring Committee 
ECOG  
Eastern Cooperative Cancer Group 
ECG  
Electrocardiography 
EORTC 
European Organization for Research and Treatment of Cancer  
G+N  
Gemcitabine and nab-paclitaxel 
G+N+D+T 
Gemcitabine and nab-paclitaxel with durvalumab and tremelimumab 
iCPD  
Immune confirmed progression disease 
iCR 
 
Immune complete response 
IN 
 
Inevaluable 
INR 
 
International Normalized Ratio (for Prothrombin Time) 
iPR 
 
Immune partial response 
irAE 
 
Immune Related Adverse Event 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
iSD 
 
Immune stable disease 
iUPD  
Immune unconfirmed progression disease 
LDH  
Serum Lactate Dehydrogenase 
LKA  
Last day the patient is Known Alive 
LLN 
 
Lower Limit of Normal 
MPV  
Major Protocol Violation 
NA 
 
Not Assessed 
NC 
 
Not Computed 
ORR  
Objective Response Rate 
OS 
 
Overall Survival 
PD 
 
Progression Disease 
PD1 
 
Programmed cell death protein 1 
PD-L1  
Programmed cell death ligand 1 
PFS 
 
Progression-free survival 
PR 
 
Partial Response 
PT 
 
Prothrombin Time 
PTT 
 
Partial Thromboplastin Time 
QLQ  
Quality of Life Questionnaire  
QOL  
Quality of Life 


PA7_SAP_draft.docx 
3 
RBC  
Red Blood Cell Count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAS 
 
Statistical Analysis System 
SD 
 
Stable Disease 
STD 
 
Standard Deviation 
WBC  
White Blood Cell Count 
 


PA7_SAP_draft.docx 
4 
TABLE OF CONTENTS 
 
1. 
Background and Rationale _______________________________________ 7 
2. 
Study Description _______________________________________________ 7 
2.1 
Study Design ______________________________________________________ 7 
2.2 
Treatment Allocation _______________________________________________ 8 
3. 
Objectives _____________________________________________________ 9 
3.1 
Primary___________________________________________________________ 9 
3.2 
Secondary _________________________________________________________ 9 
4. 
Endpoints _____________________________________________________ 9 
4.1 
Primary Efficacy ___________________________________________________ 9 
4.2 
Secondary Efficacy _________________________________________________ 9 
4.3 
Safety ____________________________________________________________ 9 
5. 
Sample Size and Power __________________________________________ 9 
6. 
Data Set Descriptions ____________________________________________ 9 
7. 
Statistical Analysis _____________________________________________ 10 
7.1 
General Methods __________________________________________________ 10 
7.2 
Data Conventions _________________________________________________ 11 
7.3 
Study Conduct ____________________________________________________ 11 
7.3.1 
Patient Disposition ____________________________________________________ 11 
7.3.2 
Accrual Patterns ______________________________________________________ 11 
7.3.3 
Eligibility Violations/Protocol Deviations __________________________________ 11 
7.4 
Study Population __________________________________________________ 12 
7.4.1 
Patient Pretreatment Characteristics _______________________________________ 12 
7.4.2 
Prior Surgery ________________________________________________________ 12 
7.4.3 
Prior Radiotherapy ____________________________________________________ 12 
7.4.4 
Prior Systemic Therapy ________________________________________________ 12 
7.4.5 
Extent of Disease _____________________________________________________ 12 
7.4.6 
Baseline Exams ______________________________________________________ 13 
7.4.7 
Concomitant Medications and Major Medical Problems at Baseline ______________ 13 
7.5 
Extent of Exposure ________________________________________________ 13 
7.5.1 
Study Therapy _______________________________________________________ 13 
7.5.2 
Dose Reduction, Omission, Discontinuation, or IV Rate Decrease or Infusion 
Interruption __________________________________________________________________ 14 
7.5.3 
Cumulative Dose, Dose Intensity and Relative Dose Intensity __________________ 14 
7.5.4 
Off Study Therapy ____________________________________________________ 14 
7.6 
Efficacy __________________________________________________________ 15 
7.6.1 
Overall survival ______________________________________________________ 15 
7.6.2 
Overall Survival by Subsets _____________________________________________ 16 
7.6.3 
Progression-free Survival _______________________________________________ 16 
7.6.4 
Progression-free survival by Subsets ______________________________________ 17 
7.6.5 
Treatment Objective Response ___________________________________________ 17 
7.6.6 
Treatment Objective Response by Subsets __________________________________ 17 


PA7_SAP_draft.docx 
5 
7.6.7 
Duration of Objective Response __________________________________________ 18 
7.6.8 
Treatment Immune Response (iRECIST) ___________________________________ 18 
7.7 
Safety ___________________________________________________________ 18 
7.7.1 
Adverse Events _______________________________________________________ 18 
7.7.2 
Laboratory Evaluations ________________________________________________ 19 
7.7.2.1 
Hematology _______________________________________________________ 19 
7.7.2.2 
Serum Chemistry ___________________________________________________ 19 
7.7.2.3 
Thyroid Function Tests _______________________________________________ 20 
7.7.2.3 
Coagulation________________________________________________________ 20 
7.7.3 
Other Safety _________________________________________________________ 20 
7.7.3.1 
ECG _____________________________________________________________ 20 
7.7.3.2 
Urinalysis _________________________________________________________ 20 
7.7.4 
Deaths on Study/Adverse Events Leading to Discontinuations of Protocol Treatment 20 
7.8 
Concomitant Medications, Other Anti-Cancer Treatments, and Major Medical 
Problems ______________________________________________________________ 20 
7.9 
Quality of Life ____________________________________________________ 21 
7.9.1 
EORTC QLQ-C30 ____________________________________________________ 21 
7.9.2 
Data Sets ____________________________________________________________ 22 
7.9.3 
Compliance __________________________________________________________ 22 
7.9.4 
Primary Analyses of QOL ______________________________________________ 22 
7.9.5 
Baseline and Change Score Analysis ______________________________________ 22 
7.9.6 
QOL Response Analysis ________________________________________________ 23 
8. 
Appendices ___________________________________________________ 24 
Appendix 1: Tables and Figure __________________________________________________ 24 
 
Tables 
 
Table 1:  Patient Disposition ..................................................................................................................24 
Table 2:  Follow-up of Patients ..............................................................................................................24 
Table 3:  Accrual by Center ...................................................................................................................25 
Table 4:  Accrual by Stratification Factor at Randomization ................................................................25 
Table 5:  Eligibility and Reasons for Ineligibility and Major Protocol Violations ................................26 
Table 6:  Treatment as Randomized Versus as Treated .........................................................................26 
Table 7:  Pretreatment Characteristics at Baseline ...............................................................................27 
Table 8:  Prior Surgery ..........................................................................................................................28 
Table 9:  Prior Radiotherapy .................................................................................................................28 
Table 10:  Prior Systemic Therapy .........................................................................................................28 
Table 11:  Extent of Disease (Target Lesions) .......................................................................................29 
Table 12:  Extent of Disease (Non-Target Lesions) ...............................................................................30 
Table 13:  Baseline Signs and Symptoms ...............................................................................................30 
Table 14:  Baseline Hematology ............................................................................................................31 
Table 15:  Baseline Chemistry ...............................................................................................................32 
Table 16:  Baseline Thyroid Function Tests ...........................................................................................35 
Table 17:  Baseline Coagulation Tests ...................................................................................................35 
Table 18:  Baseline ECG ........................................................................................................................36 
Table 19 : Baseline Urinalysis ...............................................................................................................36 
Table 20:  Concomitant Medications at Baseline...................................................................................37 
Table 21:  Major Medical Problems at Baseline ...................................................................................37 
Table 22:  Number of Patients by Cycle .................................................................................................38 
Table 23:  Number of Cycles of Protocol Therapy per Patient ..............................................................38 
Table 24:  Total Treatment Duration .....................................................................................................38 
Table 25:  Dose Reduction, Omission or Delay and Infusion Interruption ............................................39 
Table 26:  Cumulative Dose ...................................................................................................................40 


PA7_SAP_draft.docx 
6 
Table 27:  Dose Intensity........................................................................................................................40 
Table 28:  Relative Dose Intensity..........................................................................................................40 
Table 29:  Off Treatment Summary ........................................................................................................41 
Table 30:  All Deaths .............................................................................................................................42 
Table 31:  Log Rank and Cox Regression Model for Overall Survival ..................................................43 
Table 32:  Survival by Subsets ...............................................................................................................43 
Table 33:  Progression Summary ...........................................................................................................44 
Table 34:  Log Rank and Cox Regression Model for Progression Free Survival (PFS) ........................45 
Table 35:  Progression Free Survival (PFS) by Subsets ........................................................................46 
Table 36:  Treatment Objective Response ..............................................................................................47 
Table 37:  Cochran Mantel Haenszel and Logistic Regression Model for Objective Response ............48 
Table 38:  Objective Response According to Pretreatment Characteristics ..........................................49 
Table 39:  Duration of Objective Response............................................................................................49 
Table 40:  Immune Response (iRECIST) ................................................................................................50 
Table 41:  Cochran Mantel Haenszel and Logistic Regression Model for Immune Response ...............51 
Table 42:  Immune Response According to Pretreatment Characteristics .............................................52 
Table 43:  Duration of Immune Response ..............................................................................................52 
Table 44:  Acute (On Treatment) Adverse Events ..................................................................................53 
Table 45: Severe Acute (On Treatment) Adverse Events ........................................................................53 
Table 46: Drug Related Acute (on Treatment) Adverse Events ..............................................................54 
Table 47:  Immune-related Acute (On Treatment) Adverse Events ........................................................57 
Table 48: Severe Acute (On Treatment) Immune-related Adverse Events .............................................57 
Table 49:  Delayed (During Follow-up) Adverse Events .......................................................................58 
Table 50:  Hematology During Protocol Treatment: Worst Grade per Patient .....................................59 
Table 51:  Hematology During Follow-up: Worst Grade per Patient ...................................................60 
Table 52:  Serum Chemistry during Protocol Treatment:  Worst Grade per Patient.............................61 
Table 53:  Serum Chemistry During Follow-up:  Worst Grade per Patient ..........................................64 
Table 54:  Thyroid Function Tests: Worst During Protocol Treatment .................................................67 
Table 55:  Thyroid Function Tests: Worst during Follow-up ................................................................68 
Table 56: Coagulation Tests: Worst During Protocol Treatment ..........................................................69 
Table 57:  Coagulation Tests: Worst During Follow-up ........................................................................69 
Table 58:  ECG Results During Protocol Treatment .............................................................................70 
Table 59 : Urinalysis During Protocol Treatment .................................................................................70 
Table 60:  Deaths During or within 4 weeks of Last Protocol Treatment ..............................................70 
Table 61:  Adverse Event leading to Discontinuation of protocol Treatment(a) .....................................71 
Table 62:  Concomitant Medications .....................................................................................................71 
Table 63:   Anti-Cancer Treatment ........................................................................................................72 
Table 64:  Major Medical Problems ......................................................................................................72 
Table 65: Compliance Rate with QoL Assessment by Treatment Arm ...................................................73 
Table 66: Proportion of Patients with Deterioration, Improvement or Stable QoL ...............................73 
Table 67:  Time to Deterioration in QoL Primary Endpoints ................................................................74 
Table 68: QoL: Summary Baseline Scores .............................................................................................74 
Table 69: Summary QOL Change Scores from Baseline for Scale/Domain/Item at Each Time Period*
 ................................................................................................................................................................75 
Table 70: Results for QOL Response Analyses ......................................................................................76 
 
Figures 
Figure 1:  Accrual by Calendar Time ....................................................................................................25 
Figure 2:  Kaplan-Meier Curves for Overall Survival ...........................................................................42 
Figure 3:  Kaplan-Meier Curves for Progression Free Survival ...........................................................44 
 


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7 
1. 
Background and Rationale 
The purpose of this document is to describe the analysis of PA.7 for the writing of a 
Canadian Cancer Trials Group (CCTG) study report on this study.  The data are 
collected and cleaned by CCTG. All analyses will be performed by a senior 
biostatistician in CCTG and a final statistical analysis report will be prepared.  A copy 
of this report will be sent to the study chair for the writing of the manuscript and to 
AstraZeneca.   
Rationale of the Study: 
Programmed cell death ligand 1 (PD-L1), the ligand for programmed cell death protein 
1 (PD1),  is part of a complex system of receptors and ligands that are involved in 
controlling T-cell activation, which acts at multiple sites in the body to help regulate 
normal immune responses and is utilized by tumours to help evade detection and 
elimination by the host immune system. In a number of cancers including pancreatic 
cancer, overexpression of PD-L1 is associated with reduced survival and unfavourable 
prognosis. Clinically, blockade of the PD-1 inhibitory checkpoint pathway by 
inhibiting PD-L1/PD-1 engagement has been shown to induce tumour regression across 
many cancer types, including melanoma and renal cell, colon and lung cancers. CTLA-
4 is another co-inhibitory receptor expressed on activated T cells and regulates early 
stage T cell activation, reducing the amplitude of T-cell activation. Targeting both PD-
1 and CTLA-4 pathways may have additive or synergistic activity because the 
mechanisms of action of CTLA-4 and PD-1 are non-redundant. This study was 
designed to evaluate whether combining PD-1/PD-L1 and CTLA-4 inhibition with 
durvalumab and tremelimumab will lead additional benefits to standard 1st line 
chemotherapy with gemcitabine/nab-paclitaxel in metastatic pancreatic cancer. 
Research Hypothesis: 
The primary hypothesis in this study is that durvalumab and tremelimumab combined 
with standard 1st line chemotherapy with gemcitabine/nab-paclitaxel (Arm 
G+N+D+T) will have a greater clinical efficacy compared to standard 1st line 
chemotherapy with gemcitabine/nab-paclitaxel  (Arm G+N) in patients with metastatic 
pancreatic cancer as measured by overall survival. 
Schedule of Analyses: 
Only one analysis will be performed, when 150 events (deaths) have been observed. 
2. 
Study Description 
2.1 
Study Design 
PA.7 is an open-label, randomized, non-blinded, phase II clinical study of 
durvalumab+tremelimumab in combination with gemcitabine and nab-paclitaxel (Arm 
G+N+D+T) versus gemcitabine and nab-paclitaxel (Arm G+N) in patients with newly 
diagnosed, untreated, metastatic pancreatic adenocarcinoma. Prior to the randomized 
component, 10 patients would first be accrued to ensure safety and tolerability of the 
combination.  After the safety profile of these patients was assessed, 180 patients would 
be randomized in a 2:1 ratio to Arm G+N+D+T or G+N after stratification by ECOG 


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8 
performance status (0 vs. 1) and receipt of prior adjuvant therapy (yes versus no).  
Overall survival (OS) was the primary endpoint of this study. The study was conducted 
by the Canadian Cancer Trials Group (CCTG), with the support of AstraZeneca.  
CCTG Case Report Forms (CRFs) are used and the database are maintained by CCTG.   
This study opened to accrue patients on August 22, 2016. Accrual to safety run-in 
component of the study was completed on January 23, 2017 with a total of 11 patients 
enrolled.  The first analysis of the run-in patients was performed in March 2017 when 
all of the patients completed at least one cycle of treatment and, after the review of the 
results, accrual to randomized Phase II component was opened on April 10, 2017. With 
permission from the DSMC, an analysis was performed in the middle of January 2018 
on a database locked on January 12, 2018 to generate tables and figures for the internal 
planning of AstraZeneca. The results of this analysis were also presented to DSMC at 
beginning of February 2018 with a proposal to transition the trial to phase III by CCTG. 
After reviewing the results, DSMC Chair recommended to continue the phase II trial 
as currently designed and place the transition “on hold”. This recommendation was 
affirmed by DSMC after reviewing an updated analysis at their 2018 Annual Spring 
Meeting in April 2018.  The accrual of the trial was closed on July 28, 2018 after its 
accrual goal of 180 patients has been achieved.  At its Fall Teleconference in November 
2018, the DSMC reviewed a request by the trial team to support an unplanned interim 
analysis based on the endpoint of overall survival when 100 deaths had occurred for 
the purpose of informing a potential phase III study design. After reviewing the 
response to questions raised during the review, this request was approved by the DSMC 
on March 18, 2019. The analysis was performed at end of April 2019 on a database 
locked on April 12, 2019 after all deaths observed before April 8, 2019 were reviewed. 
DSMC recommended the trial continue on to its final analysis as planned after 
reviewing the results of this analysis at its meeting on May 3, 2019. This analysis plan 
describes the analyses performed for the final analysis planned when 180 events are 
observed. 
The CCTG Data Safety Monitoring Committee has been reviewing safety data every 
six months (usually at the time of the bi-annual  CCTG Spring and Fall meetings) and 
as otherwise required.  These analyses have been prepared by a CCTG/Queen’s Senior 
Biostatistician.  
2.2 
Treatment Allocation 
The study is planned to randomize 180 subjects using a 2:1 allocation to durvalumab 
and tremelimumab in combination with gemcitabine and nab-paclitaxel (G+N+D+T 
Arm) and gemcitabine and nab-paclitaxel alone (G+N Arm). The randomization was 
dynamically balanced by ECOG performance status (0 vs. 1) and receipt of prior 
adjuvant therapy (yes versus no) using the method of minimization.  A centralized 
system was used to randomize all patients in this study. 
 
 


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9 
3. 
Objectives 
3.1 
Primary 
The primary objective of this study is to compare overall survival of patients with 
metastatic pancreatic cancer treated with durvalumab and tremelimumab combined 
with gemcitabine and nab-paclitaxel to the overall survival of patients treated with 
gemcitabine and nab-paclitaxel  alone. 
3.2 
Secondary 
Secondary objectives are to: 
• Compare progression-free survival (PFS) between the two treatment arms. 
• Compare objective response rates (ORR) between the two treatment arms. 
• Assess the toxicity and safety profile of the combination of durvalumab and 
tremelimumab with gemcitabine and nab-paclitaxel .  
4. 
Endpoints 
4.1 
Primary Efficacy 
The primary efficacy endpoint is overall survival.  
4.2 
Secondary Efficacy 
The secondary efficacy endpoints are progression-free survival and objective response 
rate. 
4.3 
Safety 
The safety endpoints are serious and non-serious adverse events (clinical and 
laboratory),  laboratory parameters, dosing data (including dose interruptions, total 
delivered dose and dose modifications) and reasons off treatment.  
5. 
Sample Size and Power 
The primary objective of this study is to assess the additional effect of durvalumab and 
tremelimumab to gemcitabine and nab-paclitaxel by comparing overall survival (OS) 
between G+N+D+T and G+N Arms among all randomized patients.  It was calculated 
that with a 2-sided alpha of 10%, a total of 180 patients with 150 events (deaths) would 
be required to provide 80% power to detect a 4.6 month difference in median survival 
(a hazard ratio of 0.65) between the two treatment arms assuming a median survival of 
8.5 months for the gemcitabine and nab-paclitaxel alone arm.  The final analysis will 
be conducted after at least 150 events have been recorded.  It is estimated that 180 
patients accrued over 18 months and followed for 17 months will be required to reach 
the necessary number of events.   
6. 
Data Set Descriptions 
Three types of analysis samples will be used: 
 


PA7_SAP_draft.docx 
10 
All Randomized Patients: 
All patients who have been randomized in the study with the treatment arm being as 
randomized. 
 
Response-Evaluable Patients: 
All patients who have received at least one cycle of therapy and have their disease re-
evaluated will be considered evaluable for response (exceptions will be those who 
exhibit objective disease progression prior to the end of cycle 1 who will also be 
considered evaluable). 
 
All Treated Patients: 
All patients who received at least one dose of protocol treatment.  Patients randomized 
to G+N Arm who have received at least one dose of durvalumab and tremelimumab on 
study (from Cancer Treatment Section of Treatment Report) will be grouped with 
patients randomized to G+N+D+T in the analyses of safety. 
7. 
Statistical Analysis 
7.1 
General Methods 
All comparisons between treatment arms will be carried out using a two-sided test at 
an alpha level of 10% unless otherwise specified.   
 
When appropriate, discrete variables are summarized with the number and proportion 
of subjects falling into each category, and compared using Fisher’s exact test. 
Continuous and ordinal categorical variables are summarized using the mean, median, 
standard error, minimum and maximum values and when appropriate, compared using 
the Wilcoxon test. All confidence intervals are computed based on normal 
approximations except those for rates, which will be computed based on the exact 
method. 
 
Time to event variables are summarized using Kaplan-Meier plots.  Primary 
comparisons of the treatment groups are made using the stratified log-rank test.  
Primary estimates of the treatment differences are obtained with the hazard ratios and 
90% confidence intervals from stratified Cox regression models using treatment arm 
as the single factor.  
 
Percentages given in the summary tables will be rounded and may therefore not always 
add up to exactly 100%.  Listings, tabulations, and statistical analyses will be carried 
out using the SAS (Statistical Analysis System, SAS Institute, North Carolina, USA) 
software. 
 
Unless otherwise specified, date of randomization and stratification factors will be 
taken from the Centralized Randomization File. 
 
Baseline evaluations will be those collected on Eligibility Checklist and Baseline 
Report and closest to, but no later than, the first day of study medication for treated 


PA7_SAP_draft.docx 
11 
subjects and closest to, but no later than, the date of randomization, for subjects who 
were randomized but who never received treatment. 
 
Laboratory results, adverse events, and other symptoms are coded and graded using the 
Common Terminology Criteria for Adverse Events (CTCAE v4.0).  
7.2 
Data Conventions 
When converting a number of days to other units, the following conversion factors will 
be used: 
1 year = 365.25 days 
1 month = 30.4375 days 
 
When either day or month of a date is missing, the missing day and/or month will be 
imputed by the midpoint within the smallest known interval.  For example, if the day 
of the month is missing for any date used in a calculation, the 15th of the month will 
be used to replace the missing day.  If the month and day of the year are missing for 
any date used in a calculation, the first of July of the year will be used to replace the 
missing date. 
7.3 
Study Conduct 
All randomized patients are included in the analyses of study conduct.  Information 
will be tabulated by randomized treatment (unless otherwise indicated) and pooled 
treatments. 
7.3.1 Patient Disposition 
• Number of patients randomized, treated (on study, off study), never treated (Table 
1)  
• Number of alive patients (Table 2) 
• Median (estimated by Kaplan-Meier method) and range (minimum and maximum) 
(Table 2) of the follow-up time (months) defined as time from the day of 
randomization (as recorded in centralized randomization file) to the last day the 
patient is known alive (LKA) as the last recorded date known alive or censored at 
the time of death and calculated as  
 
[(date of death or LKA − date of randomization) + 1)]/30.4375. 
7.3.2 Accrual Patterns 
• Number of patients randomized by center (Table 3)  
• Number of patients by stratification factors at randomization (Table 4) 
• Accrual of patients by calendar time pooled across two treatment arms (Figure 1) 
7.3.3 Eligibility Violations/Protocol Deviations 
Eligibility violations of inclusion or exclusion criteria are centrally reviewed by CCTG; 
a field (y/n) for eligibility status and reason for ineligibility is entered in the database.  
A major protocol violation (MPV) is defined as a deviation from the protocol, initiated 
by the centre or the investigator, serious enough to mean that the patient's data 


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12 
contributes little, if any, information on the efficacy or toxicity of the regimen under 
study. MPVs are coded by CCTG based on its standard codes.   
• Number of patients eligible, not eligible (Table 5) 
• Reasons for ineligibility (Table 5) 
• Major protocol violations: % for each type of violations (Table 5). 
 
Deviations from randomization will be summarized as follows:  
• Treatment as randomized versus as treated (Table 6) 
7.4 
Study Population 
All randomized patients are included in the study population analyses.  Information 
will be tabulated by randomized treatment (unless otherwise indicated) and pooled 
treatments. 
7.4.1 Patient Pretreatment Characteristics  
• Gender (Table 7) 
• Race (Table 7) 
• Age:  median, minimum, maximum values; number <65, ≥65 (Table 7) 
• ECOG Performance Status: 0, 1 (Table 7) 
• BSA: median, minimum, maximum values (Table 7) 
• Months from initial diagnosis of pancreatic cancer to randomization: median, 
minimum, maximum values (Table 7) 
• Metastatic disease at initial diagnosis: Yes, No (Table 7) 
• Months from diagnosis of metastatic disease following completion of prior 
surgical/adjuvant therapy: median, minimum, maximum values (Table 7) 
7.4.2 Prior Surgery 
• Number of patients with prior surgery for colorectal cancer (Table 8) 
• Procedure/site of prior surgery (Table 8) 
7.4.3 Prior Radiotherapy 
• Number of patients with prior radiotherapy for pancreatic cancer (Table 9) 
• Prior radiotherapy by site (Table 9) 
7.4.4 Prior Systemic Therapy 
• Number of subjects with prior systemic therapy and type of prior systemic therapy 
(adjuvant, metastatic, neo-adjuvant) (Table 10) 
• Number of patients with specific drug/agent (Table 10) 
7.4.5 Extent of Disease 
• Number of patients with target lesions, number of target lesions, largest measure, 
site of target lesions (Table 11) 
• Number of patients with non-target lesions, number of non-target lesions, site of 
non-target lesions (Table 12) 


PA7_SAP_draft.docx 
13 
7.4.6 Baseline Exams 
• Baseline signs and symptoms (Table 13) 
• Baseline 
hematology: 
WBC, 
neutrophils, 
platelets, 
hemoglobin, 
RBC, 
lymphocytes, monocytes, eosinophils, basophils (Table 14) 
• Baseline serum chemistry: Total bilirubin, AST, ALT, LDH, creatinine clearance, 
serum creatinine, chloride, sodium, albumin, potassium, calcium, magnesium, 
ALP, glucose, amylase, lipase, Urea, BUN (Table 15)   
• Baseline Thyroid Function Tests (Table 16) 
• Baseline Coagulation Tests (Table 17) 
• Baseline ECG (Table 18) 
• Baseline urinalysis (Table 19) 
7.4.7 Concomitant Medications and Major Medical Problems at Baseline 
• Number of patients with concomitant medication within 14 days prior to the date 
of randomization (Table 20) 
• Number of patients with past or current major medical problems ongoing at 
baseline (Table 21) 
7.5 
Extent of Exposure  
Patients included are those who received at least one dose of protocol treatment as 
defined in Section 6. 
7.5.1 Study Therapy 
During a 4 week cycle of protocol treatment, the patients on both arms would receive 
infusion of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 
15.  Patients on G+N+D+T arm would receive in addition infusion of durvalumab 
(1500 mg) on day 1, and tremelimumab (75 mg) on day 1 of cycles 1, 2, 3 and 4 only.  
 
Duration of gemcitabine or nab-paclitaxel (in weeks) during the study is defined as 
follows: 
 
[last date of infusion of gemcitabine or nab-paclitaxel − first date of infusion of 
gemcitabine or nab-paclitaxel + 14]/7, 
 
where the first and last date of infusion is taken from Gemcitabine Administration or 
Nab-paclitaxel Administration Section of Treatment Report.  
 
Duration of durvalumab or tremelimumab (in weeks) during the study is defined as 
follows: 
 
[last date of infusion of durvalumab or tremelimumab − first date of infusion of 
durvalumab or tremelimumab + 28]/7, 
 
where the first and last date of infusion is taken from Durvalumab Administration or 
Tremelimumab Administration Section of Treatment Report).  


PA7_SAP_draft.docx 
14 
 
The following variable will be summarized using the data set of all treated patients: 
• Number of patients by cycle of therapy (Table 22) 
• Total number of cycles of treatment per patient (Table 23) 
• 
Total treatment duration per patient for each drug (Table 24) 
7.5.2 Dose Reduction, Omission, Discontinuation, or IV Rate Decrease or 
Infusion Interruption  
The administration of protocol treatment in a cycle may be modified (delayed, omitted, 
reduced, and infusion interrupted) because of toxicity or other reasons. For each drug, 
the following variables will be summarized using the data set of all treated patients: 
• Number of patients with at least one cycle reduced, omitted, delayed, or infusion 
interrupted (Table 25)  
• Reason for these dose modifications (Table 25) 
7.5.3 Cumulative Dose, Dose Intensity and Relative Dose Intensity  
The cumulative dose (mg) per patient for durvalumab and tremelimumab is the total 
dose (mg) that the patient received. The cumulative dose (mg/m2) per patient for 
gemcitabine and nab-paclitaxel is defined as the sum over all cycles of the total actual 
dose received divided by the BSA in a given cycle (Table 26). 
 
The actual dose intensity of a drug (mg/week) per patient is defined as: 
 
Actual Dose Intensity =
Cumulative dose  (mg
𝑚𝑚2 or mg) 
Duration of treatment
. 
 
where duration of treatment is defined in 7.5.1 (Table 27).  
 
The relative dose intensity per patient for each drug is defined as the dose intensity 
(mg/m2/week or mg/week) divided by the planned weekly dose as assigned in the 
protocol, which is 375 mg/week for durvalumab, 18.75 mg/week for tremelimumab, 
750 mg/m2/week for gemcitabine, and 93.75 mg/m2/week for nab-paclitaxel.  
 
The patient relative dose intensities will be grouped according to the following 
categories: < 60%,≥ 60% - < 80%, ≥ 80% - < 90%, ≥ 90% (Table 28). 
7.5.4 Off Study Therapy 
The reason for off of each study therapy will be taken from End of Treatment Section 
of End of Treatment Report. 
 
The following information will be summarized for each of protocol treatment (Table 
29): 
• Number of patients off study treatment 
• Reason off protocol therapy 


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15 
7.6 
Efficacy 
7.6.1 Overall survival 
For all randomized patients, survival is calculated from the day of randomization (as 
recorded in Centralized Randomization File) to death (Date/Cause of Death Section of 
Death Report).  For alive patients, survival is censored at the last day the patient is 
known alive (LKA) as the last recorded date known alive (last date of infusion of 
gemcitabine, nab-paclitaxel, durvalumab or tremelimumab in Treatment Report, Date 
of Attendance/Last Contact on 4-Week Post Treatment Report, Follow-up Report, 
Short Follow Up Report, and Minimal Follow-up Report).  Survival time (in months) 
is defined as  
 
[(date of death or LKA − date of randomization) + 1)]/30.4375. 
 
A frequency table for the number of patients who died and cause of death in each 
treatment arm will be provided (Table 30). Kaplan-Meier curve for proportions of 
survival in each treatment arm will be displayed (Figure 2).  
 
The comparison of overall survival between the two treatment arms is the primary 
objective of this study. The primary analysis will be the log-rank test (Table 31) 
stratified by the factors coded as: 
 
Stratification Factors (at randomization) 
 
 
Performance status  
1 = ECOG 0 
0 = ECOG 1 
  Prior adjuvant chemotherapy  
                   1=Yes                      0=No  
 
The hazard ratio of durvalumab and tremelimumab combined with gemcitabine and 
nab-paclitaxel  (G+N+D+T Arm) over gemcitabine and nab-paclitaxel  alone (G+N 
Arm) and two-sided 90% CI will be calculated (Table 31) based on the Cox regression 
model stratified by above stratification factors, and with treatment arm coded as 
G+N+D+T Arm=1 and G+N Arm=0.  The 90% confidence intervals for the median 
survival will be computed using the method of Brookmeyer and Crowley [2].     
 
In order to assess the influence of the potential prognostic factors shown and coded 
below on the comparison of survival between treatment arms, a stratified Cox 
regression model will be used with all variables (treatment arm and prognostic factors) 
included to estimate hazard ratios and 90% confidence intervals (Table 31). 
 
Prognostic factors (at baseline) 
 
 
Gender 
0 = Female 
1 = Male 
Age 
0 = ≥65 
1 = < 65 
Number of organ sites 
0 = >2 
1= ≤ 2 
 
No interactions will be considered in the model. 


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16 
7.6.2 Overall Survival by Subsets 
For each level of the following baseline variables, a Kaplan-Meier plot of survival by 
treatment arm will be produced as well as medians with 90% C.I. and the hazard ratio 
(unstratified) with 90% CI of durvalumab or tremelimumab combined with 
gemcitabine and nab-paclitaxel  (G+N+D+T Arm) over gemcitabine and nab-paclitaxel  
alone (G+N Arm) (Table 32): 
 
• Gender: male, female  
• Age: <65, ≥65 
• Race: white, black, other 
• Performance status at baseline: ECOG 0, 1 
• Number of organ sites involved at baseline: ≤ 2 versus > 2  
7.6.3 Progression-free Survival 
Progression-free survival (PFS) will be calculated for all patients from the day of 
randomization until the first observation of disease progression (date of objective 
relapse or progression of Relapse/Progression Report) or death due to any cause 
(recorded in Date/Cause of Death Section of Death Report) as the (difference+1). 
 
If a patient has not progressed or died, PFS will be censored on the date of last disease 
assessment defined as the earliest test date of target lesion or non-target lesions (if 
patient has no target lesions), whichever is latest. 
 
A frequency table will be provided describing progression and censoring  as follows 
(Table 33): 
• Number of patients who progress (documented progression, death without 
documented progression) 
• Number of patients censored (alive and not progressed) 
 
Analyses for PFS will be similar to that for overall survival as previously described. A 
Kaplan-Meier curve for PFS in each treatment arm will be displayed (Figure 3).  In the 
primary analysis, median PFS for the two treatments will be compared using the 
stratified log-rank test (Table 34).  A stratified Cox regression model will estimate the 
durvalumab and tremelimumab combined with gemcitabine and nab-paclitaxel  
(G+N+D+T Arm) over gemcitabine and nab-paclitaxel  alone (G+N Arm) PFS hazard 
ratio and 90% C. I. (Table 34).  In addition, a stratified Cox regression model adjusted 
for covariates will be applied to verify the impact of the prognostic factors on the 
treatment effect (Table 34).  
 
Coding for treatment arm, stratification variables and prognostic factors is identical to 
that presented in Section 7.6.1. 
 
Some patients received other anti-cancer therapy before progression or death.  
Sensitivity analyses will be performed by censoring those who have received anti-
cancer therapy prior to documentation of disease relapse/progression or death on the 


PA7_SAP_draft.docx 
17 
earliest date cancer treatment began or treating them as having PFS events at the earliest 
date when the treatment began. 
7.6.4 Progression-free survival by Subsets 
Subset analyses performed for overall survival will also be performed for PFS (Table 
35). 
7.6.5 Treatment Objective Response 
All patients will have their best objective response on study classified every 8 weeks 
until disease progression, using the RECIST (Response Evaluation Criteria in Solid 
Tumors) criteria 1.1. The best response to protocol treatment is collected in “Best 
Overall Response” section of END OF TREATMENT REPPORT. For patients who 
are still on protocol treatment and followed for response at final clinical cut-off, their 
best objective response is defined as the “best verified” objective response they have 
achieved up to the time of clinical cut-off determined by CCTG Senior Investigator 
based on data on “Response Assessment” section of TREATMENT REPORT. 
Best objective response to protocol treatment will be summarized for all randomized 
patients (Table 36). 
 
The primary analysis of objective response will be the comparison of the objective 
response rate (CR+PR) between treatment arms among all the randomized patients 
using the Cochran-Mantel-Haenszel (CMH) statistic adjusted for stratification factor 
for all randomized patients (Table 37) as defined in Section 6.   
 
In addition, a stratified logistic regression model adjusted for covariates will be applied 
to verify the impact of the prognostic factors on the treatment effect (Table 37). For all 
stratified logistic regression models, estimates of the odds ratio(s) and 90% confidence 
interval(s) will be given. 
 
Stratified logistic regression odds ratios will be estimated using PROC PHREG in SAS 
[5].  A dummy time variable will be created, where all responders will be classified as 
events with an arbitrary time = t0, and non-responders as censored with time t1, where 
t1 > t0.  The DISCRETE option will be used for tied observations. 
 
Coding for treatment, stratification variable and prognostic factors is identical to that 
presented in Section 7.4.1. 
7.6.6 Treatment Objective Response by Subsets  
For all randomized patients, the objective response rate will be presented for each 
treatment arm in the subgroups defined by the categorical variables listed below (Table 
38). No formal comparisons are planned: 
 
• gender (male, female) 
• age (<65 years, ≥65 years) 
• race (white, black, other) 


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18 
• performance status at baseline (ECOG 0, ECOG 1) 
• Number of organ sites involved at baseline (≤ 2 versus > 2).  
7.6.7 Duration of Objective Response  
For patients whose best objective responses are classified as CR or PR at any reporting 
period during the study, the duration of objective response is calculated as the time from 
CR or PR is documented (whichever is the first) until first observation of objective disease 
relapse or progression or death due to any cause. If a patient has not relapsed/progressed 
or died, duration of response will be censored on the date of last disease assessment defined 
as the earliest test date of target lesion or non-target lesions (if patient has no target lesions), 
whichever is latest.  
 
All randomized patients with CR or PR are included in this analysis. The median duration 
of objective response and associated 95% confidence intervals will be computed and 
compared by the stratified log-rank test adjusting for stratification factors at randomization 
(Table 39). 
7.6.8 Treatment Immune Response (iRECIST) 
All patients will also have their response classified every 8 weeks using the modified 
iRECIST guidelines. The best immune response (iRECIST) to protocol treatment is 
collected in “Best Objective Response i-RECIST” section of END OF TREATMENT 
REPPORT. For patients who are still on protocol treatment and followed for response 
at final clinical cut-off, their best immune response is defined as the “best verified” 
response they have achieved up to the time of clinical cut-off determined by CCTG 
Senior Investigator based on data on “Investigator Assessment-i-RECIST” section of 
TREATMENT REPORT. 
All analyses performed for objective response as listed above will be performed 
similarly for immune response (Table 40 to Table 43Error! Reference source not 
found.). 
7.7 
Safety 
 
The safety analyses will based on the All Treated population defined in Section 6. 
Adverse events and laboratories are graded and categorized using the CTCAE v4.0 
criteria except where CTCAE grades are not available. 
7.7.1 Adverse Events 
Adverse events will be recorded on the CCTG toxicity/adverse event-intercurrent 
illness case report form. Events reported on Treatment Report or 4-Week Post-
Treatment Follow-Up Report will be defined as acute (on treatment) adverse events;  
Events reported on Follow-up Report or Short Follow-up Report will be defined as 
delayed adverse events. 
 
Drug related adverse events are those events with a relation to protocol therapy of 
3=possible, 4=probable or 5=definite. 


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19 
 
Severe adverse events are those events reported with a CTCAE Grade of 3 or higher. 
 
Comparisons between treatment arms on acute adverse events (any vs. other, severe vs. 
other) will be carried out using a two sided Fisher’s exact test at an alpha level of two-
sided 10%. 
 
The following variables are summarized.  Tabulations of overall adverse events will be 
presented by treatment group. 
 
• 
Acute Adverse events:  worst CTCAE grade per patient (Table 44) 
• Severe acute adverse events: worst CTCAE grade per patient (Table 45) 
• Drug related acute adverse events: worst CTCAE grade per patient (Table 46) 
• Immune-related acute adverse event: worst CTCAE grade per patient (Table 47) 
• Severe immune-related acute adverse event: worst CTCAE grade per patient 
(Table 48) 
• Delayed adverse events:  worst CTCAE grade per patient (Table 49) 
7.7.2 Laboratory Evaluations 
Laboratory evaluations reported on Treatment Report or 4-Week Post-Treatment 
Follow-Up Report will be included in the calculation for acute (on treatment) 
laboratory adverse events.  All laboratory evaluations reported on Follow-up Report or 
Short Follow-up Reports will be included in the calculation for delayed (during follow-
up) laboratory adverse events.  Laboratory results will be classified according to 
CTCAE version 4.0.  Laboratory tests that are not covered by the CTCAE grading 
system will be summarized according to the following categories: normal and above 
the upper normal limits.   
 
7.7.2.1 Hematology 
• Hemoglobin, platelets, WBC, neutrophils, RBC, lymphocytes, monocytes, 
eosinophils, basophils on treatment:  worst CTC grade per patient (Table 
50) 
• 
Hemoglobin, platelets, WBC, neutrophils, RBC, lymphocytes, monocytes, 
eosinophils, basophils during follow-up:  worst CTC grade per patient 
(Table 51) 
 
7.7.2.2 Serum Chemistry 
• Total bilirubin, AST, ALT, LDH, creatinine clearance, serum creatinine, 
chloride, sodium, albumin, potassium, calcium, magnesium, ALP, glucose, 
amylase, lipase, Urea/BUN, CA 19-9 on treatment:  worst CTC grade per 
patient (Table 52) 
• 
Total bilirubin, AST, ALT, LDH, serum creatinine, chloride, sodium, 
albumin, potassium, calcium, magnesium, ALP, amylase, lipase during 
follow-up:  worst CTC grade per patient (Table 53) 


PA7_SAP_draft.docx 
20 
 
7.7.2.3 Thyroid Function Tests 
• TSH, T3 free, T3 total, T4 free, T4 total on treatment (Table 54) 
• TSH, T3 free, T3 total, T4 free, T4 total during follow-up (Table 55) 
 
7.7.2.3 Coagulation 
• PT, INR, PTT on treatment (Table 56) 
• PT, INR, PTT during follow-up (Table 57) 
7.7.3 Other Safety 
 
7.7.3.1 ECG 
Cardiac function of patients is evaluated as clinically indicated by ECG during protocol 
treatment with results reported on Treatment Report.  
• Number of patients by normal or abnormal ECG, by treatment group (Table 58) 
 
7.7.3.2 Urinalysis 
Dipstick urinalysis is performed as clinically indicated during protocol treatment . with 
results reported on Treatment Report.  
• Results of urinalysis, by treatment group (Table 59) 
7.7.4 Deaths on Study/Adverse Events Leading to Discontinuations of Protocol 
Treatment 
• Deaths during treatment or within 4 weeks of last protocol treatment:  number 
of patients who died and cause of death from Date/Cause of Death Section of 
Death Report (Table 60) 
• Number of patients with adverse events leading to discontinuations of protocol 
treatment as identified from Off Protocol Treatment - Adverse Events of End 
of Treatment Report (Table 61) 
7.8 
Concomitant Medications, Other Anti-Cancer Treatments, and 
Major Medical Problems 
Investigators may prescribe concomitant medications or treatments deemed necessary 
to provide adequate prophylactic or supportive care.  Administration of any other anti-
cancer therapy for pancreatic cancer is not permitted while the patient is receiving 
protocol therapy. Thereafter, patients may be treated at the investigator’s discretion. 
Major medical problems are those thought unrelated to protocol treatment.  
• Concomitant medications during or 4 weeks after protocol treatment (reported on 
Treatment Report and 4-Week Post-Treatment Follow-Up Report) (Table 62) 
• Other anti-cancer treatments for pancreatic cancer during or 4 weeks after protocol 
treatment (reported on Treatment Report and 4 Weeks 4-Week Post-Treatment 
Follow-Up Report) (Table 63) 
• Other anti-cancer treatments for pancreatic cancer during follow-up (reported on 
Follow-up Report or Short Follow-up Reports) (Table 63) 


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21 
• Major medical problem during or 4 weeks after protocol treatment (reported on 
Treatment Report and 4-Week Post-Treatment Follow-Up Report)   (Table 64) 
7.9 
Quality of Life 
 
The quality of life of patients in this study is assessed at 4, 8, 12, 16 and 24 weeks from 
randomization during protocol treatment and then every 3 months until PD or the 
initiation of another chemotherapy treatment by using EORTC QLQ-C30 (version 3.0).  
The following are the scoring algorithms for this instrument.  
7.9.1 EORTC QLQ-C30  
The EORTC core questionnaire, QLQ-C30 (version 3.0), consists of five Functional 
Scales, Global Health Status, and nine Symptoms Scales. Each scale in the 
questionnaire will be scored (0 to 100) according to the EORTC recommendations in 
the EORTC QLQ-C30 Scoring Manual.  The scoring method is summarized below. In 
this summary Qi refers to the ith question on the QLQ-C30. 
 
Functional scale’s scores: 
• Physical functioning: 
(1 - ((Q1+Q2+Q3+Q4+Q5)/5 -1)/3) * 100 
• Role functioning: 
 
(1 - ((Q6+Q7)/2-1)/3) * 100 
• Emotional functioning: 
(1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100 
• Cognitive functioning: 
(1 - ((Q20+Q25)/2-1)/3) * 100 
• Social functioning:  
(1 - ((Q26+Q27)/2-1)/3) * 100 
 
Global health status score: 
• Global health status/QOL: ((Q29+Q30)/2-1)/6 * 100 
 
Symptom scale’s scores: 
• Fatigue: 
 
 
((Q10+Q12+Q18)/3-1)/3 * 100 
• Nausea and vomiting: 
((Q14+Q15)/2-1)/3 * 100 
• Pain:  
 
 
((Q9+Q19)/2-1)/3 * 100 
• Dyspnea: 
 
 
((Q8-1)/3 * 100 
• Insomnia: 
 
 
(Q11-1)/3 * 100 
• Appetite loss: 
 
(Q13-1)/3 * 100 
• Constipation: 
 
(Q16-1)/3 * 100 
• Diarrhea: 
 
 
(Q17-1)/3 * 100 
• Financial difficulties: 
(Q28-1)/3 * 100 
 
Missing items in a scale will be handled by the methods outlined in the scoring manual.  
In particular, values will be imputed for missing items by “assuming that the missing 
items have values equal to the average of those items which are present” for any scale 
in which at least half the items are completed.  A scale in which less than half of the 
items are completed will be treated as missing. 


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22 
7.9.2 Data Sets 
The analyses of quality of life data will be restricted to randomized patients who have 
a measurement at baseline and at least one measurement after baseline.  
7.9.3 Compliance 
Compliance will be described, by time of evaluation, by the number and percentage of 
subjects who filled out a questionnaire (per subject, at least one question answered) in 
that period of evaluation. The denominator used in calculating the percentage for 
baseline will be all randomized subjects. The denominator used for all other time points 
will be the number of subjects known to be alive at the start of the time period (Table 
65).   
7.9.4 Primary Analyses of QOL 
The primary endpoints for the comparison of QOL between treatment arms will be 
proportions of patients who had deterioration in physical function and Global Health 
Status at 8 weeks and 16 weeks after the randomization.  The deterioration is defined 
as a change score from baseline which is –10 points or lower [6].  Fisher’s exact test 
will be used to compare the proportions of patients with deterioration between two 
treatment arms at these two time points (Table 66).  No multiple adjustment for these 
comparisons will be made. 
 
The proportions of patients who had improving (defined as change score from baseline 
of 10 points or higher) or stable (defined as change score from baseline of between –
10 and 10 points) physical function and Global Health Status at 8 weeks and 16 weeks 
after the randomization will also be compared between two treatment arms using 
Fisher’s exact test (Table 66). 
 
The time to definitive deterioration in physical function and Global Health Status is 
defined as the time from randomization until the change score from baseline is –10 
points or lower.  For patients whose change scores are always higher than –10 points, 
the time to definitive deterioration will be censored at their last QoL assessment times.  
The log-rank test will be used to compare the time to definitive deterioration between 
two treatment arms (Table 67).   
7.9.5 Baseline and Change Score Analysis 
Descriptive statistics for EORTC QOL score (mean, standard deviation) will be 
presented for each scale at baseline. The same statistics will be generated at each time 
of post-baseline evaluation.  The comparability of mean baseline scores and change 
scores at each time of post-baseline evaluation between treatment groups will be 
assessed using a Wilcoxon rank sum test (Table 68 and Table 69). 


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23 
7.9.6 QOL Response Analysis 
QOL response for functional scales and global health status is calculated as follows: A 
change score of 10 points from baseline is defined as clinically relevant.  Patients are 
considered to have clinical improvement if reporting a score 10-points or better than 
baseline at any time of QOL assessment. Conversely, patients are considered worsened 
if reporting a score minus 10-points or worse than baseline at any time of QOL 
assessment without any improvement.  Patients whose scores are between 10-point 
changes from baseline at every QOL assessment will be considered as stable.  In 
contrast to functional scales, for the determination of patient’s QOL response, 
classification of patients into improved and worsened categories is reversed for 
symptom scales.  A Chi-square test will then be performed to compare the distributions 
of these three categories between two arms (Table 70). 
 
 


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24 
8. 
Appendices 
 
Appendix 1: Tables and Figure 
 
Table 1:  Patient Disposition 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
G+N+D+T  
G+N 
Total 
Randomized  
N=***  
N=*** 
N=*** 
 
 
 
 
Treated 
*** (**) 
*** (**) 
*** (**) 
        On study 
*** (**) 
*** (**) 
*** (**) 
        Off study(1)  
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Never Treated 
*** (**) 
*** (**) 
*** (**) 
(1) Off all study therapies. 
 
Table 2:  Follow-up of Patients 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
G+N+D+T 
G+N 
Total 
Number of patients alive 
*** (%) 
*** (%) 
*** (%) 
 
 
 
 
Follow-up (months) 
 
 
 
 
median 
** 
** 
** 
  
Minimum-maximum      
**-**  
**-** 
**-** 


PA7_SAP_draft.docx 
25 
Table 3:  Accrual by Center 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
G+N+D+T 
N = *** 
G+N 
N = *** 
Total 
N = *** 
Center #1 
*** (**) 
*** (**) 
*** (**) 
Center #2 
*** (**) 
*** (**) 
*** (**) 
Center #3 
*** (**) 
*** (**) 
*** (**) 
... 
*** (**) 
*** (**) 
*** (**) 
 
Table 4:  Accrual by Stratification Factor at Randomization 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
G+N+D+T 
N = *** 
G+N  
N=*** 
Total 
N = *** 
Performance Status 
 
 
 
 
ECOG 0 
** (**) 
** (**) 
** (**) 
 
ECOG 1 
** (**) 
** (**) 
** (**) 
Prior adjuvant therapy 
 
 
 
 
Yes 
** (**) 
** (**) 
** (**) 
 
No 
** (**) 
** (**) 
** (**) 
Source:  Centralized Randomization File 
 
Figure 1:  Accrual by Calendar Time 
 


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26 
Table 5:  Eligibility and Reasons for Ineligibility and Major Protocol Violations 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
G+N+D+T  
N=*** 
G+N 
N=*** 
Total 
N=*** 
Eligible 
*** (**) 
*** (**) 
*** (**) 
Not Eligible 
*** (**) 
*** (**) 
*** (**) 
Reason for ineligibility  
 
 
 
 
<Reason 1> 
** 
** 
** 
 
<Reason 2> 
** 
** 
** 
 
... 
** 
** 
** 
Major protocol violation 
 
<violation type 1> 
 
<violation type 2> 
 
… 
 
** 
** 
 
** 
** 
 
** 
** 
 
Table 6:  Treatment as Randomized Versus as Treated 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
Randomized Arm 
 
G+N+D+T 
N=*** 
G+N 
N=*** 
Total 
N=*** 
Treatment received 
 
 
 
 
All G+N+D+T 
*** (**) 
*** (**) 
*** (**) 
 
Durvalumab only 
*** (**) 
*** (**) 
*** (**) 
 
Tremelimumab only 
*** (**) 
*** (**) 
*** (**) 
          
G+N Only 
*** (**) 
*** (**) 
*** (**) 
          
Not treated 
*** (**) 
*** (**) 
*** (**) 
 


PA7_SAP_draft.docx 
27 
Table 7:  Pretreatment Characteristics at Baseline 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
G+N+D+T 
N=*** 
G+N 
N=*** 
Total 
N=*** 
Gender  
 
 
 
    Female 
** (**) 
** (**) 
** (**) 
    Male 
** (**) 
** (**) 
** (**) 
Race 
 
 
 
    White 
** (**) 
** (**) 
** (**) 
    Black or African American 
** (**) 
** (**) 
** (**) 
    .... 
** (**) 
** (**) 
** (**) 
Age (years) 
 
 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
** 
** 
** - ** 
** 
** 
** - ** 
     < 65 
     ≥ 65 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
ECOG Performance Status 
 
 
 
    0 
** (**) 
** (**) 
** (**) 
    1 
** (**) 
** (**) 
** (**) 
BSA (m2) 
 
 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
** 
** 
** - ** 
** 
** 
** - ** 
Months from initial diagnosis to randomization 
 
 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
** 
** 
** - ** 
** 
** 
** - ** 
Metastatic disease at initial diagnosis 
 
 
 
 
Yes 
 
No 
**(**) 
**(**) 
**(**) 
**(**) 
** (**) 
**(**) 
Months from diagnosis of metastatic disease 
following completion of prior surgical/adjuvant 
therapy 
 
 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
** 
** 
** - ** 
** 
** 
** - ** 
 
 
 


PA7_SAP_draft.docx 
28 
Table 8:  Prior Surgery 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
 
G+N+D+T   
N=*** 
G+N 
N=*** 
Total 
N=*** 
Prior surgery 
 
 
 
 
No 
*** (**) 
*** (**) 
*** (**) 
 
Yes 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Procedure / Site 
 
 
 
 
Procedure / Site 1 
*** (**) 
*** (**) 
*** (**) 
 
Procedure / Site 2 
*** (**) 
*** (**) 
*** (**) 
              .... 
*** (**) 
*** (**) 
*** (**) 
 
Table 9:  Prior Radiotherapy 
Data set:  All Randomized Patients 
Number of patients (%) 
 
G+N+D+T  
N=*** 
G+N 
N=*** 
Total 
N=*** 
Any Prior Radiotherapy 
No 
Yes  
 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
Site of any prior radiotherapy(1) 
Site #1 
Site #2  
... 
 
*** (**) 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
***(**) 
 
*** (**) 
*** (**) 
***(**) 
(1) Patient may have more than one site of radiotherapy 
 
Table 10:  Prior Systemic Therapy 
Data set:  All Randomized Patients 
Number of patients (%) 
 
G+N+D+T   
N=*** 
G+N 
N=*** 
Total 
N=*** 
With at least one prior systemic therapy 
*** (**) 
*** (**) 
*** (**) 
Type of prior systemic therapy 
 
At least one adjuvant 
 
At least one neo-adjuvant 
 
At least one metastatic 
 
*** (**) 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
*** (**) 
Specific drug/agent(1) 
 
 
 
 
Drug/agent #1 
*** (**) 
*** (**) 
*** (**) 
 
Drug/agent #2 
*** (**) 
*** (**) 
*** (**) 
 
… 
*** (**) 
*** (**) 
*** (**) 
(1) Patient may have more than one drug/agent. 
 
 
 


PA7_SAP_draft.docx 
29 
Table 11:  Extent of Disease (Target Lesions) 
Data set:  All Randomized Patients 
 
Number of Patients with Target Lesions (%) 
 
G+N+D+T   
N=*** 
G+N 
N=*** 
Total 
N=*** 
Presence of Target Lesions 
 
 
 
              Patients with at least one target lesion 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Number of Target Lesions 
 
 
 
              1 
*** (**) 
*** (**) 
*** (**) 
              2 
*** (**) 
*** (**) 
*** (**) 
              3 
*** (**) 
*** (**) 
*** (**) 
              4 
*** (**) 
*** (**) 
*** (**) 
              5 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Largest Target Lesion in cm 
 
 
 
              < 2 
*** (**) 
*** (**) 
*** (**) 
              2-5 
*** (**) 
*** (**) 
*** (**) 
              > 5-10 
*** (**) 
*** (**) 
*** (**) 
              > 10 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
 Site of Target Lesion(1) 
 
 
 
 
Abdomen 
*** (**) 
*** (**) 
*** (**) 
 
Adrenals 
*** (**) 
*** (**) 
*** (**) 
 
Bone 
*** (**) 
*** (**) 
*** (**) 
 
Brain 
*** (**) 
*** (**) 
*** (**) 
 
Liver 
*** (**) 
*** (**) 
*** (**) 
 
Lung 
*** (**) 
*** (**) 
*** (**) 
 
Nodes 
*** (**) 
*** (**) 
*** (**) 
 
Pleura 
*** (**) 
*** (**) 
*** (**) 
 
Skin 
*** (**) 
*** (**) 
*** (**) 
 
Subcutaneous Tissue 
*** (**) 
*** (**) 
*** (**) 
              .... 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
 
 
 
 
(1) Patients may have target lesions at more than one site 
 
 


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30 
Table 12:  Extent of Disease (Non-Target Lesions) 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
G+N+D+T  N=*** 
G+N 
N=*** 
Total 
N=*** 
Patients with no-target lesion 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Site of non-target lesion(1)  
 
 
 
 
Abdomen 
*** (**) 
*** (**) 
*** (**) 
 
Adrenals 
*** (**) 
*** (**) 
*** (**) 
 
Bone 
*** (**) 
*** (**) 
*** (**) 
 
Brain 
*** (**) 
*** (**) 
*** (**) 
 
Liver 
*** (**) 
*** (**) 
*** (**) 
 
Lung 
*** (**) 
*** (**) 
*** (**) 
 
Nodes 
*** (**) 
*** (**) 
*** (**) 
 
Pleura 
*** (**) 
*** (**) 
*** (**) 
 
Skin 
*** (**) 
*** (**) 
*** (**) 
 
Subcutaneous Tissue 
*** (**) 
*** (**) 
*** (**) 
 
Other 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Number of non-target lesions 
 
 
 
              1 
*** (**) 
*** (**) 
*** (**) 
              2 
*** (**) 
*** (**) 
*** (**) 
              3 
*** (**) 
*** (**) 
*** (**) 
              4 
*** (**) 
*** (**) 
*** (**) 
              ≥5 
*** (**) 
*** (**) 
*** (**) 
(1) Patients may have non-target lesions at more than one site 
 
Table 13:  Baseline Signs and Symptoms 
Data set:  All Randomized Patients (G+N+D+T Arm) 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
NR 
1 
2 
3 
4 
 
Patients with any 
sign/symptom at baseline 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with particular sign 
or symptom, within body 
system:  
Body System 1(1) 
Event 1 
Event 2 
Event 3 
...  
Body System 2(1) 
Event 1  
...  
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a body system 
 
NOTE:  Same table to be made for G+N Arm 


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31 
Table 14:  Baseline Hematology 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
Total 
N=*** 
Hemoglobin 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Platelets 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
WBC 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Neutrophils 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Lymphocytes  
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
RBC 
 
 
 
 
Normal 
** (**) 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Monocytes 
 
 
 
 
Normal 
** (**) 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Eosinophils 
 
 
 
 
Normal 
** (**) 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Basophils 
 
 
 
 
Normal 
** (**) 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
(1) Not done or outside the 14-day window prior to start of therapy 
(2) High than upper lower limit 
 


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32 
Table 15:  Baseline Chemistry 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
Total 
N=*** 
Total bilirubin 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Creatinine clearance 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
ALT 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
AST 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
LDH 
 
 
 
 
Normal 
** (**) 
** (**) 
** (**) 
 
High(2) 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Serum Creatinine 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hypernatremia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hyponatremia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hyperkalemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hypokalemia 
 
 
 


PA7_SAP_draft.docx 
33 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hypercalcemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hypocalcemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hypermagnesemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hypomagnesemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hyperglycemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hypoglycemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hyperalbuminemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Hypoalbuminemia 
 
 
 


PA7_SAP_draft.docx 
34 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Chloride 
 
 
 
 
Normal 
** (**) 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Amylase 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
ALP 
 
 
 
 
Normal 
** (**) 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Lipase 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Urea/BUN 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
(1) Not done or outside the 14-day window prior to start of therapy 
(2) High than upper lower limit 


PA7_SAP_draft.docx 
35 
Table 16:  Baseline Thyroid Function Tests 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
Total 
N = *** 
TSH 
 
 
 
 
Normal  
** (**) 
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
** (**) 
T3 Free 
 
 
 
 
Normal  
** (**) 
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
** (**) 
T3 Total 
 
 
 
 
Normal  
** (**) 
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
** (**) 
T4 Free 
 
 
 
 
Normal  
** (**) 
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
** (**) 
T4 Total 
 
 
 
 
Normal  
** (**) 
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
** (**) 
Table 17:  Baseline Coagulation Tests 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
Total 
N = *** 
PT 
 
 
 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
INR 
 
 
 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
PTT 
 
 
 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
 


PA7_SAP_draft.docx 
36 
Table 18:  Baseline ECG 
 
Data set:  All Randomized Patients 
Number of patients (%) 
G+N+D+T   
N=*** 
G+N 
N=*** 
Total 
N=*** 
Baseline ECG:  Results 
 
 
 
 
 
Normal 
 
*** (**) 
*** (**) 
*** (**) 
 
Abnormal 
 
*** (**) 
*** (**) 
*** (**) 
 
ECG not performed 
*** (**) 
*** (**) 
*** (**) 
  
Table 19 : Baseline Urinalysis  
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
G+N+D+T 
N=*** 
G+N 
N=*** 
Total 
N=*** 
Urinalysis – SPOT Test 
 
 
 
Negative/trace 
**(**) 
**(**) 
**(**) 
1+(>20 mg/dL–30 mg/dL) 
**(**) 
**(**) 
**(**) 
2+(>30 mg/dL–100 mg/dL) 
**(**) 
**(**) 
**(**) 
3+(>100 mg/dL– 300 mg/dL) 
**(**) 
**(**) 
**(**) 
4+(>300 mg/dL) 
**(**) 
**(**) 
**(**) 
 
 
 
 
Urinalysis – 24-Hour Test (g/day) 
 
 
 
Grade 
 
 
 
1 
**(**) 
**(**) 
**(**) 
2 
**(**) 
**(**) 
**(**) 
3 
**(**) 
**(**) 
**(**) 
 
 


PA7_SAP_draft.docx 
37 
Table 20:  Concomitant Medications at Baseline 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
G+N+D+T  N=*** 
G+N 
N=*** 
Total 
N=*** 
 
 
 
 
Any concomitant medication (1)  
 
 
 
    No 
** (**) 
** (**) 
** (**) 
    Yes 
** (**) 
** (**) 
** (**) 
(1)Any medication taken within 14 days prior to randomization. 
Table 21:  Major Medical Problems at Baseline 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
Total 
N=*** 
Patients with at least one past or current major 
medical problem 
** (**) 
** (**) 
** (**) 
Medical Problem(1) 
 
 
 
(from highest to lowest in frequency) 
 
 
 
 
 
 
 
 
 
 
Diabetes 
** (**) 
** (**) 
** (**) 
... 
 
 
 
 
 
 
 
(1) patients may report more than one medical problem reported 
 
 


PA7_SAP_draft.docx 
38 
Table 22:  Number of Patients by Cycle 
Data Set: All Treated Patients  
 
Number of Patients (%) 
 
 
G+N+D+T Arm 
G+N Arm 
Cycle 
 
1 
** (**) 
** (**) 
 
 
2 
** (**) 
** (**) 
 
 
3 
** (**) 
** (**) 
 
 
... 
 
 
 
 
 
 
Table 23:  Number of Cycles of Protocol Therapy per Patient  
Data Set: All Treated Patients  
 
G+N+D+T Arm 
G+N Arm 
Number of Cycles: 
 
 
 
N 
*** 
*** 
 
Median  
* 
* 
 
Min – Max 
* - * 
* - * 
 
 
 
 
Table 24:  Total Treatment Duration  
Data Set: All Treated Patients  
 
G+N+D+T Arm 
G+N Arm 
 
Durva-
lumab 
Tremeli- 
mumab 
Gemcita-
bine 
Nab-
paclitaxel 
Gemcita-
bine 
Nab-
paclitaxel 
Duration in weeks 
 
 
 
 
 
 
 
N 
*** 
*** 
*** 
*** 
*** 
*** 
 
Median  
* 
* 
* 
* 
* 
* 
 
Min – Max 
* - * 
* - * 
* - * 
* - * 
* - * 
* - * 
 
 
 
 
 
 
 
 
 
 


PA7_SAP_draft.docx 
39 
Table 25:  Dose Reduction, Omission or Delay and Infusion Interruption  
Data Set: All Treated Patients 
 
Number of patients (%) 
 
G+N+D+T Arm 
G+N Arm 
 
Durvalu-
mab  
(N=***) 
Tremeli-
mumab 
(N=***) 
Gemcita-
bine 
(N=***) 
Nab-
paclitaxel 
(N=***) 
Gemcita-
bine 
(N=***) 
Nab-
paclitaxel 
(N=***) 
 
 
 
 
 
 
 
At least one dose reduction  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Reason for dose reduction: 
 
 
 
 
 
 
 
<reason 1> 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
<reason 2> 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
... 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
At least one dose omission  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Reason for dose omission: 
 
 
 
 
 
 
 
<reason 1> 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
<reason 2> 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
... 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
At least one dose delay  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Reason for delay: 
 
 
 
 
 
 
 
<reason 1> 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
<reason 2> 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
... 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
At least one infusion interruption  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Reason for interruption: 
 
 
 
 
 
 
 
<reason 1> 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
<reason 2> 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
... 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 


PA7_SAP_draft.docx 
40 
Table 26:  Cumulative Dose  
Data Set: All Treated Patients  
 
G+N+D+T Arm 
G+N Arm 
 
Durva-
lumab 
Tremeli- 
mumab 
Gemcita-
bine 
Nab-
paclitaxel 
Gemcita-
bine 
Nab-
paclitaxel 
Cumulative dose  
 
 
 
 
 
 
 
N 
 
Mean (STD) 
*** 
** (**) 
*** 
** (**) 
*** 
** (**) 
*** 
** (**) 
*** 
** (**) 
*** 
** (**) 
 
Median  
* 
* 
* 
* 
* 
* 
 
Min – Max 
* - * 
* - * 
* - * 
* - * 
* - * 
* - * 
 
 
 
 
 
 
 
 
Table 27:  Dose Intensity  
Data Set: All Treated Patients  
 
G+N+D+T Arm 
G+N Arm 
 
Durva-
lumab 
Tremeli- 
mumab 
Gemcita-
bine 
Nab-
paclitaxel 
Gemcita-
bine 
Nab-
paclitaxel 
Dose Intensity  
 
 
 
 
 
 
 
N 
 
Mean (STD) 
*** 
** (**) 
*** 
** (**) 
*** 
** (**) 
*** 
** (**) 
*** 
** (**) 
*** 
** (**) 
 
Median  
* 
* 
* 
* 
* 
* 
 
Min – Max 
* - * 
* - * 
* - * 
* - * 
* - * 
* - * 
 
 
 
 
 
 
 
 
Table 28:  Relative Dose Intensity  
 
Data Set: All Treated Patients 
 
G+N+D+T Arm 
G+N Arm 
 
Durvalumab  
(N=***) 
Tremelimumab 
(N=***) 
Gemcitabine 
(N=***) 
Nab-
paclitaxel 
(N=***) 
Gemcitabine 
(N=***) 
Nab-
paclitaxel 
(N=***) 
Relative Dose 
 
intensity  
 
 
 
 
 
 
 
 
 
 
 
 
 
 ≥ 90% planned 
 
intensity  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 ≥ 80% - < 90% 
 
planned intensity  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 ≥ 60% - < 80% 
 
planned intensity 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 < 60% planned 
 
intensity   
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 


PA7_SAP_draft.docx 
41 
Table 29:  Off Treatment Summary 
 
Data Set: All Treated Patients 
 
G+N+D+T Arm 
G+N Arm 
 
Durvalumab  
(N=***) 
Tremelimumab 
(N=***) 
Gemcitabine 
(N=***) 
Nab-
paclitaxel 
(N=***) 
Gemcitabine 
(N=***) 
Nab-
paclitaxel 
(N=***) 
 
 
 
 
 
 
 
Off treatment 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
 
Reason off treatment 
 
 
 
 
 
 
  Treatment Completed 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
  Progressive disease 
  
(objective)
 Symptomatic  
  
progression  
** (**) 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
 
** (**) 
    Intercurrent Illness – 
 
adverse events 
 
unrelated to protocol 
 
treatment 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
   Adverse events related  
   to protocol therapy 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
   Patient Refusal (not 
 
related to adverse 
 
event) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
  Death 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
  Other reason 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 


PA7_SAP_draft.docx 
42 
Table 30:  All Deaths 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
G+N+D+T  
N=*** 
G+N 
N=*** 
Number of  Patients who died 
** (**) 
** (**) 
 
 
 
Cause of Death 
 
 
 
Pancreatic cancer only 
** 
** 
 
Toxicity from protocol treatment 
** 
** 
 
Pancreatic cancer + Toxicity from protocol treatment complication 
** 
** 
 
Non-protocol Treatment Complication 
** 
** 
 
Colorectal cancer + Non-protocol Treatment Complication 
** 
** 
 
Other Primary Malignancy 
** 
** 
 
Other Condition or Circumstance 
** 
** 
 
Figure 2:  Kaplan-Meier Curves for Overall Survival 
 
 
 


PA7_SAP_draft.docx 
43 
Table 31:  Log Rank and Cox Regression Model for Overall Survival 
Data set:  All Randomized Patients 
 
N 
Univariate Analysis(1) 
Multivariate Analysis(2) 
Treatment Arm/ 
Prognostic Factors at  
Baseline 
 
Median 
Survival 
(Months) 
Hazard 
Ratio(4) 
(90% CI) 
Log-
rank 
p-value 
Hazard 
Ratio(4)  
(90% C.I.) 
P-value 
from Cox 
model 
Treatment arm 
 
 
 
0.*** 
 
0.*** 
 
G+N+D+T   
*** 
**.** 
**.** 
 
**.** 
 
 
G+N 
*** 
**.** 
(**.**,**.**) 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
Gender 
 
 
 
0.*** 
 
0.*** 
 
Male 
*** 
**.** 
NC (3) 
 
**.** 
 
 
Female 
*** 
**.** 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
Age 
 
 
 
0.*** 
 
0.*** 
 
<65 
*** 
**.** 
NC 
 
**.** 
 
 
65 
*** 
**.** 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
Number of organ sites 
 
 
 
0.*** 
 
0.*** 
 
 2 
*** 
**.** 
NC 
 
**.** 
 
 
>2 
*** 
**.** 
 
 
(**.**,**.**) 
 
(1) Stratified; (2) Stratified Cox regression with all factors included; (3) NC = not computed 
(4) Hazard ratio of first category over second category 
 
Table 32:  Survival by Subsets 
Data set:  All Randomized Patients 
 
 
Factors 
 
 
Value 
G+N+D+T   
G+N 
 
 
N 
Median 
Survival 
(90% C.I.) 
 
N 
Median 
Survival 
(90% C.I.) 
Hazard Ratio(1) 
90% C.I. 
Performance Status 
at baseline 
ECOG 0 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
ECOG 1 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
Age 
<65 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
≥65 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
Gender 
Female 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
Male 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
Race 
White 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
Black 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
Other 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
Number of organ 
sites 
≤2 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
>2 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
(1) G+N+D+T  over G+N hazard ratio (Unstratified) 


PA7_SAP_draft.docx 
44 
Table 33:  Progression Summary 
 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
G+N+D+T   
N=*** 
G+N 
N=*** 
 
 
 
Patients who progressed 
*** (**) 
*** (**) 
 
 
 
 
Progression on protocol treatment 
** 
** 
 
Progression off protocol treatment 
** 
** 
 
Death (without documented progression) 
** 
** 
 
 
 
Patients who were censored 
 
*** (**) 
*** (**) 
   Reason Censored 
 
 
 
 
 
Lost to follow-up 
 
** 
 
** 
 
 
Not progressed 
 
** 
 
** 
 
 
 
 
 
 
 
Figure 3:  Kaplan-Meier Curves for Progression Free Survival 
 


PA7_SAP_draft.docx 
45 
Table 34:  Log Rank and Cox Regression Model for Progression Free Survival 
(PFS) 
Data set:  All Randomized Patients 
 
N 
Univariate Analysis(1) 
Multivariate Analysis(2) 
Treatment Arm/ 
Prognostic Factors at  
Baseline 
 
Median 
PFS 
(Months) 
Hazard 
Ratio(4) 
(90% CI) 
Log-
rank 
p-value 
Hazard 
Ratio(4)  
(90% C.I.) 
P-value 
from Cox 
model 
Treatment arm 
 
 
 
0.*** 
 
0.*** 
 
G+N+D+T   
*** 
**.** 
**.** 
 
**.** 
 
 
G+N 
*** 
**.** 
(**.**,**.**) 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
Gender 
 
 
 
0.*** 
 
0.*** 
 
Male 
*** 
**.** 
NC (3) 
 
**.** 
 
 
Female 
*** 
**.** 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
Age 
 
 
 
0.*** 
 
0.*** 
 
<65 
*** 
**.** 
NC 
 
**.** 
 
 
65 
*** 
**.** 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
Number of organ sites 
 
 
 
0.*** 
 
0.*** 
 
 2 
*** 
**.** 
NC 
 
**.** 
 
 
>2 
*** 
**.** 
 
 
(**.**,**.**) 
 
(1) Stratified; (2) Stratified Cox regression with all factors included; (3) NC = not computed 
(4) Hazard ratio of first category over second category 
 
Note: Same table will be made for sensitivity analyses which (1) censor the patients who have received 
other anti-cancer treatments prior to documentation of disease relapse/progression or death at the 
earliest time when these treatments began or (2) treat them as having PFS events at the earliest time 
when these treatments began.  
 


PA7_SAP_draft.docx 
46 
Table 35:  Progression Free Survival (PFS) by Subsets 
Data set:  All Randomized Patients 
 
 
Factors 
 
 
Value 
G+N+D+T   
G+N 
 
 
N 
Median 
Survival 
(90% C.I.) 
 
N 
Median 
Survival 
(90% C.I.) 
Hazard Ratio(1) 
90% C.I. 
Performance Status 
at baseline 
ECOG 0 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
ECOG 1 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
Age 
<65 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
≥65 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
Gender 
Female 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
Male 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
Race 
White 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
Black 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
Other 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
Number of organ 
sites 
≤2 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
>2 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
(1) G+N+D+T  over G+N hazard ratio (Unstratified) 
 


PA7_SAP_draft.docx 
47 
Table 36:  Treatment Objective Response 
 
Data set:  All Randomized  Patients 
 
Number of Patients (%)a 
N=*** 
G+N+D+T  N=*** 
G+N 
N=*** 
 
 
 
Patients with at least one target lesion 
 
Response-evaluable  
N=*** 
 
N=*** 
N=*** 
 
N=*** 
 
Complete response (CR) 
 
** (**) 
 
** (**) 
 
Partial response (PR) 
 
** (**) 
 
** (**) 
 
Stable disease (SD) 
 
** (**) 
 
** (**) 
 
Progressive disease (PD) 
 
** (**) 
 
** (**) 
 
Inevaluable for response (IN) 
<Reason 1> 
<Reason 2> 
.... 
 
** (**) 
** 
** 
... 
 
** (**) 
** 
** 
.... 
 
 
 
Not response evaluable 
N=*** 
N=*** 
 
Never treated  
 
**  
 
** 
Not assessed (NA)  
 
** 
 
** 
 
Patients with no target lesions 
 
 
N=*** 
 
N=*** 
 
Progressive disease (PD) 
 
** 
 
** 
 
Inevaluable for response (IN) 
<Reason 1> 
<Reason 2> 
.... 
 
** 
** 
** 
... 
 
** 
** 
** 
.... 
 
Not assessed (NA) 
 
** 
 
** 
 
 
 
Never treated  
 
** 
 
** 
 
 
 
a   percentages are calculated out of the number of randomized patients 
 
 
 


PA7_SAP_draft.docx 
48 
Table 37:  Cochran Mantel Haenszel and Logistic Regression Model for 
Objective Response 
Data set:  All Randomized Patients 
 
Univariate Analysis (1) 
Multivariate Analysis (2) 
 
Treatment/ Prognostic Factors 
Odds Ratio (4) 
(90%CI) 
CMH 
p-value 
Odds Ratio (4)  
(90% C.I.) 
p-value 
from logistic 
regression 
 
 
 
 
 
Treatment arm 
 
0.*** 
 
0.*** 
 
G+N+D+T: G+N 
**.** 
 
**.** 
 
 
 
(**.**,**.**) 
 
(**.**,**.**) 
 
 
 
 
 
 
Gender 
 
0.*** 
 
0.*** 
 
Male: Female 
NC (3) 
 
**.** 
 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
Age 
 
0.*** 
 
0.*** 
 
<65: ≥65 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
Number of organ sites 
 
0.*** 
 
0.*** 
 
≤2: >2 
NC 
 
**.** 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
(1) Stratified 
(2) Stratified Logistic regression, all factors included 
(3) NC = not computed 
(4) Odds ratio of first category over second category 


PA7_SAP_draft.docx 
49 
Table 38:  Objective Response According to Pretreatment Characteristics 
Data set:  All Randomized Patients 
 
Number of Objective Responses/Number of Patients (%) 
G+N+D+T   
N=*** 
G+N 
N=*** 
Gender 
 
 
 
Male 
**/** (**) 
**/** (**) 
 
Female 
**/** (**) 
**/** (**) 
Age 
 
 
 
< 65 years 
**/** (**) 
**/** (**) 
 
≥ 65 years 
**/** (**) 
**/** (**) 
Race 
 
 
 
White 
**/** (**) 
**/** (**) 
 
Black 
**/** (**) 
**/** (**) 
 
Other 
**/** (**) 
**/** (**) 
Baseline performance status 
 
 
 
ECOG 0-1 
**/** (**) 
**/** (**) 
 
ECOG 2 
**/** (**) 
**/** (**) 
Number of organ sites 
 
 
 
≤ 2 
**/** (**) 
**/** (**) 
 
>2 
**/** (**) 
**/** (**) 
 
Table 39:  Duration of Objective Response 
Data set:  All Randomized Patients with CR or PR 
 
G+N+D+T   
N=*** 
G+N 
N=*** 
P-value(1) 
Median Duration of Objective Response (months) 
(90% CI) 
***  
(**-**) 
***  
(**-**) 
.** 
(1) Stratified 
 
 
 


PA7_SAP_draft.docx 
50 
Table 40:  Immune Response (iRECIST) 
Data set:  All Randomized  Patients 
 
Number of Patients (%)a 
N=*** 
G+N+D+T 
N=*** 
G+N 
N=*** 
 
 
 
Patients with at least one target lesion 
 
Response-evaluable  
N=*** 
 
N=*** 
N=*** 
 
N=*** 
 
Immune Complete response (iCR) 
 
** (**) 
 
** (**) 
 
Immune Partial response (iPR) 
 
** (**) 
 
** (**) 
 
Immune Stable disease (iSD) 
 
** (**) 
 
** (**) 
 
Immune confirmed progression (iCPD) 
 
** (**) 
 
** (**) 
 
Immune unconfirmed progression (iUPD) 
 
** (**) 
 
** (**) 
 
Inevaluable for response (IN) 
<Reason 1> 
<Reason 2> 
.... 
 
** (**) 
** 
** 
... 
 
** (**) 
** 
** 
.... 
 
 
 
Not response evaluable 
N=*** 
N=*** 
 
Never treated  
 
**  
 
** 
Not assessed (NA)  
 
** 
 
** 
 
Patients without any target lesion 
 
 
N=*** 
 
N=*** 
 
Immune confirmed progression (iCPD) 
 
** 
 
** 
 
Immune unconfirmed progression (iUPD) 
 
** (**) 
 
** (**) 
 
Inevaluable for response (IN) 
<Reason 1> 
<Reason 2> 
.... 
 
** 
** 
** 
... 
 
** 
** 
** 
.... 
 
Not assessed (NA) 
 
** 
 
** 
 
 
 
Never treated  
 
** 
 
** 
 
 
 
a   percentages are calculated out of the number of randomized patients 
 
 
 


PA7_SAP_draft.docx 
51 
Table 41:  Cochran Mantel Haenszel and Logistic Regression Model for Immune 
Response 
Data set:  All Randomized Patients 
 
Univariate Analysis (1) 
Multivariate Analysis (2) 
 
Treatment/ Prognostic Factors 
Odds Ratio (4) 
(90%CI) 
CMH 
p-value 
Odds Ratio (4)  
(90% C.I.) 
p-value 
from logistic 
regression 
 
 
 
 
 
Treatment arm 
 
0.*** 
 
0.*** 
 
G+N+D+T: G+N 
**.** 
 
**.** 
 
 
 
(**.**,**.**) 
 
(**.**,**.**) 
 
 
 
 
 
 
Gender 
 
0.*** 
 
0.*** 
 
Male: Female 
NC (3) 
 
**.** 
 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
Age 
 
0.*** 
 
0.*** 
 
<65: ≥65 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
Number of organ sites 
 
0.*** 
 
0.*** 
 
≤2: >2 
NC 
 
**.** 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
(1) Stratified 
(2) Stratified Logistic regression, all factors included 
(3) NC = not computed 
(4) Odds ratio of first category over second category 


PA7_SAP_draft.docx 
52 
Table 42:  Immune Response According to Pretreatment Characteristics 
Data set:  All Randomized Patients 
 
Number of Immune Responses/Number of Patients (%) 
G+N+D+T   
N=*** 
G+N 
N=*** 
Gender 
 
 
 
Male 
**/** (**) 
**/** (**) 
 
Female 
**/** (**) 
**/** (**) 
Age 
 
 
 
< 65 years 
**/** (**) 
**/** (**) 
 
≥ 65 years 
**/** (**) 
**/** (**) 
Race 
 
 
 
White 
**/** (**) 
**/** (**) 
 
Black 
**/** (**) 
**/** (**) 
 
Other 
**/** (**) 
**/** (**) 
Baseline performance status 
 
 
 
ECOG 0-1 
**/** (**) 
**/** (**) 
 
ECOG 2 
**/** (**) 
**/** (**) 
Number of organ sites 
 
 
 
≤ 2 
**/** (**) 
**/** (**) 
 
>2 
**/** (**) 
**/** (**) 
 
Table 43:  Duration of Immune Response 
Data set:  All Randomized Patients with iCR or iPR 
 
G+N+D+T   
N=*** 
G+N 
N=*** 
P-value(1) 
Median Duration of Immune Response (months) 
(90% CI) 
***  
(**-**) 
***  
(**-**) 
.** 
(1) Stratified 
 


PA7_SAP_draft.docx 
53 
Table 44:  Acute (On Treatment) Adverse Events  
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any 
grade 
 
NR 
1 
2 
3 
4 
5 
 
Patients with any AE 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
Note: Same table will be made for patients on G+N Arm. 
 
Table 45: Severe Acute (On Treatment) Adverse Events  
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 3 
or higher AE 
 
 
 
 
3 
4 
5 
 
Patients with any AE 
 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 (1) Patients may have more than one event within a category. 
 
Note: Same table will be made for patients on G+N Arm. 
 
 


PA7_SAP_draft.docx 
54 
Table 46: Drug Related Acute (on Treatment) Adverse Events  
(1) Related to Durvalumab 
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
1 
2 
3 
4 
5 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE related to 
durvalumab within category 
 
Category 1(a) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(a) 
Event 1  
...  
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(a) Patients may have more than one event within a category. 
 
(2) Related to Tremelimumab 
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
1 
2 
3 
4 
5 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE related to 
Tremelimumab within category 
 
Category 1(a) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(a) 
Event 1  
...  
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(a) Patients may have more than one event within a category.


PA7_SAP_draft.docx 
55 
(3) Related to Durvalumab or Tremelimumab 
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
1 
2 
3 
4 
5 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE related to 
Durvalumab or Tremelimumab 
within category 
 
Category 1(a) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(a) 
Event 1  
...  
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(a) Patients may have more than one event within a category. 
 
(4) Related to Both Durvalumab and Tremelimumab 
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
1 
2 
3 
4 
5 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE related to both 
Durvalumab and 
Tremelimumab within category 
 
Category 1(a) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(a) 
Event 1  
...  
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 


PA7_SAP_draft.docx 
56 
(5) Related to Gemcitabine 
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
1 
2 
3 
4 
5 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE related to 
Gemecitabine within category 
 
Category 1(a) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(a) 
Event 1  
...  
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(a) Patients may have more than one event within a category. 
 
Note: Same table will be made for patients on G+N Arm. 
 
(6) Related to Nab-paclitaxel 
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
1 
2 
3 
4 
5 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE related to 
Nab-paclitaxel within category 
 
Category 1(a) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(a) 
Event 1  
...  
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(a) Patients may have more than one event within a category. 
 
Note: Same table will be made for patients on G+N Arm. 
 
 


PA7_SAP_draft.docx 
57 
 
Table 47:  Immune-related Acute (On Treatment) Adverse Events 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
1 
2 
3 
4 
5 
 
Patients with any irAE 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with irAE 
within category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
(1) Patients may have more than one event within a category. 
 
Note: Same table will be made for patients on G+N Arm. 
 
Table 48: Severe Acute (On Treatment) Immune-related Adverse Events  
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 3 or 
higher irrAE 
 
 
 
 
3 
4 
5 
 
Patients with any irAE 
 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with irAE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 (1) Patients may have more than one event within a category. 
 
Note: Same table will be made for patients on G+N Arm. 


PA7_SAP_draft.docx 
58 
Table 49:  Delayed (During Follow-up) Adverse Events 
 
Data set:  All Treated Patients on G+N+D+T Arm 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
1 
2 
3 
4 
5 
 
Patients with any 
delayed AE 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with delayed 
AE within category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
(1) Patients may have more than one event within a category. 
 
Note:  The same type of table will be made for G+N Arm. 
 
 


PA7_SAP_draft.docx 
59 
Table 50:  Hematology During Protocol Treatment: Worst Grade per Patient 
Data set:  All Treated Patients  
 
Number of Patients (%) 
 
G+N+D+T  
N = *** 
G+N  
N = *** 
Hemoglobin 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
Platelet 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
WBC 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
Neutrophils 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
RBC 
 
 
 
Normal 
** (**) 
** (**) 
 
High (1) 
** (**) 
** (**) 
Lymphocytes 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
Monocytes 
 
 
 
Normal 
** (**) 
** (**) 
 
High (1) 
** (**) 
** (**) 
Eosinophils 
 
 
 
Normal 
** (**) 
** (**) 
 
High (1) 
** (**) 
** (**) 
Basophils 
 
 
 
Normal 
** (**) 
** (**) 
 
High (1) 
** (**) 
** (**) 
(1) Greater than upper normal limit 
 
 
 
 
 


PA7_SAP_draft.docx 
60 
Table 51:  Hematology During Follow-up: Worst Grade per Patient 
Data set:  All Treated Patients 
 
Number of Patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
Hemoglobin 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
Platelet 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
WBC 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
Neutrophils 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
RBC 
 
 
 
Normal 
** (**) 
** (**) 
 
High (1) 
** (**) 
** (**) 
Lymphocytes 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
Monocytes 
 
 
 
Normal 
** (**) 
** (**) 
 
High (1) 
** (**) 
** (**) 
Eosinophils 
 
 
 
Normal 
** (**) 
** (**) 
 
High (1) 
** (**) 
** (**) 
Basophils 
 
 
 
Normal 
** (**) 
** (**) 
 
High (1) 
** (**) 
** (**) 
(1) Greater than upper normal limit 


PA7_SAP_draft.docx 
61 
Table 52:  Serum Chemistry during Protocol Treatment:  Worst Grade per 
Patient 
Data set:  All Treated Patients  
 
Number of Patients (%) 
 
G+N+D+T  
N = *** 
G+N  
N = *** 
Total bilirubin 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Creatinine clearance 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
ALT 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
AST 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
LDH 
 
 
 
Normal 
** (**) 
** (**) 
 
High(2) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Serum Creatinine 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypernatremia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hyponatremia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hyperkalemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 


PA7_SAP_draft.docx 
62 
 
Not reported (1) 
** (**) 
** (**) 
Hypokalemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypercalcemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypocalcemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypermagnesemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypomagnesemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hyperglycemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypoglycemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hyperalbuminemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 


PA7_SAP_draft.docx 
63 
 
Not reported (1) 
** (**) 
** (**) 
Hypoalbuminemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Chloride 
 
 
 
Normal 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Amylase 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
ALP 
 
 
 
Normal 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Lipase 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Urea/BUN 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
(1) Greater than upper normal limit 
 


PA7_SAP_draft.docx 
64 
Table 53:  Serum Chemistry During Follow-up:  Worst Grade per Patient 
Data set:  All Treated Patients 
 
Number of Patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
Total bilirubin 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Creatinine clearance 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
ALT 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
AST 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
LDH 
 
 
 
Normal 
** (**) 
** (**) 
 
High(2) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Serum Creatinine 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypernatremia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hyponatremia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hyperkalemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 


PA7_SAP_draft.docx 
65 
Hypokalemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypercalcemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypocalcemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypermagnesemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypomagnesemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hyperglycemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hypoglycemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Hyperalbuminemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 


PA7_SAP_draft.docx 
66 
Hypoalbuminemia 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Chloride 
 
 
 
Normal 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Amylase 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
ALP 
 
 
 
Normal 
** (**) 
** (**) 
 
High (2) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Lipase 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
Urea/BUN 
 
 
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
(1) Greater than upper normal limit 


PA7_SAP_draft.docx 
67 
Table 54:  Thyroid Function Tests: Worst During Protocol Treatment 
Data set:  All Treated Patients  
 
Number of Patients (%) 
 
G+N+D+T  
N = *** 
G+N  
N = *** 
TSH 
 
 
 
Normal  
** (**) 
 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
 
** (**) 
T3 Free 
** (**) 
 
 
Normal  
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
T3 Total 
 
** (**) 
 
Normal  
** (**) 
 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
T4 Free 
 
** (**) 
 
Normal  
** (**) 
 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
T4 Total 
 
** (**) 
 
Normal  
** (**) 
 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
 
 
 


PA7_SAP_draft.docx 
68 
Table 55:  Thyroid Function Tests: Worst during Follow-up 
Data set:  All Treated Patients 
 
Number of Patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
TSH 
 
 
 
Normal  
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
T3 Free 
 
 
 
Normal  
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
T3 Total 
 
 
 
Normal  
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
T4 Free 
 
 
 
Normal  
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
T4 Total 
 
 
 
Normal  
** (**) 
** (**) 
 
<1-0.5xLLN 
** (**) 
** (**) 
 
<0.5-0.1xLLN 
** (**) 
** (**) 
 
<0.1xLLN 
** (**) 
** (**) 
 


PA7_SAP_draft.docx 
69 
Table 56: Coagulation Tests: Worst During Protocol Treatment 
 
Data set:  All Treated Patients 
 
Number of Patients (%) 
 
G+N+D+T 
N = *** 
G+N 
N = *** 
PT 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
INR 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
 
 
PTT 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
Table 57:  Coagulation Tests: Worst During Follow-up 
Data set:  All Treated Patients 
 
Number of Patients (%) 
 
G+N+D+T   
N = *** 
G+N 
N = *** 
PT 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
INR 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
PTT 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 


PA7_SAP_draft.docx 
70 
Table 58:  ECG Results During Protocol Treatment 
Data set:  All Treated Patients  
 
Number of patients (%) 
 
G+N+D+T 
N=*** 
G+N 
N=*** 
ECG reported  
*** (**) 
*** (**) 
All Normal 
** 
** 
At least one abnormal but none clinically important 
At least one abnormal and clinically important 
** 
** 
 
 
 
ECG not reported/not performed 
*** (**) 
*** (**) 
 
 Table 59 : Urinalysis During Protocol Treatment 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
G+N+D+T 
N=*** 
G+N 
N=*** 
Urinalysis – SPOT Test 
 
 
Negative/trace 
**(**) 
**(**) 
1+(>20 mg/dL–30 mg/dL) 
**(**) 
**(**) 
2+(>30 mg/dL–100 mg/dL) 
**(**) 
**(**) 
3+(>100 mg/dL– 300 mg/dL) 
**(**) 
**(**) 
4+(>300 mg/dL) 
**(**) 
**(**) 
 
 
 
Urinalysis – 24-Hour Test (g/day) 
 
 
Grade 
 
 
1 
**(**) 
**(**) 
2 
**(**) 
**(**) 
3 
**(**) 
**(**) 
 
Table 60:  Deaths During or within 4 weeks of Last Protocol Treatment 
Data set:  All Treated Patients  
 
Number of Patients (%) 
 
G+N+D+T   
N=*** 
G+N  
N=*** 
Number of  Patients who died during or within 4 
weeks of last protocol treatment  
** (**) 
** (**) 
 
 
 
Cause of Death 
 
 
 
Colorectal cancer 
** 
** 
 
Toxicity from protocol treatment 
** 
** 
 
Colorectal cancer + Toxicity from protocol 
 
 
treatment complication 
** 
** 
 
Non-protocol Treatment Complication 
** 
** 
 
Colorectal cancer + Non-protocol  
 
 
Treatment Complication 
** 
** 
 
Other Primary Malignancy 
** 
** 
 
Other Condition or Circumstance 
** 
** 


PA7_SAP_draft.docx 
71 
 
Table 61:  Adverse Event leading to Discontinuation of protocol Treatment(a) 
Data set:  All Treated Patients  
 
Number of patients (%) 
 
G+N+D+T  
N=*** 
G+N  
N=*** 
Number discontinued durvalumab from adverse events 
 
      <Adverse event 1> 
      <Adverse event 2> 
      .... 
 
** (**) 
 
 
** 
** 
 
** (**) 
 
 
** 
** 
 
Number discontinued Tremelimunab from adverse events 
 
      <Adverse event 1> 
      <Adverse event 2> 
      .... 
 
** (**) 
 
 
** 
** 
 
** (**) 
 
 
** 
** 
 
Number discontinued Gemcitabine from adverse events 
 
      <Adverse event 1> 
      <Adverse event 2> 
      .... 
 
** (**) 
 
 
** 
** 
 
** (**) 
 
 
** 
** 
 
Number discontinued Nan-paclitaxel from adverse events 
 
      <Adverse event 1> 
      <Adverse event 2> 
      .... 
 
** (**) 
 
 
** 
** 
 
** (**) 
 
 
** 
** 
 
** (**) 
 
 
** 
** 
 
** (**) 
 
** 
** 
 
** (**) 
 
 
** 
** 
 
** (**) 
 
** 
** 
 
(a) From End of Treatment Form with off reasons= =”Adverse events related to protocol therapy”. 
 
Table 62:  Concomitant Medications 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
G+N+D+T 
N = *** 
G+N 
N=*** 
Any concomitant medication during or 4 weeks after protocol treatment  
No 
Yes 
 
 
 
** (**) 
** (**) 
 
 
 
** (**) 
** (**) 
 
 
 
Type of concomitant medications(1) 
 
Medication A 
 
… 
 
** (**) 
 
** (**) 
 
 
 
(1):  patients may have received more than one concomitant medication. 


PA7_SAP_draft.docx 
72 
Table 63:   Anti-Cancer Treatment 
 
Number of patients (%) 
 
G+N+D+T   
N=*** 
G+N 
N =*** 
Number of patients with any anti-cancer treatment during or 
4 weeks after protocol treatment 
*** (**) 
NAP (NAP) 
   Chemotherapy (1) 
 
Drug 1 … 
   Radiotherapy (1) 
   Hormonal therapy (1) 
 
Drug 1 … 
   Immunotherapy (1) 
 
Drug 1 … 
   Other (1) 
 
Drug 1 … 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
NAP (NAP) 
NAP (NAP) 
NAP (NAP) 
NAP (NAP) 
NAP (NAP) 
NAP (NAP) 
NAP (NAP) 
NAP (NAP) 
NAP (NAP) 
Number of patients with any anti-cancer treatment during 
follow-up 
*** (**) 
*** (**) 
   Chemotherapy (1) 
 
Drug 1 … 
   Radiotherapy (1) 
   Hormonal therapy (1) 
 
Drug 1 … 
   Immunotherapy (1) 
 
Drug 1 … 
   Other (1) 
 
Drug 1 … 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
 
(1) Patients could have more than one type of anti-cancer treatment. NA=Not applicable. 
 
Table 64:  Major Medical Problems 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
G+N+D+T 
N = *** 
G+N 
N=*** 
Any major medical problem during or 4 weeks after protocol treatment  
No 
Yes 
 
 
 
** (**) 
** (**) 
 
 
 
** (**) 
** (**) 
 
 
 
Type of major medical problems(1) 
 
Medication A 
 
… 
 
** (**) 
 
** (**) 
 
 
 
(1):  patients may have more than one major medical problem. 
 


PA7_SAP_draft.docx 
73 
Table 65: Compliance Rate with QoL Assessment by Treatment Arm 
 
G+N+D+T 
G+N 
 
Expected 
Received (%) 
Expected 
Received (%) 
Baseline 
*** 
** (**) 
*** 
** (**) 
During protocol treatment 
 
 
 
 
 
4 weeks 
*** 
** (**) 
*** 
** (**) 
 
8 weeks 
*** 
** (**) 
*** 
** (**) 
 
12 weeks 
*** 
** (**) 
*** 
** (**) 
 
16 weeks 
*** 
** (**) 
*** 
** (**) 
 
24 weeks 
*** 
** (**) 
*** 
** (**) 
After protocol treatment 
 
 
 
 
 
3 months 
*** 
** (**) 
*** 
** (**) 
 
6 months 
*** 
** (**) 
*** 
** (**) 
 
12 months 
*** 
** (**) 
*** 
** (**) 
 
15 months 
*** 
** (**) 
*** 
** (**) 
 
18 months 
*** 
** (**) 
*** 
** (**) 
 
21 months 
*** 
** (**) 
*** 
** (**) 
 
24 months 
*** 
** (**) 
*** 
** (**) 
 
Table 66: Proportion of Patients with Deterioration, Improvement or Stable 
QoL 
 
N 
G+N+D+T   
N (%) 
G+N 
N (%) 
P value* 
 
Deterioration 
 
 
 
 
   Physical function 
 
 
 
0.*** 
 
Week 8 
*** 
*** (**.**) 
*** (**.**) 
 
 
Week 16 
*** 
*** (**.**) 
*** (**.**) 
 
   Global health status 
 
 
 
0.*** 
 
Week 8 
*** 
*** (**.**) 
*** (**.**) 
 
 
Week 16 
*** 
*** (**.**) 
*** (**.**) 
 
 
 
 
 
 
 
Improvement 
 
 
 
 
   Physical function 
 
 
 
0.*** 
 
Week 8 
*** 
*** (**.**) 
*** (**.**) 
 
 
Week 16 
*** 
*** (**.**) 
*** (**.**) 
 
   Global health status 
 
 
 
0.*** 
 
Week 8 
*** 
*** (**.**) 
*** (**.**) 
 
 
Week 16 
*** 
*** (**.**) 
*** (**.**) 
 
 
 
 
 
 
Stable 
 
 
 
 
   Physical function 
 
 
 
0.*** 
 
Week 8 
*** 
*** (**.**) 
*** (**.**) 
 
 
Week 16 
*** 
*** (**.**) 
*** (**.**) 
 
   Global health status 
 
 
 
0.*** 
 
Week 8 
*** 
*** (**.**) 
*** (**.**) 
 
 
Week 16 
*** 
*** (**.**) 
*** (**.**) 
 
* Fisher’s exact test 
 
 


PA7_SAP_draft.docx 
74 
Table 67:  Time to Deterioration in QoL Primary Endpoints 
 
Data set:  All patients who had baseline and at least one follow-up QoL assessment 
G+N+D+T 
G+N 
N 
Median (months) 
(90% CI) 
N 
Median (months) 
(90% CI) 
Physical function 
*** 
**.** 
(**.**, **.**) 
*** 
**.** 
(**.**, **.**) 
Global Health Scale 
*** 
**.** 
(**.**, **.**) 
*** 
**.** 
(**.**, **.**) 
 
Table 68: QoL: Summary Baseline Scores 
 
G+N+D+T   
G+N 
P value* 
 
Functional scales 
 
 
 
Physical 
 
 
0.*** 
 
N 
*** 
*** 
 
 
Mean 
*** 
*** 
 
 
STD 
*** 
*** 
 
... 
... 
... 
 
Global health status 
 
 
0.*** 
 
N 
*** 
*** 
 
 
Mean 
*** 
*** 
 
 
STD 
*** 
*** 
 
Symptom scales 
 
 
 
Fatigue 
 
 
0.*** 
 
N 
*** 
*** 
 
 
Mean 
*** 
*** 
 
 
STD 
*** 
*** 
 
… 
… 
… 
 
* Wilcoxon rank sum test 
 
 
 


PA7_SAP_draft.docx 
75 
Table 69: Summary QOL Change Scores from Baseline for Scale/Domain/Item 
at Each Time Period* 
 
G+N+D+T   
G+N 
 
P Value** 
 
 
Scale/Domain/Item 
 
 
 
During protocol treatment 
  Week 4 
 
 
.** 
 
N 
***  
*** 
 
 
Mean (STD) 
** (**) 
** (**) 
 
  Week 8 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
 Week 12 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
 Week 16 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
 Week 24 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
After protocol treatment 
  3 months 
 
 
.** 
 
N 
*** 
*** 
 
 
Mean (STD) 
** (**) 
** (**) 
 
  6 months 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
 9 months 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
 12 months 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
 15 months 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
18 months 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
 21 months 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
 24 months 
 
 
.** 
 
N 
 
 
 
 
Mean (STD) 
** (**) 
** (**) 
 
* Table will be provided for each scale/domain/item. 
** Wilcoxon rank sum test 
 
 
 
 


PA7_SAP_draft.docx 
76 
Table 70: Results for QOL Response Analyses 
 
 
Domain 
G+N+D+T  
Improved     Stable    Worsened 
N (%) 
G+N 
Improved     Stable    Worsened 
N (%) 
 
P-value* 
EORTC QLQ-C30 
Physical 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Role 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Emotional 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Cognitive 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Social 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Global 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Pain 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Fatigue 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Nausea 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Dyspnea 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Sleep 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Appetite 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Constipation 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Diarrhea 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
Financial 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
***(**) 
.** 
* Chi-square test