Clinical trial NCT03094286
Conditions: HIV Cancer
Keywords: HIV HIV with cancer patient D006678
Sponsor: Spanish Lung Cancer Group
Start date: 2017-04-24; Completion date: 2022-03-22
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The proposal is a phase II clinical study designed to assess the feasibility of durvalumab (MEDI4736) in HIV-1-infected individuals with solid tumors. Additionally, to obtain data that lets understand the possible benefit of this treatment in cancer patients and HIV infection, exploring if activity of durvalumab (MEDI4736) could be higher in cancer that has been produced at least in part due to the chronic immunosupression. Simultaneously, it will allow us to investigate the effect of disrupting this immunoregulatory pathway might have in reversing cancer pathways and HIV-specific T-cell function during persistent chronic HIV infection in humans.

Detailed description:
PD-1/ PD-L1 coinhibitory pathway plays a significant role in the regulation of the immune response in both chronic infectious diseases and cancer.

Preclinical and animal data support the safety and promising activity of anti-PD-1 antibody in HIV-1 infection.

Demonstrated anticancer activity and safety profile of durvalumab (MEDI4736) in cancer clinical trials.

Unlikely drug interactions of durvalumab (MEDI4736) and antiretroviral treatments.

The proposal is a phase II clinical study designed to assess the feasibility of durvalumab (MEDI4736) in HIV-1-infected individuals with solid tumors. Additionally, to obtain data that lets understand the possible benefit of this treatment in cancer patients and HIV infection, exploring if activity of durvalumab (MEDI4736) could be higher in cancer that has been produced at least in part due to the chronic immunosupression. Simultaneously, it will allow us to investigate the effect of disrupting this immunoregulatory pathway might have in reversing cancer pathways and HIV-specific T-cell function during persistent chronic HIV infection in humans.

In this regard, our hypothesis is:

HIV patients with cancer have a similar outcome in terms of tolerability when treated with durvalumab (MEDI4736) monotherapy at the recommended dose than non HIV infected patients.

Arms: arm 1: Durvalumab (MEDI4736) monotherapy at the recommended dose of 1500mg every 4 weeks in solid tumors in HIV-1-infected patients
Interventions: intervention 1: Durvalumab
Intervention descriptions: intervention 1: Durvalumab monotherapy of 1500mg every 4 weeks in solid tumors in HIV-1-infected patients until progression significant clinical deterioration, unacceptable toxicity, any criterion for withdrawal from the trial or trial drug is fulfilled

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
 
Official Title:  A phase II exploratory study of durvalumab (MEDI4736) in HIV-1 
patients with advanced solid tumors. 
 
 
NCT Number: NCT03094286 
 
Document Dates: Protocol Amendment Version 4.1: 14 November 2018 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 2 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
 
 
 
 
A PHASE II EXPLORATORY STUDY OF DURVALUMAB 
(MEDI4736) IN HIV-1 PATIENTS WITH ADVANCED SOLID 
TUMORS 
DURVAST: Durvalumab in solid tumors 
 
 
Study Sponsor: Fundación GECP 
EudraCT Number: 2016-004524-38  
Sponsor code: GECP 16/04 
Astra Zeneca Study number: ESR 15-10869 
  
Version 4.1 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 3 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
 
 
 
Protocol Signature Page 
A PHASE II EXPLORATORY STUDY OF DURVALUMAB (MEDI4736) IN 
HIV-1 PATIENTS WITH ADVANCED SOLID TUMORS 
DURVAST: Durvalumab in solid tumors 
Sponsor code: GECP 16/04 
Approved By 
Signature 
 
___________________ 
Dr. Rafael Rosell 
Principal investigator 
Signature 
 
 
__________________ 
Dra. González Cao 
Study coordinator 
Signature 
 
_________________ 
Dr. Mariano Provencio 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 4 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Fundación GECP President 
 
Principal Investigator Protocol Signature Page 
Study Title: “A phase II exploratory study of durvalumab (MEDI4736) in HIV-1 patients with 
advanced solid tumors” 
Sponsor protocol code: GECP 16/04 
EudraCT Number: 2016-004524-38  
Protocol version: v 4.1, 14th November 2018 
As principal investigator of this site, I hereby confirm that: 
I have read the protocol and agree that it contains all necessary details for conducting this trial. I will 
conduct the trial as outlined in the following protocol and in compliance with GCP, and will apply due 
diligence to avoid protocol deviations.  
I will provide copies of the protocol and all drug information relating to pre-clinical and prior clinical 
experience furnished to me by the Fundación GECP, to all physicians responsible to me who participate 
in this trial. I will discuss this material with them to assure that they are fully informed regarding the drug 
and the conduct of the trial.  
I agree to keep accurate records on all patient information including patient's informed consent statement, 
drug shipment and return forms, and all other information collected during the trial for a minimum period 
of 25 years according to the new Royal Decree 1090/2015 approved in Spain. 
 
Name of Principal Investigator:_______________________________________________ 
 
Institution’s name and place:_________________________________________________ 
 
_____________________________________________________ 
______________ 
 
Signature                                                                                                                 Date 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 5 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Investigational Drug 
Substance(s) 
Durvalumab (Medi4736)  
Version 
4.1 
Date 
14th November 2018 
A phase II exploratory study of durvalumab (MEDI4736) in HIV-1 patients with advanced 
solid tumors 
Sponsor:  
 
Fundación GECP 
 
 
 
 
 
Av. Meridiana, 358 6ª Planta 
 
 
 
 
 
08027 Barcelona 
 
 
 
 
 
Phone:+34 93 430 20 06 / Fax: +34 93 419 17 68 
 
 
 
 
 
E-mail: gecp@gecp.org 
Principal Investigator: 
 
Dr. Rafael Rosell 
Instituto Oncológico Dr. Rosell 
Oncology Department 
Sabino Arana 5 
08028 Barcelona 
Phone: +34935460135 / Fax: +34935460196 
E-mail: rrosell@iconcologia.net 
Study Coordinator:  
 
Dr. María Gonzalez-Cao 
Instituto Oncológico Dr. Rosell 
Oncology Department 
Sabino Arana 5 
08028 Barcelona 
Phone: +34935460135 
E-mail: mgonzalezcao@oncorosell.com 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 6 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
 
PROTOCOL SYNOPSIS 
Clinical Protocol GECP16/04 (ESR 15-10869) 
Study Title:Phase II exploratory study of durvalumab (MEDI4736) in HIV-1 patients with advanced 
solid tumors 
 
Protocol Number: GECP 16/04 (ESR-15-10869) 
 
Clinical Phase: II 
 
Study Duration: 
Recruitment period will be 12 months 
First subject in: Q1, 2016 
Last subject out: Q1, 2018 
Survival follow-up will continue until 5 years after the last subject receives the last dose of durvalumab 
 
Investigational Product(s) and Reference Therapy: 
Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 50 
mg/mL for intravenous (IV) administration. 
 
Research Hypothesis 
PD-1/ PD-L1 coinhibitory pathway plays a significant role in the regulation of the immune response in 
both chronic infectious diseases and cancer.  
Preclinical and animal data support the safety and promising activity of anti-PD-1 antibody in HIV-1 
infection. 
Demonstrated anticancer activity and safety profile of durvalumab (MEDI4736) in cancer clinical trials. 
Unlikely drug interactions of durvalumab (MEDI4736) and antiretroviral treatments. 
We propose a phase II clinical study designed to assess the feasibility of durvalumab (MEDI4736) in 
HIV-1-infected individuals with solid tumors. Additionally we hope to obtain data that let us understand 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 7 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
the possible benefit of this treatment in cancer patients and HIV infection, exploring if activity of 
durvalumab (MEDI4736) could be higher in cancer that has been produced at least in part due to the 
chronic immunosupression. Simultaneously, it will allow us to investigate the effect of disrupting this 
immunoregulatory pathway might have in reversing cancer pathways and HIV-specific T-cell function 
during persistent chronic HIV infection in humans. 
In this regard, our hypothesis is: 
HIV patients with cancer have a similar outcome in terms of tolerability when treated with durvalumab 
(MEDI4736) monotherapy at the recommended dose than non HIV infected patients. 
Objectives: 
Primary Objectives: 
To explore the feasibility of durvalumab (MEDI4736) monotherapy at the recommended dose of 
1500mg every 4 weeks in solid tumors in HIV-1-infected patients.  
Secondary Objective(s): 
• 
To assess ORR (RECIST 1.1 and irRECIST) and duration of response. 
• 
To evaluate the PFS rate at 6 months. 
• 
To evaluate the OS rate at 12 months. 
Exploratory Objective(s): 
• 
To measure activity of durvalumab (MEDI4736) in terms of antiviral activity, exploring: 
o Changes in the viral reservoir. 
o Changes in residual viral replication. 
o Changes in the composition and function of circulating T lymphocytes. 
• 
To explore molecular predictive factors of antitumoral activity in pretreatment tumor samples 
and blood samples. 
 
Study Design: 
This is a multicenter, national, nonrandomized, open label trial, phase II trial in subjects with advanced 
solid tumors and HIV-1 infection. Twenty patients will receive durvalumab. 
Patients have to be diagnosed of advanced (metastatic or locally advanced disease without cure options 
with surgery or radiotherapy) cancer of any of these types: lung cancer, head and neck cancer, cervical 
cancer, melanoma, anal cancer, pancreatic cancer, gastro-esophageal cancer, triple negative breast 
cancer, bladder cancer, renal cancer, Cholangiocarcinoma, Kaposi sarcoma, lymphomas, ovarian cancer, 
Merkel cell carcinoma or any other tumor type in which anti PD-1 or anti PD-L1 antibodies have 
demonstrated antitumoral activity. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 8 of 151 
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Adverse events (AEs) will be assessed throughout and evaluated using National Cancer Institute (NCI) 
Common Technology Criteria version of Adverse Events version 4.03 (CTCAE v 4.03). 
Tumor measurements by PET-CT, CT scan or MRI will be performed every 8 weeks to determine 
response to treatment. Response will be evaluated using Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1) and immune related response criteria (irRECIST). 
Treatment will continue until disease progression, significant clinical deterioration, unacceptable 
toxicity, any criterion for withdrawal from the trial or trial drug is fulfilled. Treatment may continue past 
the initial determination of disease progression per RECIST1.1 if the subject`s performance status has 
remained stable, and if the opinion of the Investigator, the subject will benefit from continued treatment 
and if other criteria are fulfilled as outline in the protocol.  
Number of Centers: between 5 and 10 
Number of Subjects: 20 
Study Population: 
The study will be performed in 20 HIV patients with a histological confirmed diagnosed of advanced 
solid tumors (lung cancer, head and neck cancer, cervical cancer, melanoma, anal cancer, pancreatic 
cancer, gastro-esophageal cancer, triple negative breast cancer, bladder cancer, renal cancer, 
Cholangiocarcinoma, Kaposi sarcoma, lymphomas, ovarian cancer, Merkel cell carcinoma  or any other 
tumor type in which anti PD-1 or anti PD-L1 antibodies have demonstrated antitumoral activity) 
for which no additional oncologic standard treatment is available, or for which the subject declines 
standard treatment.  
Recruitment period will be 12 months. 
Patients will continue their antiretroviral treatment during study time, following standard HIV-1 
treatment recommendations. 
Inclusion Criteria: 
1. 
Written informed consent obtained from the subject prior to performing any protocol-
related procedures, including screening evaluations.  
2. 
Age > 18 years at time of study entry. 
3. 
Eastern Cooperative Oncology Group (ECOG) 0-2 
4. 
Life expectancy of > 16 weeks 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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5. 
Adequate normal organ and marrow function as defined below:  
− 
Haemoglobin ≥ 9.0 g/dL 
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
− 
Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
− 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will not 
apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of 
haemolysis or hepatic pathology), who will be allowed only in consultation with 
their physician. 
− 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 5x ULN 
− 
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance: 
 
 
 
 
 
 
6. 
Female subjects must either be of non-reproductive potential (ie, post-menopausal by 
history: ≥60 years old and no menses for 1 year without an alternative medical cause; 
OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of 
bilateral oophorectomy) or must have a negative serum pregnancy test upon study 
entry.   
Males: 
 
 
Creatinine 
CL (mL/min) 
= 
Weight(kg)x(140 – Age)  
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine 
CL (mL/min) 
= 
Weight (kg) x (140 – Age)  x0.85 
72 x serum creatinine (mg/dL) 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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7. 
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including 
follow up. 
8. 
Subjects with histologically or cytologically advanced/metatasic-documented lung 
cancer, head and neck cancer, cervical cancer, melanoma, anal cancer, pancreatic 
cancer, gastroesophageal cancer, triple negative breast cancer, bladder cancer, renal 
cancer, Cholangiocarcinoma, Kaposi sarcoma, lymphomas, ovarian cancer, Merkel cell 
carcinoma or any other tumor type in which anti PD-1 or anti PD-L1 antibodies have 
demonstrated antitumoral activity, refractory to standard treatment, intolerant of 
standard treatment, or for which no standard therapy exists or who refuse the standard 
treatment. 
9. 
Subjects may be included irrespectively of number of previous lines of treatment for 
advanced disease. 
10. 
Prior palliative radiotherapy must have been completed at least 2 weeks prior to start 
the study treatment (subjects may receive localized palliative radiotherapy while 
receiving study drug). 
11. 
Documented HIV-1 infection  
12. 
Undetectable viral load in the last analysis.  
13. 
Subjects with brain metastases are eligible if they are asymptomatic, are treated or 
are neurological stable for at least 2 weeks without the use of steroids or on stable or 
decreasing dose of < 10 mg daily prednisone or equivalent. 
14. 
Subjects must be following an antiretroviral therapy at the moment of the inclusion. 
 
Exclusion Criteria: 
1. Involvement in the planning and/or conduct of the study. Previous enrollment in the 
present study. 
2. Participation in another clinical study with an investigational product during the last 4 
weeks. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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3. Other untreated coexisting HIV related malignancies. 
4. Any previous treatment with a PD1, PD-L1 or PD-L2 inhibitor, including durvalumab. 
5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, other investigational agent) 28 days prior to the first dose of study drug. 
6. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia’s Correction. 
7. Current or prior use of immunosuppressive medication within 28 days before the first 
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of 
prednisone, or an equivalent corticosteroid. 
8. Any unresolved toxicity (CTCAE grade 2) from previous anti-cancer therapy.  Subjects 
with irreversible toxicity that is not reasonably expected to be exacerbated by the 
investigational product may be included (e.g., hearing loss, peripherally neuropathy). 
9. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1.  
10. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects 
with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the 
past 2 years) are not excluded. 
11. Any syndrome that requires systemic corticosteroid/immunosuppressive medications 
EXCEPT for syndromes which would not be expected to recur in the absence of an 
external trigger (vitiligo, autoimmune thyroiditis, or type 1 diabetes mellitus are 
permitted to enroll) 
12. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis). 
13. History of primary immunodeficiency. 
14. History of allogeneic organ transplant.  
15. History of hypersensitivity to durvalumab or any excipient. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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16. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active 
bleeding diatheses including any subject known to have evidence of acute or chronic 
hepatitis B or C, or psychiatric illness/social situations that would limit compliance with 
study requirements or compromise the ability of the subject to give written informed 
consent. 
17. Known history of active tuberculosis. 
18. Any serious or uncontrolled medical disorder or active infection non HIV, that would 
impair the ability of the subject to receive the treatment of protocol therapy under 
treating physician criteria. 
19. Subjects with previous malignances (except non melanoma skin cancer, and cancer in 
situ of: bladder, gastric, colon, cervical/dysplasia, melanoma, breast) are excluded unless 
a complete remission was achieved at least 5 years prior to study entry and no additional 
therapy is required or anticipated to be required during the study period. 
20. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 
days of receiving durvalumab. 
21. Female subjects who are pregnant, breast-feeding, male, or female patients of 
reproductive potential who are not employing an effective method of birth control. 
22. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results. 
23. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive 
of but not limited to surgery, radiation and/or corticosteroids.  
24. Subjects with uncontrolled seizures. 
25. Patients with tumoral disease in the head and neck region, such as peritracheal or 
periesophageal lymph node involvement, with infiltration of structures of the digestive, 
aerea or vascular pathways that represent a risk of increased bleeding. 
26. Patients with neuroendocrine tumors of pulmonary origin or pulmonary metastases 
with evidence of active bleeding. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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27. Patients with digestive bleeding. 
Investigational Product(s), Dose and Mode of Administration: 
Durvalumab, 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) if> 30 kg. 
If patient is ≤30 kg, weight-based dosing, equivalent to 20 mg/kg Q4W, should be used (Appendix 2). 
 
Study Assessments and Criteria for Evaluation: 
Safety Assessments: 
- Safety assessments will be based on adverse event reports, results of clinical laboratory tests, immune 
safety tests, physical examinations, vital sign measurements, ECOG performance status during the study 
and up to six months following the last study drug administration. It will be reported based on Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0.  
Efficacy Assessments: 
-Tumor response evaluation will be classified according to RECIST 1.1 criteria and irRECIST criteria. 
- Progression free survival at 6 months and overall survival at 12 months. 
Translational study 
All patients will undergo baseline tumor tissue acquisition (paraffin-embedded cores) prior to 
enrollment. If it is not possible to perform a new biopsy, patient can be included if they have an archival 
tissue biopsy. 
Peripheral blood samples will be collected: pretreatment, after 2 weeks, 4 weeks, 12 weeks, 24 weeks. 
Patients that continue on treatment after 24 weeks will have peripheral blood samples every 12 weeks 
until disease progression or at least until week 72 in the absence of progression. The following 
analyses will be performed in the blood samples: 
o Changes in the viral reservoir. 
o Changes in residual viral replication. 
o Changes in the composition and function of circulating T lymphocytes. 
o Molecular analysis of circulating tumor DNA 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 14 of 151 
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Statistical Methods and Data Analysis: 
The primary endpoint of the study is the feasibility of durvalumab monotherapy at the recommended 
dose of 1500 mg every 4 weeks in solid tumors in HIV-1-infected patients.  
 
Feasibility will be defined based on the rate of patients that will complete at least 4 treatment cycles. 
One cycle is four weeks with infusions every four weeks. It is assumed that at least 50% of patients must 
be complete 4 cycles for considering feasible the treatment with durvalumab. 
Kaplan Meier method will be used to estimate the survival function. Secondary measurements will be 
PFS rate at 6 months and OS rate at 12 months. 
Sample Size Determination: 
Sample size calculation for an estimated proportion of 50% with a level of confidence of 95% and a 
accuracy of 22%: 20 patients must be included in this study. 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 15 of 151 
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Table 1. SCHEDULE OF STUDY ASSESSMENTS 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Written informed 
consent/assignment of  subject 
identification number 
X 
 
 
 
 
 
 
 
 
Preliminary eligibility 
fulfillment (investigator’s 
opinion) 
X 
 
 
 
 
 
 
 
 
Demography and history of 
tobacco  
X 
 
 
 
 
 
 
 
 
Previous treatments for solid 
tumors 
X 
 
 
 
 
 
 
 
 
Archival FFPE tumor tissue 
sample 
X 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Archived or new biopsy, 
(Section 8.3 further detail) 
X 
 
 
 
 
 
 
 
 
Formal verification of 
eligibility criteria 
X 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
HIV infection history 
X 
 
 
 
 
 
 
 
 
Hepatitis B and C; HIV 
serology 
X 
 
 
 
 
 
 
 
 
Urine hCG or serum βhCGb 
X 
 
 
X 
 
X 
 
X  (only in month 
4 and if the patient 
ends treatment for 
a different reason 
than progression 
disease) 
 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Durvalumab administration 
(monotherapy) 
 
X 
X 
 
 
 
 
 
 
Physical examinationc 
X 
X 
X 
 
 
X 
 
 
 
Vital signs (pre- during and 
post-infusion vital signs 
assessments) 
X 
X d 
X d 
 
 
X 
 
 
 
Weight 
X 
X 
X 
 
 
X 
 
 
 


Clinical Study Protocol 
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Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Electrocardiograme 
X 
X (as 
clinically 
indicated
) 
 
X (week 16 
only) 
 
 
 
 
 
Adverse event/serious adverse 
event assessmentk 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medicationsk 
X 
X 
X 
X 
X 
X 
X 
 
 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
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Date 14h November 2018 
 
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CONFIDENTIAL AND PROPRIETARY 
  
 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X (only in months 
6 and 9 since last 
dose and if the 
patient  completed 
the treatment 
without 
progression) 
X (only if the 
patient  completed 
the treatment 
without 
progression) 
Serum Chemistry (complete 
clin chem. panel including 
Liver enzymes) 
X 
X f 
X 
 
 
X 
X 
 
 
Thyroid function tests (TSH 
and fT3 and fT4)g 
X 
X 
X 
 
 
X 
 
 
 


Clinical Study Protocol 
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Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
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CONFIDENTIAL AND PROPRIETARY 
  
 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Hematology, CD4+ T cell 
counts,  CD8+ T cell counts 
and Plasma viral load 
X 
Xf 
X 
 
 
X 
X 
 
X               
 
 
 
 
 
 
 
 
 
 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
Page 22 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
 
 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject. 
Screening Baseline 
Every 4 
weeks 
Every 
8 Weeks 
Every 
12 Weeks 
First Follow 
up 
Follow up 
month 2 and 3 
since last dose 
Follow up 
months 4, 6, 8 
and 10 since  
last dose 
Follow up 
month 12 since 
last dose, then 
every 6 month 
Day 
-28 to -1 
1 
 
 
 
30 days  
since last 
dose 
 
 
 
Week 
-4 to -1 
0 
4, 8, 12, 16, 
20,  etc 
8, 16, 24, 
32, 40 and 
48 
12, 24, 36, 48 
 
 
 
 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
(-3/+1 days) 
(±3 days) 
(±7 days) 
(±7 days) 
(±14 days) 
Urinalysish 
X 
X 
X 
 
 
 
 
 
 
Coagulation parametersi 
X 
 
 
 
 
 
 
 
 
Blood samples translational 
study and plasma viral load l 
X 
 
X (only week 
2 and 4) 
 
X  
 
 
 
 
Flow cytometry collection of 
whole blood CD4, CD8 
subsetsl 
X 
 
X (only week 
2 and 4) 
 
X 
 
 
 
 
Tumor assessment (PET-CT, 
CT or MRI)j 
X 
 
 
X (-5 days) 
X (±7 days) 
(after 48 weeks) 
 
 
 
 
Palliative radiotherapy 
 
 
 
 
 
As clinically indicated 
Subsequent anti-cancer therapy 
 
 
 
 
 
X 
X 
X 
X 
Survival statusm 
 
 
 
 
 
 
X 
X 
X (every 2 month) 


Clinical Study Protocol 
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Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
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CONFIDENTIAL AND PROPRIETARY 
  
 
 
 
 
 
b  
 Pre-menopausal female subjects of childbearing potential only. This test has to be done every 2 cycles and in the first follow up. 
 
c  
Full physical examination at baseline; targeted physical examination at other timepoints.  
 
d  
Subjects will have their blood pressure and pulse measured before, during and after the infusion at the following times (based on a 60-minute infusion): 
• At the beginning of the infusion (at 0 minutes) 
• At 30 minutes during the infusion (±5 minutes) 
• At the end of the infusion (at 60 minutes ±5 minutes) 
• In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the start of the infusion) (±5 minutes) 
– for the first infusion only and then for subsequent infusions as clinically indicated.  If the infusion takes longer than 60 minutes then blood pressure 
and pulse measurements should be collected every 30 minutes (±5 minutes) and as described above or more frequently if clinically indicated. 
 
e 
ECG during screening, at Day1 and week 16. Thereafter as clinically indicated. Screening and abnormal ECG at any time in triplicate others single.  On 
Day 1 and week 16, ECGs should be taken within an hour prior to the start of the infusion and at least one time point 0 to 3 hours after the infusion. 
 
f 
If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1. Results for safety bloods must 
be available and reviewed before commencing an infusion. Gamma glutamyltransferase tested at Screening, Day 1 and as clinically indicated.    
 
g 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to 
the endocrine system. 
 
h 
Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated. 
 
i 
Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
 
j 
CT (preferred) or MRI scans, preferably with IV contrast, are collected during screening (for baseline) and as close to and prior to initiation of study 
treatment. Timing of on-treatment (follow-up) CT/MRI scans is every 8 weeks (-5 days) for the first 48 weeks and then every 12 weeks (± 1 week) until 
PD or off-study. Response according to RECIST 1.1 criteria (CR, PR) requires a confirmatory scan preferably at the next regularly scheduled imaging 
visit and no earlier than 4 weeks after the prior assessment of CR, PR, or SD. If MRI is used, CT of chest is mandatory). A brain MRI scan is required 
only following the investigator criteria. For subjects who achieve disease control following 12 months of treatment, tumour assessments should be 
performed every 12 weeks (± 1 week) relative to the date of first infusion thereafter until confirmed PD by RECIST 1.1 by investigational site review. 
For subjects who discontinue durvalumab due to toxicity (or symptomatic deterioration), tumour assessments should be performed relative to the date of 
first infusion as follows: every 8 weeks (± 1 week) for the first 48 weeks , then every 12 weeks(± 1 week) until confirmed PD by RECIST 1.1 by 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14h November 2018 
 
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CONFIDENTIAL AND PROPRIETARY 
  
 
investigational site review. Upon confirmed PD, scans should be conducted according to local standard clinical practice and submitted for central review 
until a new treatment is started (these scans are optional). 
 
 
k 
AEs and concomitant medications will be documented at each trial visit and between visits by weekly telephone contact.  
 
l 
 Blood samples for determination of soluble factors will be collected from all subjects prior to infusion on Day 1 ( baseline samples for soluble factors 
may also be collected at Screening, instead of on Day 1 prior to dosing) and within 2 hours before infusion. 
 
m 
Phone contact with subjects who refuse to return for evaluations and agree to be contacted 


Clinical Study Protocol 
 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
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TABLE OF CONTENTS 
PAGE 
SYNOPSIS ............................................................................................................................... 3 
SCHEDULE OF ASSESSMENTS .......................................................................................... 5 
TABLE OF CONTENTS ....................................................................................................... 25 
ABBREVIATIONS AND DEFINITION OF TERMS .......................................................... 32 
1. 
INTRODUCTION.................................................................................................. 39 
1.1 
Disease Background ............................................................................................... 39 
1.1.1  
Immunotherapies ................................................................................................... 39 
1.2 
Durvalumab Background ....................................................................................... 42 
1.2.1 
Summary of non-clinical experience ..................................................................... 42 
1.2.2 
Summary of clinical experience ............................................................................. 44 
1.3 
Research hypothesis ............................................................................................... 50 
1.4 
Rationale for conducting this study ........................................................................ 51 
1.5 
Benefit/risk and ethical assessment ........................................................................ 51 
2. 
STUDY OBJECTIVES .......................................................................................... 52 
2.1 
Primary objective(s) ............................................................................................... 52 
2.2 
Secondary objective(s) ........................................................................................... 52 
2.3 
Exploratory objective(s) ......................................................................................... 53 
3. 
STUDY DESIGN ................................................................................................... 55 
3.1 
Overview of study design ....................................................................................... 55 


Clinical Study Protocol 
 
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Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
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3.2 
Study schema ......................................................................................................... 55 
3.3 
Study Oversight for Safety Evaluation .................................................................. 57 
4. 
SUBJECT SELECTION ........................................................................................ 57 
4.1 
Inclusion criteria ..................................................................................................... 57 
4.2 
Exclusion criteria ................................................................................................... 59 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study ................................ 61 
4.4 
Replacement of subjects ......................................................................................... 63 
5. 
INVESTIGATIONAL PRODUCT(S) ................................................................... 63 
5.1 
Durvalumab ............................................................................................................ 63 
5.1.1 
Formulation/packaging/storage .............................................................................. 63 
5.1.2 
Durvalumab Doses and treatment regimens .......................................................... 63 
5.1.3 
Study drug preparation ........................................................................................... 63 
5.1.4 
Monitoring of dose administration ......................................................................... 65 
5.1.5 
Accountability and dispensation ............................................................................ 66 
5.1.6 
Disposition of unused investigational study drug .................................................. 67 
6. 
TREATMENT PLAN ............................................................................................ 67 
6.1 
Subject enrollment ................................................................................................. 67 
6.1.1 
Procedures for handling subjects incorrectly enrolled ........................................... 67 
6.2 
Dosage and Administration .................................................................................... 68 
6.3 
Dose Modification and Toxicity Management ...................................................... 68 
6.3.1 
Durvalumab ............................................................................................................ 68 
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENT(S) 70 
7.1 
Restrictions during the study .................................................................................. 70 


Clinical Study Protocol 
 
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7.2 
Concomitant treatment(s) ....................................................................................... 71 
7.2.1 
Permitted concomitant medications ....................................................................... 71 
7.2.2 
Excluded Concomitant Medications ...................................................................... 71 
8. 
STUDY PROCEDURES ....................................................................................... 72 
8.1 
Schedule of study procedures................................................................................. 72 
8.1.1 
Screening Phase ..................................................................................................... 73 
8.1.2 
Treatment Phase ..................................................................................................... 74 
8.1.3 
End of Treatment .................................................................................................... 75 
8.2 
Description of study procedures ............................................................................. 76 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and vital signs 
76 
8.2.2 
Clinical laboratory tests .......................................................................................... 77 
8.3 
Biological sampling procedures ............................................................................. 79 
8.3.1 
Biomarker/Pharmacodynamic sampling and evaluation methods ......................... 79 
8.3.2 
Estimate of volume of blood to be collected .......................................................... 83 
8.3.3 
Withdrawal of informed consent for donated biological samples ......................... 84 
9. 
DISEASE EVALUATION AND METHODS ...................................................... 84 
9.1.1 
ORR and PFS rate .................................................................................................. 85 
9.1.2 
OS 
 ............................................................................ 86 
10. 
ASSESSMENT OF SAFETY ................................................................................ 86 
10.1.1 
Safety Parameters ................................................................................................... 86 
10.1.1.1 Definition of adverse events................................................................................... 86 
10.1.2 
Definition of serious adverse events ...................................................................... 87 
10.1.3 
Definition of adverse events of special interest (AESI) ......................................... 88 
10.1.4 
Pneumonitis ............................................................................................................ 89 
10.1.5 
Hypersensitivity Reactions..................................................................................... 89 
10.1.6 
Hepatic function abnormalities (hepatotoxicity) .................................................... 89 
10.1.7 
Gastrointestinal disorders ....................................................................................... 90 


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10.1.8 
Endocrine disorders ................................................................................................ 90 
10.1.9 
Pancreatic disorders ............................................................................................... 90 
10.1.10 
Neurotoxicity .......................................................................................................... 90 
10.1.11 
Nephritis ................................................................................................................. 91 
10.1.12 
Bleeding ................................................................................................................. 91 
10.2 
Assessment of safety parameters ........................................................................... 92 
10.2.1 
Assessment of severity ........................................................................................... 92 
10.2.2 
Assessment of relationship ..................................................................................... 93 
10.3 
Recording of adverse events and serious adverse events ....................................... 93 
10.3.1 
Study recording period and follow-up for adverse events and serious adverse events 
94 
10.3.2 
Reporting of serious adverse events ....................................................................... 95 
10.3.3 
Reporting of deaths ................................................................................................ 96 
10.3.4 
Other events requiring reporting ............................................................................ 97 
10.3.5 
Overdose ................................................................................................................ 97 
10.3.6 
Hepatic function abnormality ................................................................................. 97 
10.3.7 
Pregnancy ............................................................................................................... 98 
10.3.8 
Maternal exposure .................................................................................................. 98 
10.3.9 
Paternal exposure ................................................................................................... 98 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 99 
11.1 
Description of analysis sets .................................................................................... 99 
11.1.1 
Safety analysis set .................................................................................................. 99 
11.1.2 
Efficacy analysis set ............................................................................................... 99 
11.2 
Methods of statistical analyses ............................................................................... 99 
11.2.1 
Safety Analyses .................................................................................................... 100 
Analysis of safety endpoint(s) .............................................................................................. 100 
11.2.2 
Efficacy Analyses ................................................................................................. 100 


Clinical Study Protocol 
 
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Analysis of efficacy endpoint(s) ........................................................................................... 100 
11.2.3 
Exploratory Analyses ........................................................................................... 100 
Analysis of immunohistochemistry ...................................................................................... 100 
Analysis of gene expression ................................................................................................. 100 
Analysis of anti HIV activity in blood .................................................................................. 100 
Analysis of residual plasma viremia ..................................................................................... 101 
Analysis of HIV-1 RNA expression ..................................................................................... 101 
Analysis of 2LTR ................................................................................................................. 101 
Analysis of CD4+ and CD8+ T-cell subsets in peripheral blood ......................................... 101 
Analysis of functional effector responses of T cells ............................................................. 101 
Analysis of predictive factors of antitumoral activity in pretreatment tumor samples ......... 101 
11.2.4 
Interim analyses ................................................................................................... 101 
11.3 
Determination of sample size ............................................................................... 101 
12. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 102 
12.1 
Ethical conduct of the study ................................................................................. 102 
12.2 
Ethics and regulatory review ................................................................................ 102 
12.3 
Informed consent .................................................................................................. 102 
12.4 
Changes to the protocol and informed consent form ........................................... 103 
12.5 
Audits and inspections ......................................................................................... 104 
12.6 
Insurance .............................................................................................................. 104 
12.7 
Publications .......................................................................................................... 105 


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13. 
STUDY MANAGEMENT................................................................................... 105 
13.1 
Training of study site personnel ........................................................................... 105 
13.2 
Monitoring of the study ........................................................................................ 106 
13.2.1 
Source data ........................................................................................................... 106 
13.2.2 
Study documentation ............................................................................................ 106 
13.3 
Study timetable and end of study ......................................................................... 107 
14. 
DATA MANAGEMENT ..................................................................................... 107 
14.1 
Study governance and oversight .......................................................................... 108 
15. 
LIST OF REFERENCES ..................................................................................... 109 
LIST OF TABLES 
Table 1. SCHEDULE OF STUDY ASSESSMENTS ........................................................... 15 
Table 2. Effective methods of contraception (two methods must be used) ........................... 70 
Table 3. Prohibited and Rescue Medications ......................................................................... 72 
Table 4. Hematology Laboratory Tests ................................................................................. 78 
Table 5. Clinical chemistry (Serum or Plasma) Laboratory Tests ......................................... 78 
Table 6. Urinalysis Testsa ...................................................................................................... 79 
Table 7. Serology .................................................................................................................. 79 
Table 8. Volume of Blood to Be Drawn From Each Subject ................................................ 84 


Clinical Study Protocol 
 
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LIST OF FIGURES 
Figure 1. Study flow chart ..................................................................................................... 55 
 
LIST OF APPENDICES 
Appendix 1.  
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and 
Non Immune-mediated Reactions for Durvalumab Monotherapy ..............  
Appendix 2  
Durvalumab dose calculations ............................................................... 146 
Appendix 3 
Schedule of study procedures: follow-up for subjects who have completed durvalumab treatment and 
achieved disease control (until confirmed progression of disease) and subjects who have discontinued 
durvalumab due to toxicity in the absence of confirmed progression of disease 147 
Appendix 4  
Schedule of study procedures: follow-up for subjects who have discontinued durvalumab treatment due 
to confirmed progression of disease at the discretion of the investigator149 
Appendix 5:  
Contact Details ....................................................................................... 150 


Clinical Study Protocol 
 
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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APC 
antigen-presenting cells 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
CDC 
Complement dependent cytotoxicity 
CI 
confidence interval 
CL 
clearance 
Cmax 
peak concentration 
Cmax,ss 
peak concentration at steady state 


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Abbreviation or 
special term 
Explanation 
Cmin 
trough concentration 
Cmin,ss 
trough concentration at steady state 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen-4 
DC 
disease control 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
disodium edetate dihydrate 
Fc 
fragment crystallizable 
FFPE 
formalin fixed paraffin embedded 


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Abbreviation or 
special term 
Explanation 
FSH 
follicle-stimulating hormone 
FTIH 
first-time-in-human 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
HCl 
hydrochloride 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IGF 
insulin-like growth factor 
IgG1 
immunoglobulin G1 
IgG2 
immunoglobulin G2 
IGSF 
immunoglobulin superfamily 
IHC 
immunohistochemistry  


Clinical Study Protocol 
 
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Abbreviation or 
special term 
Explanation 
IL 
interleukin 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
MAb 
monoclonal antibody 
MDSC 
Myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
micro ribonucleic acid 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung cancer 
OR 
objective response 


Clinical Study Protocol 
 
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Abbreviation or 
special term 
Explanation 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
PVC 
polyvinyl chloride 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
Q12W 
every 12 weeks 


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Abbreviation or 
special term 
Explanation 
QoL 
quality of life 
QTc 
the time between the start of the Q wave and the end of the T wave 
corrected for heart rate 
QTcF 
QT interval on ECG corrected using the Frederica’s formula 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
stable disease 
SID 
subject identification 
sPD-L1 
soluble programmed cell death ligand 1 
SOCS3 
suppressor of cytokine signaling 3 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
TEAE 
treatment-emergent adverse event 
TIL 
tumor infiltrating lymphocyte 
Tmax 
time to peak concentration 


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Abbreviation or 
special term 
Explanation 
Tmax,ss 
time to peak concentration at steady state 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
USA 
United States of America 
WFI 
water for injection 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
1.1 
Disease Background 
After more than three decades fighting the Human Immunodeficiency Virus type 1 (HIV-1) – the etiologic agent of the acquired 
immunodeficiency syndrome (AIDS) – this lentivirus has spread worldwide, causing a pandemic that seriously challenges public 
health. In 2012, 35 million people were living with HIV-1, 1.6 million people had died from AIDS and 2.3 million people got newly 
infected (AIDS epidemic update 2013; http://www.unaids.org). Major advances in Antiretroviral Therapy (ART) have resulted in a 
dramatic decline in HIV-related deaths. However, no current treatment regimen leads to viral eradication or restoration of HIV-
specific immune responses capable of durable viral control after cessation of ART. Thus, there is a need for novel interventions that 
could complement ART in order to eliminate virus or reach a state of "functional cure"(1, 2). It has been shown in murine models 
and humans that the negative co-signaling molecule programmed-death 1 (PD-1) plays an active and reversible role in mediating T-
cell exhaustion in chronic infections (3). Therefore, there is a potential of immunotherapeutic interventions targeting PD-1 in order 
to augment immune responses or facilitate viral eradication. 
Malignancies account for more than a third of all deaths in human immunodeficiency virus (HIV)-positive patients. Although acquired 
immunodeficiency syndrome-related mortality is decreasing with the introduction of effective antiretroviral therapy, it has been 
reported a significant increase in the proportion of non-acquired immunodeficiency syndrome defining malignancies (NADC) from 
20% in the pre-HAART era to 71% of all tumors now. People infected with HIV are at least 25 times more likely to be diagnosed 
with anal cancer than uninfected people, 5 times as likely to be diagnosed with liver cancer and 3 times as likely to be diagnosed with 
lung cancer(4). Often these patients present with advanced disease and at a younger age than general population(5). As HAART has 
reduced the number of deaths from AIDS, the HIV-infected population has grown in size and become older. The fastest growing 
proportion of HIV-infected individuals is the over-40 age group. These individuals are now developing cancers common in older age. 
In 2003, the proportion of these other cancers exceeded the number of AIDS-defining malignancies(6).  Lung cancer has now become 
the leading cause of mortality among the non-acquired immunodeficiency syndrome defining malignancies.  Development of lung 
cancer in patients with HIV has been linked to various factors including not only smoking habit, but also CD4 count, viral load and 
the intensity and duration of immune deficiency(4). 


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Immune responses directed against tumors are one of the body’s natural defenses against the growth and proliferation of cancer cells. 
However, over time and under pressure from immune attack, cancers develop strategies to evade immune-mediated killing allowing 
them to develop unchecked. One such mechanism involves upregulation of surface proteins that deliver inhibitory signals to cytotoxic 
T cells. Programmed cell death ligand 1 (PD-L1) is one such protein, and is upregulated in a broad range of cancers with a high 
frequency, with up to 88% expression in some tumor types. In a number of these cancers, including lung(7), renal(8), pancreatic(9), 
ovarian cancer(10) and hematologic malignancies(11, 12)tumor cell expression of PD-L1 is associated with reduced survival and an 
unfavorable prognosis. 
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are involved in controlling T-cell activation. 
PD-L1 acts at multiple sites in the body to help regulate normal immune responses and is utilized by tumors to help evade detection 
and elimination by the host immune system tumor response. In the lymph nodes, PD-L1 on antigen-presenting cells binds to PD-1 or 
CD80 on activated T cells and delivers an inhibitory signal to the T cell(13, 14). This results in reduced T-cell activation and fewer 
activated T cells in circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and CD80 on activated 
T cells reaching the tumor. This delivers an inhibitory signal to those T cells, preventing them from killing target cancer cells and 
protecting the tumor from immune elimination (15). 
1.1.1 
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and, under some circumstances, the immune system 
may control or even eliminate tumors. PD-L1 is a member of the B7 family of ligands that inhibit T-cell activity through binding to 
the PD-1 receptor  and to CD80 (PD-L1 expression is an adaptive response that helps tumors evade detection and elimination by the 
immune system. Expression of PD-L1 protein is induced by inflammatory signals that are typically associated with an adaptive 
immune response (e.g., IFNγ) and can be found on both tumor cells (TC) and tumor-infiltrating IC. The binding of PD-L1 to PD-1 
on activated T cells delivers an inhibitory signal to the T cells, preventing them from killing target TC and protecting the tumor from 
immune elimination (). PD-L1 may also inhibit T cells through binding to CD80, although the exact mechanism is still not elucidated). 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of evading immune detection and 
elimination. The binding of an anti–PD-L1 agent to the PD-L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 


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receptors expressed on immune cells. This activity overcomes PD-L1–mediated inhibition of antitumor immunity. While functional 
blockade of PD-L1 results in T-cell reactivation, this mechanism of action is different from direct agonism of a stimulatory receptor 
such as CD28. 
In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T cell–dependent mechanism PD-L1 is 
expressed in a broad range of cancers. Based on these findings, an anti–PD-L1 antibody could be used therapeutically to enhance 
antitumor immune responses in patients with cancer. Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety profile, supporting the 
hypothesis that an anti–PD-L1 antibody could be used to therapeutically enhance antitumor immune response in cancer patients (with 
responses that tend to be more pronounced in patients with tumors that express PD-L1 (. In addition, high mutational burden (e.g., in 
bladder carcinoma [) may contribute to the responses seen with immune therapy. 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively expressed by regulatory T cells and upregulated 
on activated T cells. CTLA-4 delivers a negative regulatory signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands 
on antigen-presenting cells. Blockade of CTLA-4 binding to CD80/86 by anti–CTLA-4 antibodies results in markedly enhanced T-
cell activation and antitumor activity in animal models, including killing of established murine solid tumors and induction of 
protective antitumor immunity. Therefore, it is expected that treatment with an anti–CTLA-4 antibody will lead to increased activation 
of the human immune system, increasing antitumor activity in patients with solid tumors. 
Pre-clinical data have now been added to with a wealth of clinical data showing that blockade of negative regulatory signals to T-
cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) has promising clinical activity. 
Ipilimumab was granted United States (US) Food and Drug Administration (FDA) approval for the treatment of metastatic melanoma 
and is currently under investigation for several other malignancies, whilst nivolumab and pembrolizumab, two anti–PD-1 agents, and 
atezolizumab, an anti–PD-L1, agent have been granted approvals by agencies such as the US FDA and the European Medicines 
Agency approval for the treatment of a number of malignancies including metastatic melanoma, squamous and non-squamous cell 
non-small-cell lung cancer and urothelial carcinoma. In addition, there are data from agents in the anti–PD-1/PD-L1class showing 
clinical activity in a wide range of tumor types. 
 


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1.2 
Durvalumab Background 
Investigators should be familiar with the current durvalumab Investigator Brochure (IB Version 12.0) 
Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid tumors. 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. 
1.2.1 
Summary of non-clinical experience 
The non-clinical experience is fully described in the current version of the durvalumab Investigator’s Brochure (IB Version 12.0). 
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 tumor 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 tumor model when given as monotherapy and resulted in 
complete tumor regression in > 50% of treated mice when given in combination with chemotherapy. Combination therapy (dual 
targeting of PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) resulted in tumor regression in a mouse model of 
colorectal cancer.  


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Cynomolgus monkeys were selected as the only relevant species for evaluation of the pharmacokinetics (PK)/pharmacodynamics and 
potential toxicity of durvalumab. Following intravenous (IV) administration, the PK of durvalumab in cynomolgus monkeys was 
nonlinear. Systemic clearance (CL) decreased and concentration half-life (t1/2) increased with increasing doses, suggesting saturable 
target binding-mediated clearance of durvalumab. No apparent gender differences in PK profiles were observed for durvalumab.  
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. Adverse findings in the non-Good Laboratory Practice (GLP) PK/pharmacodynamics 
and dose range-finding study, and a GLP 4-week repeat-dose toxicity study were consistent with antidrug antibody (ADA)-associated 
morbidity and mortality in individual animals. The death of a single animal in the non-GLP, PK/pharmacodynamics, and dose range-
finding study was consistent with an ADA-associated acute anaphylactic reaction. The spectrum of findings, especially the clinical 
signs and microscopic pathology, in a single animal in the GLP, 4-week, repeat-dose study was also consistent with ADA immune 
complex deposition, and ADA:durvalumab immune complexes were identified in a subsequent non-GLP, investigative 
immunohistochemistry study. Similar observations were reported in cynomolgus monkeys administered human mAbs unrelated to 
durvalumab. Given that immunogenicity of human mAbs in nonclinical species is generally not predictive of responses in humans, 
the ADA-associated morbidity and mortality were not considered for the determination of the no-observed-adverse-effect level 
(NOAEL) of durvalumab.  
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. 
Preclinical data suggests that blocking PD-L1 may improve also immune function in HIV patients (16). Different studies have shown 
that during chronic HIV-1 infection PD-1 expression on HIV-1–specific T cells correlates with viral load and that blocking PD-1 
engagement restores T cell effector functions in vitro. Additionally, in vivo PD-1 blockade in chronic SIV infection restored CD8+ T 
cell function, reduced viral load levels, and increased survival of SIV-infected macaques (17). However, the consequence of in vivo 


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PD-1 blockade to restored CD8+ T cell function, and ultimately reduce viral persistence and reservoirs in HIV-1-infected patients 
with effective ART, remains to be determined. 
1.2.2 
Summary of clinical experience 
Clinical experience with durvalumab is fully described in the current version of the durvalumab Investigator’s Brochure (Version 
12.0). 
As of the DCO date (12 July 2016), a total of 2878 patients have been exposed to 1or more doses of durvalumab in ongoing open-
label AstraZeneca-or MedImmune-sponsored Phase I-III monotherapy and combination therapy studies across all indications.. 
Refer to the current durvalumab Investigator’s Brochure for a complete summary of non-clinical and clinical information including 
safety, efficacy and pharmacokinetics. . 
Durvalumab (MEDI4736) is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that inhibits 
binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a wholly 
owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). As 
durvalumab is an engineered mAb, it does not induce antibody-dependent cellular cytotoxicity or complement-dependent 
cytotoxicity. The proposed mechanism of action for durvalumab is interference of the interaction of PD-L1 with PD-1 and CD80..  It 
is engineered with a triple mutation in the Fc domain to avoid Fc-mediated ADCC. Preliminary results from the phase I study of 
patients with solid tumors reported clinical activity and durable disease stabilization in different tumor types, with no dose limiting 
toxicities or grade 3–4 treatment-related adverse events(18). In the phase II trial the drug was tested on 85 pretreated NSCLC patients. 
From 53 evaluable patients, 12 had an objective response by RECIST criteria (23%). At 2014 ASCO meeting, results from a phase I 
multi-arm expansion study of the anti PD-L1 MEDI4736 were presented. It was reported that the dose-escalation phase has been 
completed for doses of 0.1 to 10 mg/kg every 2 weeks with extension to 15 mg/kg every 3 weeks. MEDI4736 was well tolerated at 
all doses tested, with no treatment-related serious adverse events such as colitis, hyperglycemia, or pneumonitis at any grade(19). 
Neil Segal and colleagues presented preliminary data on the ongoing study of MEDI4736 at a dosage of 10 mg/kg every 2 weeks for 
1 year for 346 patients with solid tumors, including 143 with NSCLC. The median duration of treatment was 8 weeks. As of May 18, 
2014, there were very few (6%) grade 3/4 drug-related serious adverse events. Clinical activity was observed as early as 6 weeks, 


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with maintenance for over 67 weeks and off active therapy; overall response rate (ORR) rate in NSCLC was 13%(20). Development 
is most advanced in non-small cell lung cancer, with a program currently comprising two phase III trials (NCT02352948, 
NCT02125461)and several phase I combination studies (NCT02000947, NCT02179671, NCT02143466). A pivotal program for 
MEDI4736 in head and neck cancer began in late 2014.  
PD-1 interacts with the ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), which result in diminished T-cell proliferation, altered cytokine 
production and initiation of T-cell exhaustion and/or apoptosis leading to tumor initiation and progression(21). 
Pharmacokinetics and Product Metabolism  
Study CD-ON-durvalumab-1108: As of09Feb2015, PK data were available for 378 subjects in the dose-escalation and dose-
expansion phases of Study CD-ON-durvalumab-1108following treatment with durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 
15 mg/kg every 3 weeks (Q3W). The maximum observed concentration (Cmax) increased in an approximately dose-proportional 
manner over the dose range of 0.1 to 15 mg/kg. The area under the concentration-time curve from 0 to 14 days (AUC0-14) increased 
in a greater than dose-proportional manner over the dose range of 0.1 to 3 mg/kg and increased dose-proportionally at ≥ 3 mg/kg. 
These results suggest durvalumab exhibits nonlinear PK likely due to saturable target-mediated CL at doses < 3 mg/kg and approaches 
linearity at doses ≥ 3 mg/kg. Near complete target saturation (soluble programmed cell death ligand 1 [sPD-L1] and membrane bound) 
is expected with durvalumab ≥ 3 mg/kg Q2W. Exposures after multiple doses showed accumulation consistent with PK parameters 
estimated from the first dose. In addition, PK simulations indicate that following durvalumab 10 mg/kg Q2W dosing, > 90% of 
subjects are expected to maintain PK exposure ≥ 40 µg/mL throughout the dosing interval. 
As of 09Feb2015, a total of 388subjects provided samples for ADA analysis. Only 8 of 388 subjects (1 subject each in 0.1, 1, 3, and 
15 mg/kg cohorts, and 4 subjects in 10 mg/kg cohort) were ADA positive with an impact on PK/pharmacodynamics in 1 subject in 
the 3 mg/kg cohort. 
 
 


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Safety  
The safety profile of durvalumab as monotherapy and combined with other anticancer agents was consistent with the pharmacology 
of the target and other agents in the immune checkpoint inhibitor class. No tumor 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 colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. 
In addition, pancreatitis is an important potential risk particularly with durvalumab and tremelimumab combination therapy. These 
events are manageable by available/established treatment guidelines as described in the study protocols. 
AEs reported with durvalumab monotherapy in key clinical studies are described below. 
Adverse Event Profile of durvalumab Monotherapy 
Study CD-ON-durvalumab-1108: The safetyprofile of durvalumab monotherapy in the 694 subjects with advanced solid tumors 
treated at 10 mg/kg Q2W in Study CD-ON-durvalumab-1108 has been broadly consistent with that of the overall 1,279 subjects who 
have received durvalumab monotherapy (not including subjects treated with blinded investigational product) across the clinical 
development program. The majority of treatment-related AEs were manageable with dose delays, symptomatic treatment, and in the 
case of events suspected to have an immune basis, the use of established treatment guidelines for immune-mediated toxicity. As of 
07May2015, among the694 subjects treated with durvalumab 10 mg/kg Q2W in Study CD-ON-durvalumab-1108, a total of 378 
subjects (54.5%) experienced a treatment-related AE, with the most frequent (occurring in ≥5% of subjects) being fatigue (17.7%), 
nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%),pruritus (6.3%), rash (6.1%),and vomiting (5.0%). A majority of the 
treatment-related AEs were Grade 1 or Grade 2 in severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). Treatment-related 
≥ Grade 3 events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased aspartate aminotransferase 
(AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase (GGT; 6 subjects, 0.9%);increased alanine aminotransferase (ALT; 
5 subjects, 0.7%); and colitis, vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had treatment-
related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) 
and 1 subject had a treatment-related Grade 5 event (pneumonia). Treatment-related serious adverse events (SAEs) that occurred in 


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≥ 2 subjects were colitis and pneumonitis (3 subjects each). A majority of the treatment-related SAEs were ≥ Grade 3 in severity and 
resolved with or without sequelae. AEs that resulted in permanent discontinuation of durvalumab were considered as treatment related 
in 18 subjects (2.6%), with colitis being the most frequent treatment-related AE resulting in discontinuation (3 subjects). A majority 
of the treatment-related AEs resulting in discontinuation of durvalumab were ≥ Grade 3 in severity and resolved with or without 
sequelae.  
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in Study CD-ON-durvalumab-1108 is generally 
consistent with that of Study D4191C00003/ATLANTIC in subjects with locally advanced or metastatic non-small-cell lung cancer 
(NSCLC) treated with durvalumab 10 mg/kg Q2W. As of 05May2015, 264 of 303 subjects (87.1%) reported any AE in Study 
D4191C00003/ATLANTIC. Overall, events reported in ≥ 10% of subjects were dyspnea (18.8%), fatigue (17.8%), decreased appetite 
(17.5%), cough (14.2%), pyrexia (12.2%), asthenia (11.9%), and nausea (11.2%). Nearly two-thirds of the subjects experienced AEs 
that were Grade 1 or 2 in severity and manageable by general treatment guidelines as described in the current durvalumab study 
protocols. Grade 3 or higher AEs were reported in 107 of 303 subjects (35.3%). A total of 128 subjects (42.2%) reported AEs that 
were considered by the investigator as related to investigational product. Treatment-related AEs (all grades) reported in ≥ 2% of 
subjects were decreased appetite (6.6%); fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea,hyperthyroidism, 
hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased (2.3%); and vomiting (2.0%). Treatment-related Grade 3 
AEs reported in ≥ 2 subjects were pneumonitis (3 subjects) and increased GGT (2 subjects). There was no treatment-related Grade 4 
or 5 AEs. Ninety-four of 303 subjects (31.0%) reported any SAE. SAEs that occurred in ≥ 1.0% of subjects were dyspnea (6.6%); 
pleural effusion, general physical health deterioration (2.3% each); pneumonia (2.0%); hemoptysis, pulmonary embolism (1.3% 
each); and pneumonitis, respiratory failure, disease progression (1.0% each). Nine subjects had an SAE considered by the investigator 
as related to durvalumab. Each treatment-related SAE occurred in 1 subject each with the exception of pneumonitis, which occurred 
in 3 subjects. Fifteen of 303 subjects (5.0%) have died due to an AE (pneumonia [3 subjects]; general physical health deterioration, 
disease progression, hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, respiratory distress, cardiopulmonary arrest [verbatim 
term (VT)], hepatic failure, and sepsis [1 subject each]). None of these events was considered related to durvalumab. Twenty-three 
of 303 subjects (7.6%) permanently discontinued durvalumab treatment due to AEs. Events that led to discontinuation of durvalumab 


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in ≥ 2 subjects were dyspnea, general physical health deterioration, and pneumonia. Treatment-related AEs that led to discontinuation 
were increased ALT and increased hepatic enzyme, which occurred in 1 subject each. 
 
Efficacy  
Study CD-ON-durvalumab-1108: Overall, 456 of 694 subjects treated with durvalumab10 mg/kg Q2W were evaluable for response 
(defined as having ≥ 24 weeks follow-up, measurable disease at baseline, and ≥ 1 follow-up scan, or discontinued due to disease 
progression or death without any follow-up scan). In PD-L1 unselected patients, the objective response rate (ORR), based on 
investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST)v1.1, ranged from 0% in uveal melanoma (n = 
23) to 20.0% in bladder cancer (n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% in triple-negative breast 
cancer (TNBC; n = 24) to 39.1% in advanced cutaneous melanoma (n = 23). PD-L1 status was known for 383 of the 456 response 
evaluable subjects. Across the PD-L1-positive tumors, ORR was highest for bladder cancer, advanced cutaneous melanoma, 
hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 26.7%), and squamous cell carcinoma of the head and 
neck (SCCHN; n = 22, 18.2%). In the PD-L1-positive subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 66.7%), 
NSCLC (n = 86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%).  
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) treated in Study D4190C00007, 21 subjects had at 
least 1 post-baseline disease assessment. Among these subjects, the best overall responses were marrow complete remission (mCR) 
in 4 subjects (19.0%); stable disease (SD) in 4 subjects (19.0%); and progressive disease (PD) in 5 subjects (23.8%). The remaining 
8 subjects (38.1%) did not meet the criteria for complete remission (CR), mCR, partial remission (PR), SD, or PD at the date of 
assessment. 


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Study CD-ON-durvalumab-1161: Of the 65 subjects with metastatic or unresectable melanoma treated with the combination of 
durvalumab and BRAF inhibitor (BRAFi; dabrafenib)/MEK inhibitor (MEKi; trametinib), 63 subjects were evaluable for response. 
A total of 35 subjects (55.6%) had a best overall response of confirmed or unconfirmed PR. The disease control rate (DCR; CR + PR 
[regardless of confirmation] + SD ≥ 12 weeks) was 79.4%.  
Fixed Dosing  
A population PK model was developed for durvalumabusing 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.   
 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 2012, Narwal et al 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 et al 2012].  
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing errors. Given expectation 
of similar pharmacokinetic exposure and variability, we considered it feasible to switch to fixed dosing regimens. Based on average 
body WT of 75 kg, a fixed dose of 1500 mg Q4Wdurvalumab (equivalent to 20 mg/kg Q4W) is included in the current study. Fixed 
dosing of durvalumab is recommend only for subjects with > 30kg 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 (Appendix 2).  


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1.3 
Research hypothesis 
Taking into account: 
• PD-1/ PD-L1 coinhibitory pathway plays a significant role in the regulation of the immune response in both chronic infectious 
diseases and cancer.  
• Preclinical and animal data support the safety and promising activity of anti-PD-1 antibody in HIV-1 infection 
• Demonstrated anticancer activity and safety profile of durvalumab (MEDI4736) in cancer clinical trials. 
• Unlikely drug interactions of durvalumab (MEDI4736) and antiretroviral treatments. 
We propose a phase II clinical study designed to assess the feasibility of durvalumab (MEDI4736) in HIV-1-infected individuals with 
solid tumors. Additionally we hope to obtain data that let us understand the possible benefit of this treatment in cancer patients and 
HIV, exploring if activity of durvalumab (MEDI4736) could be higher in cancer that has been produce at least in part due to the 
chronic immunosupression. Simultaneously, it will allow  us to investigate the effect of disrupting this immunoregulatory pathway 
might have in reversing cancer pathways and HIV-specific T-cell function during persistent chronic HIV infection in humans. 
In this regard, our hypothesis is: 
HIV infected patients with cancer have a similar outcome in terms of tolerability when treated with MEDI4736 monotherapy at the 
recommended dose than non-HIV infected patients. 


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Drug Substance Durvalumab (Medi4736) 
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Version Number 4.1 
Date 14th November 2018 
 
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1.4 
Rationale for conducting this study 
HIV-1-infected patients with cancer have been systematically excluded from clinical trials of anti cancer drugs because of concerns 
related to drug interactions and the unknown effect of the underlying HIV infection on the safety and activity of the investigational 
drugs.  Anti PD-L1 antibody durvalumab (MEDI4736) could be an active treatment both for cancer and for HIV infection, with non-
expected drugs interactions. 
1.5 
Benefit/risk and ethical assessment 
The benefit-risk relationship has been carefully considered in the planning of the trial. Based on the nonclinical and clinical studies 
available to date, the conduct of the trial is considered justificable using the dose and dose regimen of the durvalumab as specified in 
this clinical trial protocol. 
The trial shall be discontinued in the event of any new findings that indicate a relevant deterioration of the risk-benefit relationship 
that would render continuation of the trial unjustificable. 
The primary known risks of exposure to durvalumab include: 
- 
Infusion-related reactions and 
- 
irAEs 
In addition, since durvalumab could induce antibody-dependent cell-mediated cytotoxicity (ADCC), there is a potential risk of tumor 
lysis syndrome. 
Clinical trials with antibodies that block PD-1/PD-L1 interaction have been reported to produce objective response rates of 7% to 
38% in patients with advanced or metastatic solid tumors, with response duration of 1 year or more for the majority of patients(22-
30). 


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Given the suboptimal treatment options for patients with recurrent locally advanced or metastatic solid tumors in HIV-1 infected 
patients, and the safety profile of durvalumab, the risk-benefit ratio of treatment with durvalumab in the targeted trial population is 
considered positive. 
This clinical trial protocol will be conducted in compliance with the clinical trial protocol, ICH GCP and the applicable national 
regulatory requirements. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
To explore the feasibility of durvalumab (MEDI4736) monotherapy at the recommended dose of 1500 mg every 4 weeks in solid 
tumors in HIV-1-infected patients.  
 
HIV-1-infected patients with cancer have been systematically excluded from clinical trials of anti cancer drugs because of concerns 
related to drug interactions and the unknown effect of the underlying HIV infection on the safety and activity of the investigational 
drugs. Anti PD-L1 antibody durvalumab (MEDI4736) could be an active treatment both for cancer and for HIV infection, with non-
expected drugs interactions. The aim of this study is to explore the feasibility  of durvalumab (MEDI4736) in HIV-1-infected patients 
who are diagnosed with a solid tumor (lung cancer, head and neck cancer, cervical cancer, melanoma, anal cancer, pancreatic cancer, 
gastroesophageal cancer, triple negative breast cancer, bladder cancer, renal cancer, Cholangiocarcinoma, Kaposi sarcoma, lymphomas, 
ovarian cancer, Merkel cell carcinoma or any other tumor type in which anti PD-1 or anti PD-L1 antibodies have demonstrated 
antitumoral activity) for which no additional oncologic standard treatment is available, or for which the subject declines standard 
treatment.  
2.2 
Secondary objective(s) 
• To assess ORR (RECIST 1.1 and irRECIST) and duration of response  


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• To evaluate the PFS rate at 6 months  
• 
To evaluate the OS rate at 12 months 
 
Durvalumab (MEDI4736) has demonstrated activity in several cancer types in the general population. In this study, as secondary 
objective, we will analyze activity of the drug as activity in terms of Response rate according to RECIST1.1 criteria, and according 
to OS rate at 12 months and PFS at 6 months. 
Several data indicate that anti PD-1/PD-L1 treatments in oncology could have activity in terms of OS with long responders, that it is 
not always correlated to classical endpoint of response rate or median survival. 
In this trial given that patients will be included with different solid tumors, and different lines of treatment, activity of the drug is a 
secondary objective, in order to determine if activity looks similar to activity reported in solid tumors without HIV- infection. 
 
2.3 
Exploratory objective(s) 
Anti PD-1/PD-L1 antibodies could have a therapeutic effect on HIV infection. We will measure activity of durvalumab (MEDI4736) 
in terms of antiviral activity, measuring the changes in the viral reservoir, measuring the changes in residual viral replication and 
exploring changes in the composition and function of circulating T lymphocytes. 
For this analysis we will use blood samples (pretreatment and shortly after treatment initiation (2, 4, 12, 24 weeks), and then in the 
longer time frame every 12 weeks) (+/-3 days). This will include the following: 
• Analysis by digital droplet PCR (ddPCR) of HIV-1 DNA associated to CD4+ T cells obtained from peripheral blood. 
• Analysis of residual plasma viremia using an ultrasensitive single copy assay (these patients would be on antiretroviral 
treatment, so standard techniques for determine viral load with not be useful). 
• Analysis by ddPCR of HIV-1 RNA expression on CD4+ T cells obtained from peripheral blood. 
• Change in 2LTR mean levels in CD4+ T cells. 
• Analysis by multicolor flow cytometry of the percentage of naïve, memory and activated CD4+ and CD8+ T-cell subsets in 
peripheral blood, including analysis of PD-1 expression. 


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Date 14th November 2018 
 
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• Analysis by multicolor flow cytometry of the functional effector responses of T cells elicited by different viral and non viral 
antigens. 
• Determination of the ex vivo effect of durvalumab on baseline peripheral blood mononuclear cells (PBMCs): 
o To evaluate whether the ex vivo gain of lymphocyte effector function after durvalumab signaling blockade predicts anti-HIV 
function after in vivo therapy 
o To evaluate whether the effect of durvalumab signaling blockade on regulatory T cells restrains the enhancement in the 
lymphocyte effector function 
 
 
 
In addition, the study will explore predictive factors of antitumoral activity in pretreatment tumor samples. 
Tumor samples obtained by excisional or incisional biopsy (also EBUS samples in case of lung tumors) must be obtained. If it is not 
possible to obtain a new biopsy, the patients can be included if they have some archival tissue available (there must be analysed taking 
account if these samples have been performed more than 6 months before of starting durvalumab treatment) 
To explore antitumoral effects according to immunohistochemical and molecular predictive markers, perform correlative studies with 
the objective of analyzing the expression of other biomarkers such as: 
• mRNA expression (RT-PCR) of Interferon gamma, HLA-DR and PD-L1. 
• Immunohistochemistry: PDL-1 and HLA-DR. 
A set of immune response genes/proteins will be tested (both RT-PCR and immunohistochemistry). 
Also, ctDNA analysis will be performed in the planned blood extractions. 


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Drug Substance Durvalumab (Medi4736) 
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Version Number 4.1 
Date 14th November 2018 
 
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3. 
STUDY DESIGN 
3.1 
Overview of study design 
This is a multicenter, national, non-randomized, phase II study in HIV-1 infected patients with advanced solid tumors. 
Twenty evaluable patients will be included in the trial. Patients will be included irrespective of number the previous line of treatments. 
The clinical trial will be performed in 10 hospitals from the Spanish Lung Cancer Group in Spain with a competitive enrollment. 
It is a single arm study. All patients included will received the treatment with durvalumab (MEDI4736). There is not placebo treated 
patients. 
Patients must have stopped the previous treatments for cancer at least 30 days before starting study medication. 
3.2 
Study schema 
 
Figure 1. Study flow chart 
 
 
 
Screening/ 
enrolment 
Treatment every 4 
weeks 
 
Progression 
Free survival 
Overall 
survival 


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Drug Substance Durvalumab (Medi4736) 
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Date 14th November 2018 
 
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Version Number 4.1 
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3.3 
Study Oversight for Safety Evaluation 
The whole trial may be discontinued prematurely in the event of any of the following situations: 
• New information leading to unfavourable risk-benefit judgement of the trial drug, as 
inefficacy of the drug for this population, significant previously unknown adverse 
reactions or unfavourable safety findings. 
• Sponsor’s decision that continuation of the study is unjustifiable for medical or ethical 
reasons. 
4. 
SUBJECT SELECTION 
Only persons meeting the inclusion criteria and no exclusion criteria may be enrolled into the 
trial. Prior to performing any trial assessments not part of the routine medical care, the 
investigator will ensure that the subjects have provided written informed consent. 
4.1 
Inclusion criteria 
For inclusion in the study subjects must fulfill all of the following criteria: 
1. 
Written informed consent obtained from the subject prior to performing any protocol-
related procedures, including screening evaluations. 
2. 
Age > 18 years at time of study entry. 
3. 
Eastern Cooperative Oncology Group (ECOG) 0-2. 
4. 
Life expectancy of >16 weeks. 
5. 
Adequate normal organ and marrow function as defined below:  
− 
Haemoglobin ≥ 9.0 g/dL 
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
− 
Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
− 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will not 
apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 


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hyperbilirubinemia that is predominantly unconjugated in the absence of 
hemolysis or hepatic pathology), who will be allowed only in consultation with 
their physician. 
− 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 5x ULN 
− 
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance: 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)     
72 x serum creatinine (mg/dL) 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)  x 0.85 
72 x serum creatinine (mg/dL) 
 
6. 
Female subjects must either be of non-reproductive potential (ie, post-menopausal by 
history: ≥60 years old and no menses for 1 year without an alternative medical 
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history 
of bilateral oophorectomy) or must have a negative serum pregnancy test upon study 
entry.   
7. 
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including 
follow up. 
8. 
Subjects with histologically or cytologically-documented advanced/metastasic lung 
cancer, head and neck cancer, cervical cancer, melanoma, anal cancer, pancreatic 
cancer, gastroesophageal cancer, triple negative breast cancer, bladder cancer,  renal 
cancer, Cholangiocarcinoma, Kaposi sarcoma, lymphomas, ovarian cancer, Merkel cell 
carcinoma or any other tumor type in which anti PD-1 or anti PD-L1 antibodies have 
demonstrated antitumoral activity, refractory to standard treatment, intolerant of 
standard treatment, or for which no standard therapy exists or who refuse the standard 
treatment. 


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9. 
Subjects may be included irrespectively of number of previous lines of treatment for 
advanced disease. 
10. 
Prior palliative radiotherapy must have been completed at least 2 weeks prior to start 
the study treatment (subjects may receive localized palliative radiotherapy while 
receiving study drug). 
11. 
Documented HIV-1 infection  
12. Undetectable viral load in the last analysis.  
13. 
Subjects with brain metastases are eligible if they are asymptomatic, are treated or 
are neurological stable for at least 2 weeks without the use of steroids or on stable or 
decreasing dose of < 10 mg daily prednisone or equivalent. 
14. 
Subjects must be following an antiretroviral therapy at the moment of the inclusion. 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Involvement in the planning and/or conduct of the study. Previous enrollment in the 
present study. 
2. 
Participation in another clinical study with an investigational product during the last 
4 weeks. 
3. 
Other untreated coexisting HIV related malignancies. 
4. 
Any previous treatment with a PD1, PD-L1 or PD-L2 inhibitor, including 
durvalumab. 
5. 
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, 
monoclonal antibodies, other investigational agent) 28 days prior to the first dose of 
study drug. 
6. 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia’s Correction. 


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7. 
Current or prior use of immunosuppressive medication within 28 days before the first 
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day 
of prednisone, or an equivalent corticosteroid. 
8. 
Any unresolved toxicity (CTCAE grade 2) from previous anti-cancer therapy.  
Subjects with irreversible toxicity that is not reasonably expected to be exacerbated 
by the investigational product may be included (e.g., hearing loss, peripherally 
neuropathy). 
9. 
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any 
previous immunotherapy agent, or any unresolved irAE >Grade 1. 
10. 
Active or prior documented autoimmune disease within the past 2 years 
NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded. 
11. 
Any syndrome that requires systemic corticosteroid/immunosuppressive medications 
EXCEPT for syndromes which would not be expected to recur in the absence of an 
external trigger (vitiligo, autoimmune thyroiditis, or type 1 diabetes mellitus are 
permitted to enroll). 
12. 
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis). 
13. 
History of primary immunodeficiency. 
14. 
History of allogeneic organ transplant. 
15. 
History of hypersensitivity to durvalumabor any excipient. 
16. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active 
bleeding diatheses including any subject known to have evidence of acute or chronic 
hepatitis B or C, or psychiatric illness/social situations that would limit compliance 
with study requirements or compromise the ability of the subject to give written 
informed consent. 
17. 
Known history of active tuberculosis. 


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18. 
Any serious or uncontrolled medical disorder or active infection non HIV, that would 
impair the ability of the subject to receive the treatment of protocol therapy under 
treating physician criteria. 
19. 
Subjects with previous malignances (except non melanoma skin cancer, and cancer 
in situ of: bladder, gastric, colon, cervical/dysplasia, melanoma, breast) are excluded 
unless a complete remission was achieved at least 5 years prior to study entry and no 
additional therapy is required or anticipated to be required during the study period. 
20. 
Receipt of live attenuated vaccination within 30 days prior to study entry or within 
30 days of receiving durvalumab. 
21. 
Female subjects who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control. 
22. 
Any condition that, in the opinion of the investigator, would interfere with evaluation 
of study treatment or interpretation of patient safety or study results. 
23. 
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, 
inclusive of but not limited to surgery, radiation and/or corticosteroids.  
24. 
Subjects with uncontrolled seizures. 
25. 
Patients with tumoral disease in the head and neck region, such as peritracheal or 
periesophageal lymph node involvement, with infiltration of structures of the 
digestive, aerea or vascular pathways that represent a risk of increased bleeding. 
26. 
Patients with neuroendocrine tumors of pulmonary origin or pulmonary metastases 
with evidence of active bleeding. 
27. 
Patients with digestive bleeding. 
 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study 
Permanent discontinuation of investigational product 
An individual subject will not receive any further investigational product if any of the following 
occur in the subject in question: 
1. 
Withdrawal of consent or lost to follow-up. 


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2. 
Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing. 
3. 
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute 
asafety risk. 
4. 
Pregnancy or intent to become pregnant. 
5. 
Any AE that meets criteria for discontinuation as defined in Appendix 1, Section 
10.1.3 
6. 
Adverse event related to durvalumab of any Grade>3 ADRs or repetitive Grade 3 
ADRs with the exception of toxicities that do not meet the criteria for discontinuation 
as defined in Section 10.1.3, Appendix 1 
7. 
Grade ≥ 3 infusion reaction. 
8. 
Subject non-compliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; eg, refusal to adhere to scheduled visits. 
9. 
Initiation of alternative anticancer therapy including another investigational agent. 
10. 
Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with durvalumab. 
 
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified ashaving 
permanently discontinued treatment.  
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section10.3.1 and Appendix 3 or 4, including the collection of any 
protocol-specified blood specimens, unless consent is withdrawn or the subject is lost to follow-
up or enrolled in another clinical study.  All subjects will be followed for survival.  Subjects 
who decline to return to the site for evaluations will be offered follow-up by phone every 3 
months as an alternative. 
 
Withdrawal of consent 


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If consent is withdrawn, the subject will not receive any further investigational product or 
further study observation.  
4.4 
Replacement of subjects 
Subjects withdrawn from the study will not be replaced. 
5. 
INVESTIGATIONAL PRODUCT(S) 
5.1 
Durvalumab 
The sponsor will supply durvalumab to the site’s pharmacies as a 500-mg vial solution for 
infusion after dilution. 
5.1.1 
Formulation/packaging/storage 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. 
The 
solution 
contains 
50 
mg/mL 
durvalumab, 
26 
mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) 
polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10 mL.  Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Durvalumab must be used 
within the individually assigned expiry date on the label. 
The trial medication and its packaging will be labeled in accordance with annex 13 of EU 
Guidelines to Good Manufacturing Practice.  
5.1.2 
Durvalumab Doses and treatment regimens 
Durvalumab 1500 mg IV commences on Day 1 following confirmation of eligibility into the 
study and continues on a Q4W schedule until confirmed PD (unless the investigator considers 
the subject to continue to receive benefit from treatment), initiation of alternative cancer 
therapy, unacceptable toxicity, withdrawal of consent, or if other reasons to discontinue study 
treatment occur.   
5.1.3 
Study drug preparation 
For patients weighing > 30 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 
mg/kg Q4W) (based on an average body WT of 75 kg) should be prepared. For subjects ≤30 kg 
body weight, dose is determined using body mass, calculating the stock volume of durvalumab 
(equivalent to 20 mg/kg Q4W) to achieve the accurate dose according to Appendix 2.   


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Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
Infusion solutions must be allowed to equilibrate to room temperature prior to commencement 
of administration.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. Dose of 1500 mg Q4W durvalumab for patients >30 kg will be administered 
using an IV bag containing 0.9% (w/v) saline with a final durvalumab concentration ranging 
from 1 to 20 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-
line filter. 
Remove a volume of IV solution from the IV bag equal to the calculated volume of durvalumab 
to be added to the IV bag prior to addition of durvalumab.  Next, the volume of durvalumab (ie, 
15.0 mL for 750 mg) is added to the IV bag such that final concentration is within 1 to 20 mg/mL 
(IV bag volumes 100 to 1000 mL).  Mix the bag by gently inverting to ensure homogeneity of 
the dose in the bag. 
Patient weight at baseline should be used for dosing calculations in patients≤30 kg unless there 
is a ≥10% change in weight.  Dosing day weight can be used for dosing calculations instead of 
baseline weight per institutional standard. 
For patients ≤30kg, Calculate the dose volume of durvalumab and number of vials needed for 
the subject to achieve the accurate dose according to Appendix 2 (equivalent to 20 mg/kg Q4W). 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
durvalumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 
minutes is considered a deviation. 


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The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is administered 
and document if the line was not flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  The table below summarizes time 
allowances and temperatures. 
Durvalumab hold and infusion times 
Maximum time from needle puncture to start 
of administration 
4 hours at room temperature, 24 hours at 2°C to 
8°C 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
 
In the event that either preparation time or infusion time exceeds the time limits outlined above, 
a new dose must be prepared from new vials.  Durvalumab does not contain preservatives, and 
any unused portion must be discarded. 
5.1.4 
Monitoring of dose administration 
Subjects will be monitored before, during and after the infusion with assessment of vital signs 
at the times specified in the Schedule of Assessment. Subjects are monitored (pulse rate, blood 
pressure) every 30 minutes during the infusion period (including times where infusion rate is 
slowed or temporarily stopped). 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion.  For subjects with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial 
rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator.  If the infusion-related reaction is Grade 3 or higher in severity, study drug will be 
discontinued. The standard infusion time is one hour, however if there are interruptions during 
infusion, the total allowed time from infusion start to completion of infusion should not exceed 
4 hours at room temperature, with maximum total time at room temperature not exceeding 
8 hours (otherwise requires new infusion preparation).   


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As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis.  The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary. 
5.1.5 
Accountability and dispensation 
The investigator is responsible for ensuring accountability for trial drug, including 
reconciliation of drugs and maintenance of drug records. 
Upon receipt of trial drug, the investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing and dating the documentation provided by the sponsor and 
returning it to the sponsor. A copy will be retained for the investigator File. 
The dispensing of durvalumab will be carefully recorded on the appropriate drug accountability 
forms provided by the sponsor and an accurate accounting will be available for verification by 
the sponsor`s medical monitor at each monitoring visit. 
Trial drug accountability records will include: 
• confirmation of trial drug delivery to the trial site; 
• the inventory at the site of trial drug provided by the Sponsor and prepared at the site; 
• the use of each dose by each subject; 
• the return to the Sponsor or alternative disposition of unused trial drug; and dates, 
quantities, batch numbers, expiry dates and (for trial drug prepared at the site) 
• formulation, as well as the subjects’ trial numbers. 
 
The Investigator should maintain records that adequately document 
• that the subjects were provided the doses specified by the clinical trial protocol / 
• amendment(s); and 
• That all trial drug provided by the Sponsor was fully reconciled. 
 
Unused trial drug must not be discarded or used for any purpose other than the present trial. 
Any trial drug that has been dispensed to a subject must not be redispensed to a different subject. 
The Sponsor’s Monitor will periodically collect the trial drug accountability forms and will 
check all returns (both unused and used containers) before arranging for their return to the 
Sponsor or authorizing their destruction by the trial site. 
 


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At the conclusion or termination of this trial, trial site personnel and the Clinical Trial Monitor 
will conduct a final product supply inventory on the Investigational Drug Accountability Forms 
and all unused containers will be destroyed. Instructions for destruction of product will be 
provided to the site. The Clinical Trial Monitor will be supplied with a copy for filing of the 
Investigational Drug Accountability Forms. This documentation must contain a record of 
clinical supplies used, unused, and destroyed and shall include information on: 
• all administered units, 
• all unused units, 
• all destroyed units (during the trial), 
• all destroyed units at the end of the trial, 
• date of destruction(s), 
• name and signature of the Investigator / pharmacist. 
 
It must be ensured at each trial site that the trial drug is not used: 
• after the expiry date, and 
• after the retest date unless the trial drug is reanalyzed and its retest date extended. 
 
This is to be closely monitored by the Clinical Trial Monitor. 
5.1.6 
Disposition of unused investigational study drug 
The site will account for all investigational study drug dispensed and also for appropriate 
destruction.  Certificates of delivery and destruction must be signed. 
6. 
TREATMENT PLAN 
6.1 
Subject enrollment 
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the 
trial as subjects. Prior to performing any trial assessments not part of the subject`s routine 
medical care, the investigator will ensure that the subject or his/her legal representative, has 
provided written informed consent following the procedure. 
6.1.1 
Procedures for handling subjects incorrectly enrolled 
Subjects who are incorrectly enrolled or initiated on treatment should be withdrawn from the 
study. 


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6.2 
Dosage and Administration 
Subjects will receive an IV infusion of durvalumab at a dose of 1500 mg, once every four weeks. 
When the patients weight is less than or equal to 30 kg, the dosage will be calculated based on 
the weight of the subject determined on the day prior to or the day of each drug administration 
(dosage equivalent to 20mg/kg Q4W). 
Treatment may continue past the initial determination of disease progression per RECIST1.1. 
as long as the following criteria are met: 
• Investigator assessed clinical benefit without any rapid disease progression. 
• Tolerance of durvalumab. 
• Stable ECOG PS. 
• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression 
The decision to continue treatment should be discussed with the Medical Monitor and 
documented in the trial records. 
A radiographic assessment should be performed within 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the subject is clinically 
deteriorating and unlikely to receive any benefit from continued treatment with durvalumab. 
If the Investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according 
to the Schedule of Assessments. 
 
6.3 
Dose Modification and Toxicity Management 
6.3.1 
Durvalumab 
For adverse events (AEs) that are considered at least partly due to administration of durvalumab, 
the following dose adjustment guidance may be applied: 


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• Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
• If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of durvalumab along with appropriate continuing supportive 
care.  If medically appropriate, dose modifications are permitted for durvalumab (see 
Appendix 1). 
• All dose modifications should be documented with clear reasoning and documentation 
of the approach taken. 
 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued. 
 
Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed (see Appendix 1).   
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune related Adverse Events (irAEs) during the conduct 
of this study.  Potential irAEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies. Subjects should be monitored for signs and symptoms of irAEs.  In the 
absence of an alternate etiology (e.g., infection or PD) signs or symptoms of enterocolitis, 
dermatitis, hepatitis, and endocrinopathy should be considered to be immune-related.   
Dose modification recommendations and toxicity management guidelines for immune-
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions are 
detailed in Appendix 1.   
In addition, management guidelines for adverse events of special interest (AESIs) are detailed 
in Section 10.1.3. All toxicities will be graded according to NCI CTCAE v4.03. 
 


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7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7.1 
Restrictions during the study 
Contraception 
Females of childbearing potential who are sexually active with a non sterilised male partner 
must use effective contraception from screening, and must agree to continue using such 
precautions for at least 90 days following the last infusion of durvalumab; cessation of birth 
control after this point should be discussed with a responsible physician.  Periodic abstinence, 
the rhythm method, and the withdrawal method are not acceptable methods of birth control. 
• Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause). 
• Subjects must use acceptable methods of effective contraception as described in Table 2. 
• Non-sterilised males who are sexually active with a female partner of childbearing potential 
must use acceptable methods of effective contraception (see Table 2) from Day 1 and for 90 
days after receipt of the final dose of investigational product. 
Table 2. Effective methods of contraception  
Barrier Methods 
Intrauterine Device Methods 
Hormonal 
Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone shot or 
injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
Combined pill 
Minipill 
Patch 
a 
This is also considered a hormonal method. 
 


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Blood donation 
As patients are HIV infected, they do not donate blood while participating in this study neither 
after its finalization. 
7.2 
Concomitant treatment(s) 
7.2.1 
Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed in Section 7.2.2. 
Patients will continue their antiretroviral treatment during study time, following standard 
treatment recommendations. 
7.2.2 
Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapies. 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for non cancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable.  NOTE: Local treatment of isolated lesions for 
palliative intent is acceptable (e.g., by local surgery or radiotherapy). 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. 
In addition, use of inhaled and intranasal corticosteroids is permitted. A temporary 
period of steroids will be allowed for different indications, at the discretion of the 
principal investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, 
etc). 
4. Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to the 
first dose, during treatment with durvalumab and for 30 days post discontinuation of 
durvalumab.  Inactivated vaccines, such as the injectable influenza vaccine, are 
permitted. 


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 In patients with head and neck cancer it is not yet known whether the risk of bleeding 
would increase with durvalumab. The principal investigator must ask the patients for 
any medications that might increase risk for example: aspirin; that they are taking. The 
physician must evaluate if it is possible to use alternative treatments. If it is not the case 
the therapeutic international normalized ratio (INR) must be monitored in the case of 
warfarin or similar drugs. Treatment with low molecular weight heparin (LMWH) is 
allowed. 
 
Table 3. Prohibited and Rescue Medications 
Rescue/supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(eg, acetaminophen 
or 
diphenhydramine) 
deemed necessary by the Investigator to provide 
adequate prophylactic or supportive care, 
except for those medications identified as 
“prohibited” as listed above 
To be administered as prescribed by the Investigator 
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc]) 
Should be used when necessary for all patients 
 
8. 
STUDY PROCEDURES 
8.1 
Schedule of study procedures 
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments. Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated.  The 
Schedules of Assessments during the screening and treatment period is provided following the 
Protocol Synopsis. 


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8.1.1 
Screening Phase 
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified.  
All subjects must first read, understand, and sign the IEC-approved ICF before any study-
specific screening procedures are performed.  After signing the ICF, completing all screening 
procedures, and being deemed eligible for entry, subjects will be enrolled in the study.  
Procedures that are performed prior to the signing of the ICF and are considered standard of 
care may be used as screening assessments if they fall within the 28-day screening window.  
The following procedures will be performed during the Screening Visit: 
• Informed Consent. 
• Assignment of subject identification number. 
• Review of eligibility criteria. 
• Medical and surgical history.  
• HIV infection history.  
• Demographics and history of tobacco and alcohol use. 
• Review of prior/concomitant medications, including treatments for solid tumors. 
• Complete physical exam. 
• ECOG Performance Status. 
• Vitals signs, weight and height. 
• 12-lead ECG (in triplicate [2-5 minutes apart]). 
• Tumor biopsy (archival tissue or resulting from a screening biopsy of the subject if no 
archival tissue is available). 
• Imaging by PET-CT/CT/MRI. Tumor evaluation will be performed using CT scan or 
PET-CT or MRI (if MRI is used, CT of chest is mandatory). A brain MRI scan is 
required only following the investigator criteria. 
• Blood samples for the translational study, will be collected before or on Day 1 before 
trial treatment starts. 
• Clinical laboratory tests for: 
o Hematology (see Table 4). 
o Clinical chemistry (see Table 5). 
o TSH (and T3 and T4, if TSH is abnormal). 
o Coagulation (PT, APTT, INR). 
o Creatinine Clearance. 
o Serum pregnancy test (for women of childbearing potential only). 
o Hepatitis B and C, and HIVserologies. 


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o Plasma viral load (PVL test) 
o Urinalysis (see Table 6), including, when applicable, urine hCG or serum βhCG 
(pre-menopausal female subjects of childbearing potential only) 
8.1.2 
Treatment Phase 
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Assessments.  Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do 
not need to be repeated on C1D1. 
In this trial the treatment will be given until PD, significant clinical deterioration (clinical 
progression), unacceptable toxicity, or any criterion of withdrawal from the trial or trial drug is 
fulfilled. 
Treatment may continue past the initial determination of PD according to RECIST1.1 if the 
subject’s ECOG PS has remained stable and in opinion of the Investigator, the subject will 
benefit from continued treatment. 
Patients will be asked for to visit the trial site center once every 4 weeks. 
A time window of up 3 days before or 1 day after the scheduled visit day (-3/+1) will be allowed 
for all trial procedures. 
In addition, the tumor evaluation has a tumor assessment visiting time window of 5 days prior 
to the scheduled day (-5 days). 
AEs and concomitant medications will be documented at each trial visit and between visits by 
weekly telephone contact. 
ECOG PS will be assessed at Day 1 and every 4 weeks thereafter. 
Vital signs will be performed at Day 1 and every 4 weeks thereafter. Subjects will have their 
blood pressure and pulse measured before, during and after the infusion at the following times 
(based on a 60-minute infusion): 
• At the beginning of the infusion (at 0 minutes) 
• At 30 minutes during the infusion (±5 minutes) 
• At the end of the infusion (at 60 minutes ±5 minutes) 
For the first infusion only and then for subsequent infusions as clinically indicated: In the 1 hour 
observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes 
from the start of the infusion) (±5 minutes). 


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 If the infusion takes longer than 60 minutes then blood pressure and pulse measurements should 
be collected every 30 minutes (±5 minutes) and as described above or more frequently if 
clinically indicated 
Physical examinations and body weight will be assessed in each visit. 
The laboratory hematology serum chemistry tests will be assessed at Day 1 (if screening 
laboratory assessments are performed within 3 days prior to Day 1 they do not need to be 
repeated at Day 1) and every 4 weeks thereafter.  
Liver enzyme panel will be assessed in each visit (if screening laboratory assessments are 
performed within 3 days prior to Day 1 they do not need to be repeated at Day 1). 
Thyroid function tests will be assessed at Day 1 and every 4 weeks thereafter.  
Urinalysis should be performed every 4 weeks. 
Urine or serum β-HCG pregnancy tests are performed every 2 cycles and in the first follow up 
(pre-menopausal female subjects of childbearing potential only). Coagulation parameters are 
performed at screening and as clinically indicated. 
Tumor evaluation (PET-CT, CT or MRI) will be performed every 8 weeks, with a tumor 
assessment visiting time window of 5 days prior to dosing until week 48. After that the tumor 
evaluation must be performed every 12 weeks (±7 days). 
 
. 
Blood samples for the translational study, will be collected at week 2, 4, 12, 24. Patients that 
continue on treatment after 24 weeks will have peripheral blood samples every 12 weeks until disease 
progression or at least until week 72 in the absence of progression. 
8.1.3         End of Treatment 
End of treatment is considered the last visit where the decision is made to discontinue treatment. 
All required procedures may be completed within ± 7 days of the end of treatment visit. Repeat 
disease assessment is not required if performed within 28 days prior to the end of treatment 
visit. 


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Assessments for subjects who have discontinued durvalumab due to toxicity in the absence of 
confirmed progressive disease are provided in appendix 3.   
Assessments for subjects who have discontinued durvalumab treatment due to confirmed PD 
are presented in appendix4. 
All subjects will be followed for survival until the end of the study regardless of further 
treatments, or until the sponsor ends the study. 
8.2 
Description of study procedures 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and vital 
signs 
Findings from medical history (obtained at screening) and physical examination shall be given 
a baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the pre-study grade or below. 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-
skeletal (including spine and extremities), genital/rectal, and neurological systems and at 
screening only, height.  
ECGs are required during screening, prior to starting study treatment on Cycle 1 Day 1, at16 
weeks after starting study treatment, as well as at any other time point when clinically indicated. 
ECGs recorded during the screening period will be obtained in triplicate (with 2-5 minute lag 
time between each); ECGs recorded during the treatment phase will be single tracing. All 12-
lead ECGs should be recorded while the subject is in the supine position. A 12-lead ECG will 
be recorded for all subjects on study days noted in Section 8.1. The same method of assessment 
should be used throughout the study. Twelve-lead ECGs will be obtained after the subject has 
been resting in a supine position for at least 5 minutes in each case. On Day 1 and Week 16, 
ECGs will be recorded within an hour prior to start of infusion and at least one time point 0 to 
3 hours after the infusion. 


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Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on 
study days noted in the Schedule of Assessments. On durvalumab treatment day 1, vital signs 
will be measured within an hour prior to start of durvalumab administration, at 30 minutes 
during the infusion (± 5 minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 
minutes) and 60 minutes (± 5 minutes) post-infusion.  If the infusion takes longer than 60 
minutes, then blood pressure and pulse measurements should follow the principles described 
here, or more frequently if clinically indicated.  For subsequent doses, the 1-hour observation 
period will not be required unless a subject experiences an infusion-related reaction.  
8.2.2 
Clinical laboratory tests 
The following clinical laboratory tests will be performed (see the Schedule of Assessments, 
Appendix 3 and Appendix 4 for the time points of each test): 
• Coagulation parameters: Activated partial thromboplastin time and International normalized 
ratio to be assessed at baseline and as clinically indicated  
• Hematology test: hemogram with CD4 and CD8 count and plasma viral load (PVL) 
• Pregnancy test (female subjects of childbearing potential only) 
o 
Urine human chorionic gonadotropin 
o 
Serum beta-human chorionic gonadotropin (at screening only) 
• Thyroid Stimulating Hormone 
o 
free T3 and free T4 only if TSH is abnormal 
• Other laboratory tests 
o 
Hepatitis B surface antigen, hepatitis C antibody 
o 
HIV antibody 
 


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Table 4.Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
CD4 T cells 
Mean corpuscular hemoglobin concentration 
CD8 T cells 
 
Plasma Viral Load (pVL) 
 
Table 5. Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Alanine aminotransferase 
Lipase 
Amylase 
Magnesium 
Aspartate aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyltransferaseb 
Serum βhCGc 
Uric acid 
a   If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect 
bilirubin. 
b At baseline and as clinically indicated. 
cPre-menopausal female subjects of childbearing potential only. 
 


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Table 6.Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Urine hCGb 
Colour and appearance 
a  Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red 
blood cells. 
bIf applicable. 
 
 
Table 7.Serology 
Serology HIV, Hepatitis B, Hepatitis C 
 
 
 
 
 
8.3 
Biological sampling procedures 
8.3.1 
Biomarker/Pharmacodynamic sampling and evaluation methods 
Immunohistochemestry Testing 
PD-L1 testing 
PD-L1 testing utilizes the Ventana SP263 assay. Testing should be restricted to the Ventana 
SP263 assay and should be performed in accordance with the package insert on the Ventana 
Benchmark platform (Ultra or XT).   
The Ventana SP263 assay is fully analytically validated test characterized through to the 
completion of reader precision studies in the non-small cell lung cancer (NSCLC) and squamous 
cell carcinoma of the head & neck (SCCHN).  For these tumors, the Ventana SP263 assay has 
a fully reproducibility data package supporting cut-off and scoring algorithm.  Following 
completion of ATLANTIC and HAWK clinical trials, the assay will be associated with clinical 
utility.  In other cancer types (bladder, pancreatic, gastric, hepatocellular, triple negative breast, 
ovarian, esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, cholangiocarcinoma, 
small cell lung, melanoma and cervical HPV+ cancers), the Ventana SP263 assay has only 
limited clinical performance data.   


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Other immunohistochemistry tests: 
A panel of putative markers including molecular and cellular markers may be analyzed in tumor 
tissue to investigate a possible correlation with clinical efficacy and analyzed markers.  
 PK-L1 and HLA-DRRNA expression analysis 
A set of immune response genes/proteins will be tested for RNA expression techniques (both 
RT-PCR and inmuno-histochemistry). 
Sample collection for immunohistochemestry/ RNA expression testing 
• The preferred tumor sample for translational is the one taken following the completion 
of the most recent prior line of therapy.  Samples taken at this time reflect are considered 
clinically most relevant.   
• The sample for traslational testing was less than or equal to 6 months old.  In cases where 
a sample a less than 6 months old was not available, patients were asked to undergo a 
new biopsy if considered clinically appropriate by their treating physician.   
• Samples should be collected via a core needle of 18 gauge or larger or be collected by 
an incisional or excisional tumor biopsy.  Where institutional practice uses a smaller 
gauge needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) 
to allow for adequate immunohistochemistry analyses.   
• When the collection of a new sample is not clinically appropriate, archival samples may 
be utilized provided the specimen it is not older than 3 years of age. When archival 
samples are used, the age of the sample / date of collection should be captured.   
• Samples submitted for immunohistochemistry/RNA expression testing should be 
formalin fixed and embedded in paraffin.  Samples from fine needle aspirates (FNA) or 
decalcified bone are not appropriate for immunohistochemestry analysis.   
Sample data collection for translational study testing 
The following fields of data should be collected from the site/institution collecting and if, 
indicated shipping of the samples:   
• Patient identifier (ecode or unique identifier) 
• Specimen identifier (written on the specimen) 
• Site identifier 


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• Specimen collection date 
• Type of specimen submitted 
• Quantity of specimen 
• Date of sectioning 
• Archival of fresh tumor 
• Tumor type 
• Primary tumor location 
• Metastatic tumor location (if applicable) 
• Fixative 
The following fields of data should be collected from translational study: 
• Are the negative and positive controls stained correctly 
• Is the H&E material acceptable 
• Is morphology acceptable 
• Total percent positivity of PD-L1 in tumor cells 
• PD-L1 status (positive, negative or NA) in tumor cells  
• Total percent positivity of PD-L1 in infiltrating immune cells 
The Ventana SP263 and the other assays in tumors are experimental.  As with all tests, there is 
a chance of false positive (for example, the test shows high PD-L1 when it is not there) or false 
negative (for example, the test does not show PD-L1 when it is there) results may occur.   
Sample processing and if indicated submission process for translational study 
Preparing Stored samples for testing 
• Where samples already exist, they should be retrieved from the Bio-Bank storage 
location.  These blocks should undergo quality review, prior to evaluation or shipment.  
Where it is not possible or indicated to ship the block to a testing laboratory, unstained 
slides should be prepared from the paraffin-embedded tumor sample block (described 
below) prior to evaluation or shipment.   
Preparing newly acquired samples for testing 
• If patients are undergoing a biopsy procedure that provides the option to submit newly 
acquired samples, this sample should be used.  Where clinically acceptable, a minimum 
of 2 core biopsies should be collected and processed to FFPE in a single block.  The 


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provision of 2 cores is advised in order to provide sufficient tissue for 
immunohistochemestry assessment.  
• It is recommended that core needle tumor biopsies are collected using an 18 gauge or 
larger needle and the process should be image-guided.  Excisional or incisional samples 
are also adequate.  If this is not per the institutions normal practice and a smaller gauge 
needle is used then the number of cores collected should be increased to allow sufficient 
material for successful PD-L1 testing (>100 tumor cells) and embedded in the same 
block.  If available, a single excisional biopsy of at least 4 mm in diameter may substitute 
for all core biopsies.  
Fixation of biopsy samples for testing 
• Previously frozen tissue is not acceptable for processing to FFPE for testing.  To fix 
newly acquired tissue, place immediately (within 30 min of excision) into an adequate 
volume of 10% v/v neutral buffered formalin (NBF).  Samples should remain in fixative 
for 24 – 48 hours at room temperature.   
• It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10 
volume excess) and that large specimens (if any) are incised prior to fixation to promote 
efficient tissue preservation.   
Embedding in paraffin for testing 
• An overnight processing schedule into paraffin wax is recommended  
• Below is the suggested routine overnight processing schedule: 
Storage of tumor blocks for testing 
• FFPE blocks should be stored at ambient temperature and protected from light until 
shipment by courier at ambient temperature. FFPE blocks are stable under these 
conditions for an indefinite period. 
Quality control of samples to be used for testing 
• Tissue should be assessed by the site pathologist prior to testing.   
• Each sample should be reviewed for: 


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• Adequate fixation 
• Good preservation of morphology 
• Presence of tumor tissue 
• Histopathology consistent with indication 
 
• Greater than 100 tumor cells are required to determine PD-L1 status – tumor cell 
content must be reviewed prior to testing in order for PD-L1 obtain a valid result.   
Shipping samples to a testing laboratory 
• When submitting sample to for testing the recommendation is to ship the block in order 
for sectioning to occur at the laboratory.  Blocks should be shipped  - containing enough  
material to  be provided to allow a minimum of 5, and preferably 10, sections to be cut 
(each 4  micron thick) to be used for testing.    
Sectioning instructions 
• Where it is not possible or indicated to ship the block to laboratory for testing, unstained 
slides should be prepared from the paraffin-embedded tumor sample block as described 
below:   
• A minimum of 5-10 x 4 micron (μm) thick, unstained sections should be 
provided for testing 
• A new disposable microtome blade must be used for each block to prevent 
contamination between Slides are stable under these conditions for 6 months. 
• patient samples 
• Apply one section per slide to positively-charged Superfrost glass slides  
• The sections should be dried overnight between room temperature and 37°C. Do 
not dry sections at temperatures above 37°C. 
Sections should be stored at ambient temperature and protected from light until use or shipment 
to testing lab by courier at ambient temperature.  It is recommended that slides are cut freshly 
prior to testing and they are used within 90 days of being cut. 
8.3.2 
Estimate of volume of blood to be collected 
The total volume of blood that will be drawn from each subject in this study is as follows: 


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Table 8. Volume of Blood to Be Drawn From Each Subject 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
10 
1 
10 
 
Hematology with 
CD4 count 
Viral load 
5 
 
5 
1 
 
1 
5 
 
5 
Biomarker 
8 Ml 
8 
64 Ml 
Total 
 
 
 
For the Biomarker analysis in blood, 60-80 mL will be required. They must be sent in EDTA 
tubes (8-10ml per tube, 8 tubes) as a whole blood at temperature ambient. Samples must arrived 
to the lab before eight hours from the extraction. If it is not possible arriving in less than 8 hour, 
samples will be processed at the local lab and the products will be frozen. 
8.3.3 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated samples, the samples will be disposed 
of/destroyed, and the action documented.  As collection of the biological samples is an integral 
part of the study, then the subject is withdrawn from further study participation. 
The Principal Investigator: 
• 
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
• 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action documented and 
the signed document returned to the study site 
• 
Ensures that the subject is informed about the sample disposal. 
9. 
DISEASE EVALUATION AND METHODS 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
• Response to immunotherapy may be delayed 


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• Response to immunotherapy may occur after PD by conventional criteria 
• The appearance of new lesions may not represent PD with immunotherapy 
• SD while on immunotherapy may be durable and represent clinical benefit. 
 
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anti-
cancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating anti-
cancer compounds, the study may wish to implement the following in addition to standard 
RECIST 1.1 criteria: 
• RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence 
of clinically significant deterioration. Treatment with durvalumab would continue 
between the initial assessment of progression and confirmation for progression.  
• In addition, subjects may continue to receive durvalumab beyond confirmed PD in the 
absence of clinically significant deterioration and if investigators consider that subjects 
continue to receive benefit from treatment.  
Modification of RECIST as described may discourage the early discontinuation of durvalumab 
and provide a more complete evaluation of its anti-tumor activity than would be seen with 
conventional response criteria. Nonetheless, the efficacy analysis will be conducted by 
programmatically deriving each efficacy endpoint based on RECIST 1.1 criteria. 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than durvalumab or with symptomatic 
progression that requires urgent medical intervention (e.g., central nervous system metastasis, 
respiratory failure due to tumor compression, spinal cord compression). 
9.1.1 
ORR and PFS rate 
Subjects who are withdrawn from durvalumab treatment for reasons other than confirmed PD 
will continue to have objective tumor assessments (see Appendix 4). 
For the endpoint of BOR according to RECIST1.1, the ORR in terms of having a confirmed 
BOR of CR or PR will be calculated. Also it will be recoded the ORR by ir RECIST criteria. 
Tumor shrinkage will be summarized as the percent change in target lesions per time point from 
baseline. 


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Duration of response will be analyzed descriptively. The Kaplan-Meier estimate of median time 
along with its 95% CI, as well as estimates the survival function at 12 months will be calculated 
for duration of response. 
PFS time according to RECIST 1.1 by Kaplan-Meier analysis. 
PFS at 6 months will be the efficacy variable. 
9.1.2 
OS 
Kaplan-Meier estimates will be presented with a summary of associated statistics including the 
median survival time with two-sided 95% CIs. In particular the survival rate at 12 months will 
be estimated with corresponding two side 95% CIs. The CIs for median will be calculated 
according to Kaplan-Meier. 
10. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
10.1.1 
Safety Parameters 
10.1.1.1 
Definition of adverse events 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
an action or intervention by the investigator, or a finding judged by the investigator to represent 
a change beyond the range of normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational 
product) or non treatment emergent. A non treatment-emergent AE is any new sign or symptom, 


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disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition, that did not 
worsen from baseline, is not considered an AE (serious or non serious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 
10.1.2 
Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital abnormality or birth defect in offspring of the subject 
• 
Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
• Medical or scientific judgment should be exercised in deciding 
whether expedited reporting is appropriate in this situation. 
Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in 
hospitalizations; or development of drug dependency or drug 
abuse. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 


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10.1.3 
Definition of adverse events of special interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize 
and understand them in association with the use of this investigational product. 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-related adverse event (irAE) is defined as an adverse event 
that is associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate aetiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of 
the irAE.  
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
• Diarrhea / Colitis 
• Pneumonitis/ ILD 
• ALT/AST increases / hepatitis / hepatotoxicity  
• Neuropathy / neuromuscular toxicity (i.e. Guillain-Barré, and myasthenia gravis) 
• Endocrinopathy (i.e. events of hypophysitis, 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)   
• Bleeding 


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• Other inflammatory responses that are rare with a potential immune-mediated 
aetiology include, but are not limited to, myocarditis, pericarditis, and uveitis. 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab Investigator Brochure. 
All the AESI must be reported as a SAE to the promoter of the study in order to monitor properly 
these adverse events. 
10.1.4 
Pneumonitis 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as pneumonitis has 
been reported with anti-PD-1 MAbs (Topalian et al, NEJM 2012). Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary 
consultation is highly recommended.  
Guidelines for the management of subjects with immune-mediated events including 
pneumonitis are outlined in Appendix 1. 
10.1.5 
Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-
PD-L1 and anti-PD-1 therapy (Brahmer et al 2012). As with the administration of any foreign 
protein and/or other biologic agents, reactions following the infusion of MAbs can be caused 
by various mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and 
anaphylactoid reactions against the MAb, and serum sickness. Acute allergic reactions may 
occur, may be severe, and may result in death. Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, 
arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, 
vomiting and unresponsiveness. 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined in Appendix 1. 
10.1.6 
Hepatic function abnormalities (hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies (Brahmer et al 2012).  Inflammatory hepatitis has been reported in 3% to 9% of 
subjects treated with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab). The clinical 
manifestations of ipilimumab-treated subjects included general weakness, fatigue, nausea 


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and/or mild fever and increased liver function tests such as AST, ALT, alkaline phosphatase, 
and/or total bilirubin. 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days of 
each other. Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the investigational product. 
Guidelines for management of subjects with hepatic function abnormality are outlined in 
Appendix 1. 
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need 
to be reported as SAEs, These cases should be reported as SAEs if, after evaluation they meet 
the criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the 
SAE criteria. 
10.1.7 
Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab 
is used as monotherapy. In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.  Guidelines on management 
of diarrhea and colitis in patients receiving durvalumab are provided in Appendix 1. 
10.1.8 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine 
events are provided in Appendix 1. 
10.1.9 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Appendix 1. 
10.1.10 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis. Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in Appendix 1. 


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10.1.11 
Nephritis 
Consult with Nephrologist.  Monitor for signs and symptoms that may be related to changes in 
renal function (e.g. routine urinalysis, elevated serum BUN and creatinine, decreased creatinine 
clearance, electrolyte imbalance, decrease in urine output, proteinuria, etc). 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, infections etc). 
Steroids should be considered in the absence of clear alternative etiology even for low grade 
events (Grade 2), in order to prevent potential progression to higher grade event.  Guidelines 
for the management of patients with immune-mediated neurotoxic events are provided in 
Appendix 1. 
10.1.12    Bleeding 
Bleeding has been reported in up to 10% or greater in patients with head and neck cancer.  
Reports of bleeding, including fatal reports, have been received from head and neck cancer 
patients enrolled in MAH clinical trials with durvalumab as monotherapy or in combination. It 
is not yet known whether the risk of bleeding would be higher or lower with the experimental 
treatment than with standard chemotherapy.  Monitor bleeding as an AESI. 
Criteria for Hy’s Law (FDA Guidance 2009) 
• The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold 
or greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control 
drug or placebo. 
• Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of serum 
total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase). 
• No other reason can be found to explain the combination of increased aminotransferases 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; 
or another drug capable of causing the observed injury. 


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10.2 
Assessment of safety parameters 
10.2.1 
Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs 
and SAEs. Severity will be graded according to the NCI CTCAE v4.03. 
 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below: 
 
Grade 1 (mild)  
An event that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
 
Grade 2 (moderate)  An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the subject. 
 
Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the subject. 
 
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental disabilities that 
affect or limit the ability of the subject to perform activities of daily living 
(eating, ambulation, toileting, etc). 
 
Grade 5 (fatal)  
Death (loss of life) as a result of an event. 
 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 10.1.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
non-serious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. 


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10.2.2 
Assessment of relationship 
Investigators must systematically assess the causal relationship of AEs to the trial treatment 
using the following definitions. Decisive factors for the assessment of causal relationship of an 
AE to trial treatment include, but may not be limited to, temporal relationship between the AE 
and treatment administration, known side effects of trial treatment, medical history, concomitant 
medication, course of the underlying disease, trial procedures. 
 
Not related: Not reasonably related to the trial. The AE could not medically (pharmacologically 
/ clinically) be attributed to the trial treatment in this clinical trial protocol. A reasonable 
alternative explanation must be available. 
 
Related: Reasonably related to the trial treatment The AE could medically (pharmacologically 
/ clinically) be attributed to the trial treatment. 
 
TEAEs defined as possibly related to trial treatment will be summarized by Preferred Term and 
System Organ Class, and described in terms of intensity and relationship to treatment. 
Treatment emergent AEs are those events with onset dates occurring during the on-treatment 
period or if the worsening of an event is during the on-treatment period. Any AEs with an onset 
or worsening date after the on-treatment period will be reported separately. 
All premature terminations will be summarized by primary reason for treatment 
discontinuation/withdrawal. 
10.3 
Recording of adverse events and serious adverse events 
Adverse events will be recorded in the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. Adverse events will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets 
criteria of an SAE and therefore requires immediate notification to AstraZeneca/MedImmune 
Patient Safety.  
In cases of surgical or diagnostic procedures, the condition / illness leading to such a procedure 
is considered as the AE rather than the procedure itself. 
 
According to the Sponsor’s convention, any clinical AE with severity of Grade 4 or 5 must also 
be reported as an SAE; however, a laboratory abnormality of Grade 4, such as anemia or 


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neutropenia, is considered serious only if the condition meets one of the serious criteria 
described below. If death occurs, the primary cause of death (or event leading to death) should 
be recorded and reported as an SAE. “Fatal” will be recorded as the outcome of this respective 
event; death will not be recorded as a separate event. Only if no cause of death can be reported 
(for example, sudden death, unexplained death), the death per se might be reported as an SAE. 
 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against durvalumab (yes or no) 
• 
Action taken with regard to durvalumab 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to<<criteria>> 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
10.3.1 
Study recording period and follow-up for adverse events and serious adverse 
events 
Adverse events and serious adverse events will be recorded from time of signature of informed 
consent, throughout the treatment period and including the follow-up period (90 days after the 
last dose of durvalumab). 


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During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until 
the patient is considered to have confirmed PD and will have no further tumor assessments. 
The investigator is responsible for following all SAEs until resolution, until the subject returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF.  After 
90 days, only subjects with ongoing investigational product-related SAEs will continue to be 
followed for safety. 
AstraZeneca/MedImmune retains the right to request additional information for any subject 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring in former study 
subjects after the 90-day safety follow-up period for patients treated with durvalumab.  
However, if an investigator learns of any SAEs, including death, at any time after the subject 
has been permanently withdrawn from study, and he/she considers there is a reasonable 
possibility that the event is related to study treatment, the investigator should notify the study 
sponsor and AstraZeneca/MedImmune Drug Safety. 
 
10.3.2 
Reporting of serious adverse events 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The Sponsor is responsible for informing the Regulatory 
Authorities of the SAE as per local requirements. 


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The sponsor must inform local Health Authorities, via a CIOMS form, of any serious or 
unexpected adverse events that occur, and will concurrently forward all such reports to 
AstraZeneca.  A copy of the CIOMS report must be faxed to AstraZeneca at the time the event 
is reported to local Health Authorities.  It is the responsibility of the sponsor to compile all 
necessary information and ensure that the local Health Authorities receives a report according 
to the local  reporting requirement timelines and to ensure that these reports are also submitted 
to AstraZeneca at the same time. 
* A cover page should accompany the CIOMS form indicating the following: 
• 
“Notification from an Investigator Sponsored Study” 
• 
The EudraCT Number 
• 
The sponsor’s name and address 
• 
The trial name/title and ESR reference number (ESR-##-#####) 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events 
in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox:AEMailboxClinicalTrialTCS@astrazeneca.com 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca and the local Health Authorities. 
Serious adverse events that do not require expedited reporting to local Health Authorities still 
need to be reported to AstraZeneca preferably using the MedDRA coding language for serious 
adverse events. This information should be reported on a monthly basis and under no 
circumstance less frequently than quarterly. 
10.3.3 
Reporting of deaths 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab safety follow-up period must be reported as follows: 
• 
Death that is clearly the result of disease progression should be 
documented but should not be reported as an SAE. 


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• 
Where death is not due (or not clearly due) to progression of the 
disease under study, the AE causing the death must be reported to as 
a SAE within 24 hours (see Section 10.3.2 for further details).  The 
report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and 
contributory causes of death.   
• 
Deaths with an unknown cause should always be reported as a SAE.   
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab safety 
follow-up period will be documented as events for survival analysis, but will not be reported as 
an SAE. 
10.3.4 
Other events requiring reporting 
10.3.5 
Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that specified 
in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox(see 
Section 10.3.2 for contact information). If the overdose results in an AE, the AE must also be 
recorded as an AE (see Section 10.3). Overdose does not automatically make an AE serious, 
but if the consequences of the overdose are serious, for example death or hospitalization, the 
event is serious and must be recorded and reported as an SAE (see Section 10.1.2 and 
Section 10.3.2). There is currently no specific treatment in the event of an overdose of 
durvalumab. 
The investigator will use clinical judgment to treat any overdose. 
10.3.6 
Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 10.1.3.3) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient 
Safety using the designated Safety e-mailbox (see Section 10.3.2 for contact information), 
unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct 
obstruction) that is unrelated to investigational product has been confirmed. 


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• 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated 
to investigational product, the decision to continue dosing of the study subject will be based on 
the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor.  
10.3.7 
Pregnancy 
10.3.8 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.   
Pregnancy itself 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.  Congenital abnormalities 
or birth defects and spontaneous miscarriages should be reported and handled as SAEs.  Elective 
abortions without complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from 
the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but 
no later than 24 hours of when he or she becomes aware of it.   
The same timelines apply when outcome information is available.   
10.3.9 
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab monotherapy.   
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented.   


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Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner.  Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the Ethics 
Committees (ECs) prior to use. 
11. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
11.1 
Description of analysis sets 
The screening analysis set includes all subjects who signed the ICF. 
ITT Analysis set: the ITT analysis set will include all subjects who were included into the trials. 
Per-protocol analysis set will include all ITT subjects who do not have major protocol 
violations. 
11.1.1 
Safety analysis set 
The safety analysis set will include all subjects who were administered at least 1 dose of the 
trial drug. Analysis performed on the Safety analysis set will considered subjects as treated. 
11.1.2 
Efficacy analysis set 
Analysis of efficacy variables will also be performed on subgroups of interest as PD-L1+ on 
tumor and on TILs, Also as an exploratory endpoint efficacy in terms of antiretroviral activity 
of the drug will be performed. It will be recorded as number of CD4, viral load along the 
treatment, and viral reservoir (HIV integrated in resting T cells). 
11.2 
Methods of statistical analyses 
In general descriptive summaries will be presented for the efficacy and safety variables 
collected. Continuous variables will be summarized using mean, standard deviation, minimum, 
median, and maximum. Categorical variables will be summarized using frequency counts and 
percentages. 
Unless otherwise specified, the calculation of proportions will be based on the sample size of 
the population of interest. Count missing observations will be included in the denominator and 
presented in a separate category. 


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11.2.1 
Safety Analyses 
Analysis of safety endpoint(s) 
The extent of exposure to trial drug will be characterized by duration (weeks), number of 
administrations, cumulative dose (mg/kg), dose intensity (mg/kg/week), relative dose intensity 
(actual dose given/planned dose) and number of dose delays. 
Safety analysis will be performed on the Safety analysis set. The safety endpoints will be 
tabulated using descriptive statistics. 
Safety assessments will be based on review of incidence of AEs including AESIs, ADRs, and 
changes in vital signs, ECGs, body weight, and laboratory values (hematology, serum 
chemistry). 
The on-treatment period is defined as the time from the first trial drug administration to the last 
drug administration date +29 days or the earliest date of subsequent anticancer drug therapy 
minus 1 day, whichever occurs first, unless otherwise stated. 
11.2.2 
Efficacy Analyses 
Analysis of efficacy endpoint(s) 
Kaplan Meier method will be used to estimate the survival function. Secondary measurements 
will be PFS rate at 6 months and OS rate at 12 months. 
11.2.3 
Exploratory Analyses 
Analysis of immunohistochemistry 
Immunohistochemistry results (defined as positive or negative) in the pretreatment sample with 
their relation to response and survival. 
Analysis of gene expression 
Analysis of gene expression in relation to response and survival. 
Analysis of anti HIV activity in blood 
Analysis by digital droplet PCR (ddPCR) of HIV-1 DNA associated to CD4+ T cells obtained 
from peripheral blood. 


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Analysis of residual plasma viremia 
Using an ultrasensitive single copy assay (these patients would be on antiretroviral treatment, 
so standard techniques for determine viral load with not be useful). 
Analysis of HIV-1 RNA expression 
Analysis by ddPCR of HIV-1 RNA expression on CD4+ T cells obtained from peripheral blood. 
Analysis of 2LTR 
Change in 2LTR mean levels in CD4+ T cells. 
Analysis of CD4+ and CD8+ T-cell subsets in peripheral blood 
Analysis by multicolor flow cytometry of the percentage of naïve, memory and activated CD4+ 
and CD8+ T-cell subsets in peripheral blood, including analysis of PD-1 expression. 
Analysis of functional effector responses of T cells 
Analysis by multicolor flow cytometry of the functional effector responses of T cells elicited 
by different viral and non viral antigens. 
Analysis of predictive factors of antitumoral activity in pretreatment tumor samples 
mRNA expression (RT-PCR) of Interferon gamma, HLA-DR and PD-L1. 
 
Immunohistochemestry: PDL-1 and HLA-DR. 
 
A set of immune response genes/proteins will be tested (both RT-PCR and 
inmunohistochemistry). 
 
11.2.4 
Interim analyses 
No interim analyses are planned in this study. 
11.3 
Determination of sample size 
Feasibility will be defined based on the rate of patients that will complete at least 4 treatment 
cycles. One cycle is four weeks with infusions every four weeks. It is assumed that at least 50% 


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of patients must be complete four cycles for considering feasible the treatment with durvalumab 
(MEDI4736). 
Sample size calculation for an estimated proportion of 50% with a level of confidence of 95% 
and an accuracy of 22%: 20 patients must be included in this study. 
12. 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
12.2 
Ethics and regulatory review 
The Investigator is responsible for the conduct of the trial at his site. He/she will ensure that the 
trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their own origin in the Declaration of Helsinki, as well as with the ICH Note for 
Guidance on GCP (ICH Topic E6, 1996) and applicable regulatory requirements. In particular 
the investigator must ensure that only patients who have their informed consent are included in 
the trial. 
12.3 
Informed consent 
An unconditional prerequisite for a subject´s participation in the trial is his/her written informed 
consent. The subject´s written consent to participate in the trial must be given before any trial-
related activities are carried out. A separate specific PGx ICF will be provided to subjects who 
are willing to participate in the procedure, which refers to the extraction and analysis of 
DNA/RNA from blood and /or tumor biopsy in order to better understand how genes may affect 
the efficacy of durvalumab. 
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if 
permitted by local regulations). A subject information sheet in the local language and prepared 
in accordance with the Note for Guidance on GCP (IHC Topic E6, 1996) will be provided by 
the Sponsor for the purpose of obtaining informed consent. In addition to providing this written 
information to a potential subject, the Investigator or his /her designate will inform the subject 


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verbally of all aspects of the trial. The language used in doing so must be chosen so that the 
information can be fully and readily understood by lay persons. 
The ICF must be signed and personally dated by the Investigator and the subject. 
The signed and dated declaration of informed consent will remain at the Investigator´s site, and 
must be safely archived. A copy of the signed and dated information and ICF should be provided 
to the subject prior to participation. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly and will be requested to give 
their consent on data handling procedures in accordance with national regulations. 
A unique subject number will be assigned to each subject at inclusion by IVRS system, 
immediately after informed consent has been obtained. This number will serve as the subject`s 
identifier in the trial as well as in the clinical trial database. The subject`s data will be stored 
under this number. Only the investigator will be able to link the subject`s identity with the 
subject`trial data via an identification list kept at the site. The medical data that are reviewed at 
the site during the source data verification by the Clinical Trial Monitor, audits, and Health 
Authority inspections will be kept strictly confidential. 
Subjects will be informed accordingly and will be requested to give their consent on data 
handling procedures in accordance with national regulations. 
 
12.4 
Changes to the protocol and informed consent form 
Any change in the approved protocol will require a Protocol amendment. The Investigator must 
not make any change in the study without favorable opinion from the Ethics Committee and 
authorization from the Health Authorities, except as necessary to eliminate an impending and 
obvious risk for the subjects except when necessary to remove an apparent, immediate hazard 
to subjects.  Protocol changes introduced to eliminate an impending and obvious risk may be 
implemented immediately, but must subsequently be documented in an amendment, reported to 
the Ethics Committee and be submitted to the relevant Health Authorities within the required 
timeframe.  
Any substantial amendments to the protocol must be submitted in writing to the Investigator’s 
Ethics Committee and the Health Authorities for approval before the changes proposed in the 


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amendment are implemented. Depending on the magnitude of the change, the recruitment may 
be temporally halted. 
The sponsor does not have to notify non-substantial amendments to the Health Authorities or 
the Ethics Committee. However, any non-substantial amendments will be recorded and 
contained in the documentation when it is subsequently submitted, for example in the 
subsequent notification of a substantial amendment. Documentation of any non-substantial 
amendments will be available on request for inspection at the trial site or the sponsor premises 
as appropriate. 
Whenever important new information becomes available that may be relevant to the subject´s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor or designee and be submitted again to the IEC/IRB for 
review and favorable opinion. The agreed, revised information will be provided to each subject 
in the trial for signing and dating. The Investigator will explain the changes to the previous 
version. 
12.5 
Audits and inspections 
This trial will be monitored in accordance with the ICH Note for Guidance on GCP (ICH Topic 
E6, 1996). The clinical Trial Monitor will perform visits to the trial site at regular intervals. 
Representatives of the Sponsor´s Quality Assurance unit or a designated organization, as well 
as Health Authorities, must be permitted to inspect all trial-related documents and other 
materials at the site, including the Investigator Site File, the completed eCRFs, the trial drug, 
and the subject’s original medical records/files. 
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent quality assurance 
activities. Audits may be conducted at any time during or after the trial to ensure the validity 
and integrity of the trial data. 
12.6 
Insurance 
The sponsor contracts an insurance policy to cover the responsibilities of the investigator and 
other parties participating in the study, according to the applicable Spanish legislation. 
Insurance company: HDI Global SE 
 


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• Policy number:08057681-14129, 
 
12.7 
Publications 
The sponsor commits to responsible publication of both the positive and negative results from 
its clinical trials as required by all governing regulatory and health authorities.   
Investigators will not publish the global study results (all sites) unless the sponsor has not done 
so in a suitable time period after the clinical study report (CSR) has been available.  Should the 
Investigator(s) independently seek to publish results of this study which occur at their study 
site(s), they must inform the study sponsor of any/all drafts (including, but not limited to papers, 
manuscripts or abstracts) at least 60 days before submission to the congress, meeting or journal.  
The sponsor and Investigator(s) will agree with all aspects related to any proposed publications 
with regards to the following:  1) any proposed publications will be drafted in agreement with 
international recommendations, such as those from the International Committee of Medical 
Journal Editors (ICMJE) and all elements of the Consort Statement (2010), to maintain integrity 
of the trial results in all communications; 2) any proposed publications will state the Clinical 
Research Ethics Committees which approved the trial and the funding sources of the trial; 3) 
any proposed publications will occur before disclosure of results to lay people; 4) any proposed 
publications will not report premature or partial data prior to completion of the analysis of the 
overall results of the trial. 
13. 
STUDY MANAGEMENT 
13.1 
Training of study site personnel 
The principal investigator will maintain a record of all center staff involved in the clinical trial 
(doctors, nurses and other staff involved) ensuring that they receive appropriate training to 
perform the study, and that any new information of relevance to the study will be transmitted 
to them. 
Researchers will be instructed about the procedures of the trial in the investigator meeting and/or 
initiation visits made by monitors at each participating center prior to the study start. 
 


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13.2 
Monitoring of the study 
Spanish Lung Cancer Group is the company responsible for monitoring the study (see appendix 
5). The clinical monitors have the obligation to follow the trial closely so that all aspects of the 
trial are carefully monitored for compliance with applicable government regulations and with 
ICH E6 (R1) guidelines.   
The clinical monitors will visit the study sites and Investigators at intervals as defined in the 
monitoring plan, in addition to maintaining necessary contact through telephone, e-mail, and 
letter.  The clinical monitors will maintain current personal knowledge of the trial through 
observation, review of trial records and source documentation, and discussion of the conduct 
of the trial with the study site Investigators and staff. 
13.2.1 
Source data 
Source documents are all documents used by the Investigator or hospital that relate to the 
subject’s medical history, that verify the existence of the subject, the inclusion and exclusion 
criteria, and all records covering the subject’s participation in the study. They include enrolment 
log, investigational product accountability log, laboratory notes, memoranda, material 
dispensing records, subject files, etc. The eCRF is essentially considered a data entry form and 
should not constitute the original (or source) medical records unless otherwise specified.   
Each Investigator is responsible for maintaining source documents. These will be made 
available for inspection by the study monitor at each monitoring visit. All supportive 
documentation submitted with the eCRF, such as laboratory data should be clearly identified 
with the study, visit and subject number. Any personal information (e.g., subject name, initials) 
should be removed or rendered illegible to preserve individual confidentiality.  
13.2.2 
Study documentation 
The Investigator will be provided with an Investigator Site File upon initiation of the trial. This 
file will contain all documents necessary for the conduct of the trial and will be updated and 
completed throughout the trial. It must be available for review by the Monitor, and must be 
ready for Sponsor audit as well as for inspection by Health Authorities during and after the trial, 
and must be safely archived for at least 25 years after the end of the trial. The documents to be 
archived include the Subject Identification List and the signed subject ICFs. If archiving of the 
Investigator Site File is no longer possible at the site, the Investigator must notify the Sponsor. 
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and / or as per 
ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor. 
 


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13.3 
Study timetable and end of study 
End of study is defined as Last Subject Last Visit.   
 
• Recruitment period will be 12 months 
• Research Agreement executed: 
April, 2016 
• Projected IRB/IEC approval:  
March, 2017 
• First Subject In: 
 
 
April, 2017 
• 50% Enrollment: 
 
 
September, 2017 
• Last Subject In (100% enrollment): April 2018 
• Last Subject Last Visit (Treatment end): April 2019 
• Publication: 
 
 
 
June, 2020 
14. 
DATA MANAGEMENT 
The Investigator or designee will be responsible for entering trial data in the eCRF provided by 
the CRO and follow the data entry guidelines. It is the Investigator’s responsibility to ensure 
the accuracy of the data entered in the eCRFs and to sign the case report forms. 
The data will be entered into a validated database. The CRO will be responsible for data review 
and processing, in accordance with the CRO’s data management procedures. 
The principal CRO functions in data management are CRF tracking and query generation, 
tracking and resolution as well as to perform Eligibility, Treatment, AE, Response checks and 
inform Medical Reviewers if any doubt regarding eligibility comes up. 
Data Manager (DM) will check the database twice a week or when necessary, depending on the 
recruitment of the Study. 
Queries issued by the DM will show up in the eCRF. 
DM will send an e-mail to the investigators according the quantity of queries to be solved 
requesting their resolution as soon as possible. If there would be a lot of queries at the same 
center, DM will send an e-mail/reminder once a week. 


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DM have to access to the eCRF in regular intervals to check if any queries have been solved. 
The participant centers have to access to the eCRF to check if any queries have been issued in 
their patients. 
The data review will be done from the first patient included until the last follow of the last 
patient reported in the eCRF. 
The data cleaning consists of the exhaustive review of data from the baseline to the end of the 
follow up of the patient, performing queries when necessary. 
DM reviewers will follow the most current version of the Fundación GECP’s Data Management 
SOP. 
The field which have to be reviewed by DM will be detailed in the eCRF Data Management 
Manual. 
Database lock will occur once quality control procedures and quality assurance procedures (if 
applicable) have been completed.  
Copies of the eCRFs will be provided to the Investigators at the completion of the trial. 
The Investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and allmedical information for the subject, and should be as complete as possible.  
14.1 
Study governance and oversight 
The safety of all AstraZeneca products is closely monitored on an ongoing basis by AstraZeneca 
representatives in consultation with Patient Safety. Issues identified will be addressed; for 
instance, this could involve amendments to the study protocol and letters to Investigators. 
 
 
 
 


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15. 
LIST OF REFERENCES 
1. 
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Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 
2013;381(9883):2109-17. Epub 2013/04/02. 
2. 
Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, et al. Towards 
an HIV cure: a global scientific strategy. Nature reviews Immunology. 2012;12(8):607-14. 
Epub 2012/07/21. 
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Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: 
an update on implications for chronic infections and tumor evasion. Cancer immunology, 
immunotherapy : CII. 2007;56(5):739-45. Epub 2006/12/30. 
4. 
Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people 
with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. 
Lancet. 2007;370(9581):59-67. Epub 2007/07/10. 
5. 
Pakkala S, Ramalingam SS. Lung cancer in HIV-positive patients. J Thorac Oncol. 
2010;5(11):1864-71. Epub 2010/10/01. 
6. 
Yanik EL, Tamburro K, Eron JJ, Damania B, Napravnik S, Dittmer DP. Recent cancer 
incidence trends in an observational clinical cohort of HIV-infected patients in the US, 2000 to 
2011. Infectious agents and cancer. 2013;8(1):18. Epub 2013/05/28. 
7. 
Zhou ZJ, Zhan P, Song Y. PD-L1 over-expression and survival in patients with non-
small cell lung cancer: a meta-analysis. Transl Lung Cancer Res. 2015;4(2):203-8. Epub 
2015/04/15. 
8. 
Balan M, Mier y Teran E, Waaga-Gasser AM, Gasser M, Choueiri TK, Freeman G, et 
al. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and 
PD-L1 expression. J Biol Chem. 2015;290(13):8110-20. Epub 2015/02/04. 
9. 
Bigelow E, Bever KM, Xu H, Yager A, Wu A, Taube J, et al. Immunohistochemical 
staining of B7-H1 (PD-L1) on paraffin-embedded slides of pancreatic adenocarcinoma tissue. 
J Vis Exp. 2013(71). Epub 2013/01/19. 
10. 
Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, et al. PD-L1 on 
tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer 
through CTL dysfunction. Clin Cancer Res. 2013;19(6):1363-74. Epub 2013/01/24. 
11. 
Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, et al. Disabling 
immune tolerance by programmed death-1 blockade with pidilizumab after autologous 


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hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an 
international phase II trial. J Clin Oncol. 2013;31(33):4199-206. Epub 2013/10/16. 
12. 
Brusa D, Serra S, Coscia M, Rossi D, D'Arena G, Laurenti L, et al. The PD-1/PD-L1 
axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 
2013;98(6):953-63. Epub 2013/01/10. 
13. 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and 
immunity. Annu Rev Immunol. 2008;26:677-704. Epub 2008/01/05. 
14. 
Jung HW, Son HY, Jin GZ, Park YK. Preventive role of PD-1 on MPTP-induced 
dopamine depletion in mice. Cell biochemistry and function. 2010;28(3):217-23. Epub 
2010/02/27. 
15. 
Wei S, Shreiner AB, Takeshita N, Chen L, Zou W, Chang AE. Tumor-induced immune 
suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and 
transforming growth factor beta. Cancer Res. 2008;68(13):5432-8. Epub 2008/07/03. 
16. 
Porichis F, Kaufmann DE. Role of PD-1 in HIV pathogenesis and as target for therapy. 
Current HIV/AIDS reports. 2012;9(1):81-90. Epub 2011/12/27. 
17. 
Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, et al. Enhancing SIV-specific 
immunity in vivo by PD-1 blockade. Nature. 2009;458(7235):206-10. Epub 2008/12/17. 
18. 
Khleif S, Lutzky J, Segal N, Antonia S, Blake-Haskins A, R S. MEDI4736, an anti-PD-
L1 antibody with modified Fc domain: preclinical evaluation and early clinical results from a 
phase 1 study in patients with advanced solid tumors. European Cancer Congress 2013 Abstract 
802. 2013. 
19. 
Lutzky J, Antonia S, Blake-Haskins A, Li X, Robbins PB, Shalabi AM, et al. A phase 1 
study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors. Journal 
of Clinical Oncology. 2014;32(5s):suppl; abstr 3001. 
20. 
Segal NH, Antonia SJ, Brahmer JR, Maio M, Blake-Haskins A, Li X. Preliminary data 
from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J Clin Oncol 
2014;32(5s,abst30025s). 
21. 
Okazaki T, Okazaki IM, Wang J, Sugiura D, Nakaki F, Yoshida T, et al. PD-1 and LAG-
3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J Exp Med. 
2011;208(2):395-407. Epub 2011/02/09. 
22. 
Thoma C. Kidney cancer: CheckMate for advanced-stage ccRCC? Nivolumab and 
cabozantinib aMETEORate poor survival. Nature reviews Urology. 2015;12(12):651. Epub 
2015/10/16. 


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Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
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23. 
Nivolumab Demonstrates Efficacy in Platinum-Resistant Ovarian Cancer. Cancer 
Discov. 2015;5(11):OF6. Epub 2015/09/26. 
24. 
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab 
versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 
2015;373(17):1627-39. Epub 2015/09/29. 
25. 
Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, et al. Safety 
and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-
Resistant Ovarian Cancer. J Clin Oncol. 2015;33(34):4015-22. Epub 2015/09/10. 
26. 
Yaqub F. Nivolumab for squamous-cell non-small-cell lung cancer. Lancet Oncol. 
2015;16(7):e319. Epub 2015/06/13. 
27. 
Gunturi A, McDermott DF. Nivolumab for the treatment of cancer. Expert Opin Investig 
Drugs. 2015;24(2):253-60. Epub 2014/12/17. 
28. 
Dang TO, Ogunniyi A, Barbee MS, Drilon A. Pembrolizumab for the treatment of PD-
L1 positive advanced or metastatic non-small cell lung cancer. Expert Rev Anticancer Ther. 
2015:1-8. Epub 2015/11/22. 
29. 
Starr P. Encouraging Results for Pembrolizumab in Head and Neck Cancer. American 
health & drug benefits. 2015;8(Spec Issue):16. Epub 2015/09/19. 
30. 
Pembrolizumab shows potential in breast cancer. Cancer Discov. 2015;5(2):100-1. Epub 
2015/02/07. 
 
 


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Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
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Appendix 1 
Appendix 1. 
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) ) 1 November 2017 Version 
General Considerations 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table: 
− 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune-
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events.  
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Some events with high likelihood for morbidity and/or mortality – e.g., myo-
carditis, or other similar events even if they are not currently noted in the 
guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper). 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
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Appendix 1 
Appendix 1. 
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) ) 1 November 2017 Version 
General Considerations 
Dose Modifications 
Toxicity Management 
2. 
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study drug/study 
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
 
− 
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) 
(also refer to the individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
− 
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient. 


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AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth. 
 
Pediatric Considerations 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks after last dose of study drug/study regimen 
− 
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended. 
− 
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used 
for pediatric patients. 
− 
The infliximab 5 mg/kg IV dose recommended for adults is the same as 
recommended for pediatric patients ≥ 6 years old.  For dosing in children 
younger than 6 years old, consult with a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring. 
 
 


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Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of 
pneumonitis or ILD (new onset or worsening 
shortness of breath or cough). Patients should be 
evaluated with imaging and pulmonary function tests, 
including other diagnostic procedures as described 
below. 
− 
Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry (resting 
and exertion), laboratory work-up, and high- 
resolution CT scan. 
Grade 1 
(asymptomatic, clinical or 
diagnostic observations only; 
intervention not indicated) 
No dose modifications required. 
However, consider holding study 
drug/study regimen dose as clinically 
appropriate and during diagnostic 
work-up for other etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for 
clinical symptoms, pulse oximetry (resting and 
exertion), and laboratory work-up and then as 
clinically indicated. 
− 
Consider Pulmonary and Infectious disease consult. 
Grade 2 
(symptomatic; medical intervention 
indicated; limiting instrumental 
ADL) 
Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade 
≤1, then the decision to 
reinitiate study drug/study 
regimen will be based upon 
treating physician’s clinical 
judgment and after completion 
of steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional 
workup should be considered and prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly 
start immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). 


Clinical Study Protocol 
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Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Caution: It is important to rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation])a 
− 
Consider pulmonary and infectious disease consult. 
− 
Consider, as necessary, discussing with study 
physician. 
Grade 3 or 4 
(Grade 3: severe symptoms; 
limiting self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-threatening 
respiratory compromise; urgent 
intervention indicated [e.g., 
tracheostomy or intubation]) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain Pulmonary and Infectious disease consult; 
consider, as necessary, discussing with study 
physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days, additional 
workup should be considered and prompt treatment 
with additional immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 
weeks’ dose) started. Caution: rule out sepsis and refer 
to infliximab label for general guidance before using 
infliximab. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and, in particular, anti-PJP treatment 
(refer to current NCCN guidelines for treatment of 


Clinical Study Protocol 
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Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
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CONFIDENTIAL AND PROPRIETARY 
  
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
cancer-related infections [Category 2B 
recommendation]).a 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or 
changes in bowel habits such as increased frequency 
over baseline or blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal signs, and 
ileus). 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
other medications, or infections), including testing for 
clostridium difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in 
order to prevent potential progression to higher grade 
event. 
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(Diarrhea: stool frequency of <4 
over baseline per day) 
(Colitis: asymptomatic; clinical or 
diagnostic observations only) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., 
American Dietetic Association colitis diet), and 
loperamide. Use probiotics as per treating physician’s 
clinical judgment. 
Grade 2 
(Diarrhea: stool frequency of 4 to 6 
over baseline per day) (Colitis: 
Hold study drug/study regimen until 
resolution to Grade ≤1 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., 


Clinical Study Protocol 
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Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
abdominal pain; mucus or blood in 
stool) 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade 
≤1, then study drug/study 
regimen can be resumed after 
completion of steroid taper. 
American Dietetic Association colitis diet), and 
loperamide and/or budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or 
worsens despite prednisone at 1 to 2 mg/kg/day PO or 
IV equivalent, GI consult should be obtained for 
consideration of further workup, such as imaging 
and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as infliximab at 5 mg/kg 
once every 2 weeksa. Caution: it is important to rule 
out bowel perforation and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider, as necessary, discussing with study 
physician if no resolution to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
Grade 3 or 4 
(Grade 3 diarrhea: stool frequency 
of ≥7 over baseline per day; 
Grade 4 diarrhea: life threatening 
consequences) 
(Grade 3 colitis: severe abdominal 
Grade 3 
Permanently discontinue study 
drug/study regimen for Grade 3 if 
toxicity does not improve to Grade 
≤1 within 14 days; study drug/study 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain 
hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
pain, change in bowel habits, medi-
cal intervention indi-cated, 
peritoneal signs; 
Grade 4 colitis: life-threatening 
consequences, urgent intervention 
indicated) 
 
regimen can be resumed after 
completion of steroid taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, 
promptly start further immunosuppressives (e.g., 
infliximab at 5 mg/kg once every 2 weeks). Caution: 
Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before 
using infliximab. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
Hepatitis  
(elevated LFTs) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, ALT, 
ALP, and TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications). 
Grade 1 
(AST or ALT >ULN and 
≤3.0×ULN and/or TB > ULN and  
≤1.5×ULN) 
• 
No dose modifications. 
• 
If it worsens, then treat as Grade 
2 event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
Grade 2 
(AST or  
ALT >3.0×ULN and ≤5.0×ULN 
and/or  
TB >1.5×ULN and  ≤3.0×ULN) 
• 
Hold study drug/study regimen 
dose until Grade 2 resolution to 
Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1 
or baseline, resume study 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., every 1 
to 2 days) until elevations of these are improving or 
resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, consider, 
as necessary, discussing with study physician. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
drug/study regimen after 
completion of steroid taper. 
− 
If event is persistent (>3 to 5 days) or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional work up and start prompt 
treatment with IV methylprednisolone 2 to 
4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a 
Discuss with study physician if mycophenolate 
mofetil is not available. Infliximab should NOT be 
used. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
Grade 3 or 4 
(Grade 3: AST or  
ALT >5.0×ULN and ≤20.0×ULN 
and/or  
TB >3.0×ULN and  ≤10.0×ULN) 
 
(Grade 4: AST or  
ALT >20×ULN and/or  
TB >10×ULN) 
For Grade 3: 
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN: 
• Hold study drug/study regimen 
dose until resolution to Grade ≤1 
or baseline 
• Resume study drug/study 
regimen if elevations downgrade 
to Grade ≤1 or baseline within 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 
to 4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with immunosuppressive 
therapy (i.e., mycophenolate mofetil). Discuss with 
study physician if mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Perform hepatology consult, abdominal workup, and 
imaging as appropriate. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
PLEASE SEE 
shaded area 
immediately below 
this section tfind 
guidance for 
agement of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
14 days and after completion of 
steroid taper. 
• Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to 
Grade ≤1 or baseline within 
14 days 
For elevations in transaminases 
>8 × ULN or elevations in bilirubin 
>5 × ULN, discontinue study 
drug/study regimen. 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (AST 
and/or ALT >3 × ULN + bilirubin 
>2 × ULN without initial findings of 
cholestasis (i.e., elevated alkaline 
P04) and in the absence of any 
alternative cause.b 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any Grade 
General Guidance 
For Any Grade: 


Clinical Study Protocol 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis.  
See instructions at  
bottom of shaded area  
if transaminase rise is  
not isolated but (at any 
time) occurs in setting  
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
 
 
− 
Monitor and evaluate liver function test: AST, ALT, 
ALP, and TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications, 
worsening of liver cirrhosis [e.g., portal vein 
thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral 
load, quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate quantitative HCV viral 
load 
− 
Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of 
antiviral medications for any patient with an elevated 
HBV viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of 
antiviral HCV medications if HCV viral load 
increased by ≥2-fold 
− 
For HCV+ with HBcAB+: Evaluate for both HBV and 
HCV as above 
 
Grade 1 
(Isolated AST or ALT >ULN and 
≤5.0×ULN, whether normal or 
elevated at baseline)  
• 
No dose modifications. 
• 
If ALT/AST elevations 
represents significant worsening 
based on investigator 
assessment, then treat as Grade 2 
event. 
For all grades, see instructions at 
bottom of shaded area if 
 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients  


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transaminase rise is not isolated but 
(at any time) occurs in setting of 
either increasing bilirubin or signs 
of DILI/liver decompensation 
 
Grade 2 
(Isolated AST or ALT >5.0×ULN 
and ≤8.0×ULN, if normal at 
baseline) 
 
(Isolated AST or ALT 
>2.0×baseline and ≤12.5×ULN, if 
elevated >ULN at baseline) 
• 
Hold study drug/study regimen 
dose until Grade 2 resolution to 
Grade ≤1 or baseline. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., every 1 
to 3 days) until elevations of these are improving or 
resolved. 
− 
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver 
perfusion. 
− 
Consider, as necessary, discussing with study 
physician. 
− 
If event is persistent (>3 to 5 days) or worsens, and 
investigator suspects toxicity to be immune-mediated 
AE, recommend to start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup and treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, consider 
additional abdominal workup (including liver biopsy) 
and imaging (i.e., liver ultrasound), and consider 
starting immunosuppressives (i.e., mycophenolate 
mofetil).a Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab 


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Dose Modifications 
Toxicity Management 
should NOT be used. 
 
Grade 3 
(Isolated AST or ALT >8.0×ULN 
and ≤20.0×ULN, if normal at 
baseline) 
 
(Isolated AST or ALT >12.5×ULN 
and ≤20.0×ULN, if  elevated 
>ULN at baseline) 
• Hold study drug/study regimen 
dose until resolution to Grade ≤1 
or baseline 
• Resume study drug/study 
regimen if elevations downgrade 
to Grade ≤1 or baseline within 
14 days and after completion of 
steroid taper. 
• Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to 
Grade ≤1 or baseline within 
14 days 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria, in the 
absence of any alternative cause.b 
For Grade 3: 
− 
Regular and frequent checking of LFTs (e.g., every 1-
2 days) until elevations of these are improving or 
resolved. 
− 
Consult hepatologist (unless investigator is 
hepatologist); obtain abdominal ultrasound, including 
Doppler assessment of liver perfusion; and consider 
liver biopsy. 
− 
Consider, as necessary, discussing with study 
physician. 
− 
If investigator suspects toxicity to be immune-
mediated, promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, 
obtain liver biopsy (if it has not been done already) 
and promptly start treatment with immunosuppressive 
therapy (mycophenolate mofetil). Discuss with study 
physician if mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 


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Specific Immune-Mediated Reactions 
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Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
(Isolated AST or ALT >20×ULN,  
whether normal or elevated at 
baseline) 
Permanently discontinue study 
drug/study regimen. 
For Grade 4: 
Same as above  
(except would recommend obtaining liver biopsy early) 
 
 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if 
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise 
- 
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise 
- 
Grade 3-4: Permanently discontinue study drug/study regimen 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related 
to changes in renal function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decrease 
in urine output, or proteinuria). 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression or 
infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 
2), in order to prevent potential progression to higher 
grade event. 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
Grade 1 
(Serum creatinine > 1 to 1.5 × 
baseline; > ULN to 1.5 × ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any 
accompanying symptoms. 
• 
If creatinine returns to baseline, resume its 
regular monitoring per study protocol. 
• 
If creatinine worsens, depending on the 
severity, treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
Grade 2 
(serum creatinine >1.5 to 3.0 × 
baseline; >1.5 to 3.0 × ULN) 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.  
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 
or baseline, then resume study 
drug/study regimen after 
completion of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days 
and as clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if 
clinically indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or 
worsens despite prednisone at 1 to 2 mg/kg/day PO or 
IV equivalent, additional workup should be 
considered and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 


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Date 14th November 2018 
 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
− 
When event returns to baseline, resume study 
drug/study regimen and routine serum creatinine 
monitoring per study protocol. 
Grade 3 or 4 
(Grade 3: serum creatinine 
>3.0 × baseline; >3.0 to 
6.0 × ULN; 
 
Grade 4: serum creatinine >6.0 × 
ULN) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if 
clinically indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or 
worsens despite prednisone at 1 to 2 mg/kg/day PO or 
IV equivalent, additional workup should be 
considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE v 4.03 for 
definition of severity/grade 
depending on type of skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash 
and pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED 
AND STUDY DRUG DISCONTINUED. 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral 
antipruritics (e.g., diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) 
Grade 2 events, hold scheduled study 
drug/study regimen until resolution 
to Grade ≤1 or baseline. 
• 
If toxicity worsens, then treat 
as Grade 3. 
• 
If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study regimen after 
completion of steroid taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral 
antipruritics (e.g., diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea cream). 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 3 
to 5 days or is worsening despite symptomatic 
treatment and/or use of moderate strength topical 
steroid, consider, as necessary, discussing with study 
physician and promptly start systemic steroids such as 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Consider skin biopsy if the event is persistent for >1 to 
2 weeks or recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin 
rash to Grade ≤1 or baseline within 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as 
clinically feasible. 


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Dose Modifications 
Toxicity Management 
30 days, then permanently 
discontinue study drug/study 
regimen. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
− 
Consider, as necessary, discussing with study 
physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
 
Any Grade 
(depending on the type of 
endocrinopathy, refer to NCI 
CTCAE v4.03 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for endocrine 
events. 
− 
Consider, as necessary, discussing with study 
physician. 
− 
Monitor patients for signs and symptoms of 
endocrinopathies. Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, 
polydipsia, polyuria, hypotension, and weakness. 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression 
including brain metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor 
and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine and related labs 
(e.g., blood glucose and ketone levels, HgA1c). 
− 
For modest asymptomatic elevations in serum amylase 
and lipase, corticosteroid treatment is not indicated as 


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Specific Immune-Mediated Reactions 
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CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
long as there are no other signs or symptoms of 
pancreatic inflammation. 
− 
If a patient experiences an AE that is thought to be 
possibly of autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, or diabetes insipidus), the 
investigator should send a blood sample for 
appropriate autoimmune antibody testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH 
elevation): 
− 
Monitor patient with appropriate endocrine function 
tests. 
− 
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment 
of early-morning ACTH, cortisol, TSH and free T4; 
also consider gonadotropins, sex hormones, and 
prolactin levels, as well as cosyntropin stimulation test 
(though it may not be useful in diagnosing early 
secondary adrenal insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN, or 
consistently out of range in 2 subsequent 
measurements, include free T4 at subsequent cycles as 
clinically indicated and consider consultation of an 
endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other 
than hypothyroidism and Type 1 
diabetes mellitus, hold study 
drug/study regimen dose until patient 
is clinically stable. 
For Grade 2 (including those with symptomatic 
endocrinopathy): 
− 
Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
• 
If toxicity worsens, then treat 
as Grade 3 or Grade 4. 
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper. 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen on the 
following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable 
as per investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
− 
For all patients with abnormal endocrine work up, 
except those with isolated hypothyroidism or Type 1 
DM, and as guided by an  endocrinologist, consider 
short-term corticosteroids (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone 
replacement (e.g., hydrocortisone, sex hormones). 
− 
Isolated hypothyroidism may be treated with 
replacement therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated 
with appropriate diabetic therapy, without study 
drug/study regimen interruption, and without 
corticosteroids. 
− 
Once patients on steroids are improving, gradually 
taper  immunosuppressive steroids (as appropriate and 
with guidance of endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 
2B recommendation]).a 
− 
For patients with normal endocrine workup 
(laboratory assessment or MRI scans), repeat 
laboratory assessments/MRI as clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism and Type 
1 diabetes mellitus, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled.  
For Grade 3 or 4: 
− 
Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. Hospitalization recommended. 
− 
For all patients with abnormal endocrine work up, 
except those with isolated hypothyroidism or Type 1 
DM, and as guided by an  endocrinologist, promptly 


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CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper. 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen on the 
following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable 
as per investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent, as well as relevant 
hormone replacement (e.g., hydrocortisone, sex 
hormones). 
− 
For adrenal crisis, severe dehydration, hypotension, or 
shock, immediately initiate IV corticosteroids with 
mineralocorticoid activity. 
− 
Isolated hypothyroidism may be treated with 
replacement therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually 
taper immunosuppressive steroids (as appropriate and 
with guidance of endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 
2B recommendation]).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Any Grade 
(depending on the type of 
neurotoxicity, refer to NCI CTCAE 
v4.03 for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, 
metabolic syndromes, or medications). 
− 
Monitor patient for general symptoms (headache, 
nausea, vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing 
(e.g., electromyogram and nerve conduction 
investigations). 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Gravis and Guillain-
Barre) 
− 
Perform symptomatic treatment with neurological 
consult as appropriate. 
− 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to 
Grade ≤1. 
For sensory neuropathy/neuropathic 
pain, consider holding study 
drug/study regimen dose until 
resolution to Grade ≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be 
resumed once event improves to 
Grade ≤1 and after completion of 
steroid taper. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed 
by appropriate medications (e.g., gabapentin or 
duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with study 
physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 


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Dose Modifications 
Toxicity Management 
does not resolve to Grade ≤1 within 
30 days. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and 
promptly treat with additional immunosuppressants 
(e.g., IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain 
patients may unpredictably experience acute 
decompensations that can result in substantial 
morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that 
may predict a more severe outcome, such as 
prominent dysphagia, rapidly progressive weakness, 
and signs of respiratory insufficiency or autonomic 
instability. 
− 
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, 
metabolic syndromes or medications). It should be 
noted that the diagnosis of immune-mediated 
peripheral neuromotor syndromes can be particularly 
challenging in patients with underlying cancer, due to 
the multiple potential confounding effects of cancer 
(and its treatments) throughout the neuraxis. Given the 
importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a 
neurological consult. 
− 
Neurophysiologic diagnostic testing 
(e.g., electromyogram and nerve conduction 


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Toxicity Management 
investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon 
suspicion of such conditions and may be best 
facilitated by means of a neurology consultation. 
− 
It is important to consider that the use of steroids as 
the primary treatment of Guillain-Barre is not 
typically considered effective. Patients requiring 
treatment should be started with IV IG and followed 
by plasmapheresis if not responsive to IV IG. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
− 
Obtain a neurology consult. 
Grade 2 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days 
or if there are signs of respiratory 
insufficiency or autonomic 
instability. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain may be managed 
by appropriate medications (e.g., gabapentin or 
duloxetine). 
MYASTHENIA GRAVIS: 


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CONFIDENTIAL AND PROPRIETARY 
  
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
o 
Steroids may be successfully used to treat 
myasthenia gravis. It is important to 
consider that steroid therapy (especially with 
high doses) may result in transient 
worsening of myasthenia and should 
typically be administered in a monitored 
setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with 
plasmapheresis or IV IG. Such decisions are 
best made in consultation with a neurologist, 
taking into account the unique needs of each 
patient. 
o 
If myasthenia gravis-like neurotoxicity is 
present, consider starting AChE inhibitor 
therapy in addition to steroids. Such therapy, 
if successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use 
of steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. 
o 
Patients requiring treatment should be 
started with IV IG and followed by 
plasmapheresis if not responsive to IV IG. 
 
Grade 3 or 4 
For Grade 3: 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Consider, as necessary, discussing with study 
physician. 


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Version Number 4.1 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 
30 days or if there are signs of 
respiratory insufficiency or 
autonomic instability. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with 
plasmapheresis or IV IG. 
o 
If myasthenia gravis-like neurotoxicity 
present, consider starting AChE inhibitor 
therapy in addition to steroids. Such therapy, 
if successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use 
of steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. 
o 
Patients requiring treatment should be 
started with IV IG and followed by 
plasmapheresis if not responsive to IV IG. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in patients with 
baseline cardiopulmonary disease and reduced cardiac 
function.  


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 138 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
Monitor patients for signs and symptoms of 
myocarditis (new onset or worsening chest pain, 
arrhythmia, shortness of breath, peripheral edema). As 
some symptoms can overlap with lung toxicities, 
simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary 
embolism, congestive heart failure, malignant 
pericardial effusion). A Cardiology consultation 
should be obtained early, with prompt assessment of 
whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, 
BNP, cardiac enzymes, ECG, echocardiogram 
(ECHO), monitoring of oxygenation via pulse 
oximetry (resting and exertion), and additional 
laboratory work-up as indicated. Spiral CT or cardiac 
MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
other medications, or infections) 
 
Grade 1 
(asymptomatic with laboratory 
(e.g., BNP) or cardiac imaging 
abnormalities) 
No dose modifications required 
unless clinical suspicion is high, in 
which case hold study drug/study 
regimen dose during diagnostic 
work-up for other etiologies. If study 
drug/study regimen is held, resume 
after complete resolution to Grade 0. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-
up as clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 139 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 2, 3 or 4 
(Grade 2: Symptoms with mild to 
moderate activity or exertion) 
 
 (Grade 3: Severe with symptoms 
at rest or with minimal activity or 
exertion; intervention indicated) 
 
(Grade 4: Life-threatening 
consequences; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support)) 
 
- If Grade 2 -- Hold study 
drug/study regimen dose until 
resolution to Grade 0. If toxicity 
rapidly improves to Grade 0, then 
the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study 
regimen. 
If Grade 3-4, permanently 
discontinue study drug/study 
regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day or equivalent after Cardiology 
consultation has determined whether and when to 
complete diagnostic procedures including a cardiac 
biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly 
start immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). 
Caution: It is important to rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of 
poly/myositis. Typically, muscle weakness/pain 
occurs in proximal muscles including upper arms, 
thighs, shoulders, hips, neck and back, but rarely 
affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing 
can occur and progress rapidly. Increased general 
feelings of tiredness and fatigue may occur, and there 
can be new-onset falling, difficulty getting up from a 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 140 of 151 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
fall, and trouble climbing stairs, standing up from a 
seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology 
consultation should be obtained early, with prompt 
guidance on diagnostic procedures. Myocarditis may 
co-occur with poly/myositis; refer to guidance under 
Myocarditis. Given breathing complications, refer to 
guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously 
unknown) autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, LDH, BUN/creatinine, 
erythrocyte sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional laboratory 
work-up as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider whether 
a rheumatologist consultation is indicated and could 
guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as 
anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of 
the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other medications, 
or infections). 
 
Grade 1 
- No dose modifications. 
For Grade 1: 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 141 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
(mild pain) 
− 
Monitor and closely follow up in 2 to 4 days for 
clinical symptoms and initiate evaluation as clinically 
indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study 
physician. 
 
Grade 2 
(moderate pain associated with 
weakness; pain limiting 
instrumental activities of daily 
living [ADLs]) 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 
days or if there are signs of 
respiratory insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), 
promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant  
− 
If clinical course is not rapidly progressive, start 
systemic steroids (e.g., prednisone 1 to 2 mg/kg/day 
PO or IV equivalent); if no improvement within 3 to 5 
days, continue additional work up and start treatment 
with IV methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 
days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is important to rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 142 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate 
aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event (NCI 
CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
Grade 3 or 4 
(pain associated with severe 
weakness; limiting self-care ADLs) 
For Grade 3: 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 
30 days or if there are signs of 
respiratory insufficiency. 
 
For Grade 4: 
- Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend 
hospitalization. 
− 
Obtain Neurology consult, and complete full 
evaluation. 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant. 
− 
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 
days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is important to rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. 
− 
Consider whether patient may require IV IG, 
plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 143 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic 
resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as 
Pneumocystis carinii pneumonia); PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating 
hormone; ULN Upper limit of normal. 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 144 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 145 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Non–Immune-Mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 146 of 151 
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Appendix 2 Durvalumab dose calculations 
Durvalumab Dosing 
The durvalumab dosing should be done depending on subject weight (if subject is ≤ 30kg): 
1. Cohort dose: X mg/kg (An equivalent dose of 20 mg/kg should be administered for patients 
weighting ≤30 kg) 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration  
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 
mL). Dose adjustments for each cycle only needed for greater than 10% change in weight. 
5. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula: 
Number of vials = Dose (mL) / 10 (mL/vial) 
Example:  
1. Cohort dose: 20 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 600 mg = 20 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 600 mg / 50 (mg/mL) = 12.0 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 12.0 (mL) / 10.0 (mL/vial) = 2 vials 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 147 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Appendix 3 
Schedule of study procedures: follow-up for 
subjects 
who 
have 
completed 
durvalumab 
treatment and achieved disease control (until 
confirmed progression of disease) and subjects 
who have discontinued durvalumab due to toxicity 
in the absence of confirmed progression of 
disease 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
12 Months and Every 
6 Months  
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examinationa 
X 
 
 
 
 
 
 
 
Vital signs (temperature, 
respiratory rate, blood pressure, 
pulse) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
Urine hCG or serum βhCG 
X 
 
 
x 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
Palliative radiotherapy 
As clinically indicated  
ECOG performance status 
X 
X 
X 
 
X (and 
month 9) 
 
 
X 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact 
with subjects who refuse to 
return for evaluations and agree 
to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Hematology 
X 
X 
X 
 
 
 
 
X 
Serum chemistry  
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, 
and fT3 and fT4)b 
X 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 148 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Appendix 3 
Schedule of study procedures: follow-up for 
subjects 
who 
have 
completed 
durvalumab 
treatment and achieved disease control (until 
confirmed progression of disease) and subjects 
who have discontinued durvalumab due to toxicity 
in the absence of confirmed progression of 
disease 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
12 Months and Every 
6 Months  
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Tumour assessment (CT or 
MRI) 
For subjects who achieve disease control following 12 months of treatment, tumour 
assessments should be performed every 12 weeks (± 1 week) relative to the date of first 
infusion thereafter until confirmed PD by RECIST 1.1 by investigational site review.  
Please refer to Table 1: schedule of assessmentsfor timings of confirmatory scans.   
For subjects who discontinue durvalumab due to toxicity (or symptomatic 
deterioration), tumour assessments should be performed relative to the relative to the 
date of first infusion as follows: every 8 weeks (± 1 week) for the first 48 weeks , then 
every 12 weeks(± 1 week)  until confirmed PD by RECIST 1.1 by investigational site 
review.  Please refer to Table 1: schedule of assessmentsfor timings of confirmatory 
scans.   
Upon confirmed PD, scans should be conducted according to local standard clinical 
practice and submitted for central review until a new treatment is started (these scans are 
optional). 
a  
Full physical exam 
b 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical 
suspicion of an adverse event related to the endocrine system. 
c 
For patient questionnaires different approaches based on indication and study design 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 149 of 151 
CONFIDENTIAL AND PROPRIETARY 
  
 
Appendix 4 
Schedule of study procedures: follow-up for 
subjects who have discontinued durvalumab 
treatment due to confirmed progression of disease 
at the discretion of the investigator 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
12 Months and Every 
6 Months  
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examinationa 
X 
 
 
 
 
 
 
 
Vital signs (temperature, respiratory 
rate, blood pressure, pulse) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
Palliative radiotherapy 
As clinically indicated 
ECOG performance statusb 
X 
X 
X 
 
 
 
 
 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with 
subjects who refuse to return for 
evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Urine hCG or serum βhCG 
X 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
 
 
 
 
 
Serum chemistry  
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, and fT3 
and fT4)c 
X 
 
 
 
 
 
 
 
Tumour assessment (CT or MRI) 
For subjects who continue on durvalumab post-confirmed progression at the 
investigator’s discretion(following consultation with the sponsor), tumour 
assessments should be performed relative to the date of first infusion per 
schedule of assessmentsuntil durvalumab is stopped. 
For subjects who discontinue durvalumab following confirmed progression, 
scans should be conducted according to local clinical practice and 
submitted for central review until a new treatment is started (these scans are 
optional). 
a   
Full physical exam 
b 
PS to be collected if available at the 2 monthly calls to obtain subsequent anti-cancer therapy and survival status 
c 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical 
suspicion of an adverse event related to the endocrine system. 
d 
For patient questionnaires different approaches based on indication and study design 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
Page 150 of 151 
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Appendix 5: Contact Details 
Sponsor 
Fundación GECP 
Avenida Meridiana 358, 6ª planta 
08027 Barcelona 
Phone Number. +34 93 430 20 06 
Fax. +34 93 419 17 68 
E-mail: gecp@gecp.org 
 
Principal investigator 
Dr. Rafael Rosell 
Instituto Oncológico Dr. Rosell 
Phone. +34935460135 
Fax. +34935460196 
E-mail: rrosell@iconcologia.net 
 
Participating 
investigators 
Dr. Maria Gonzalez-Cao 
Hospital Instituto Oncológico Dr. Rosell 
Department Oncology Department 
Address Sabino Arana 5 
08028 Barcelona 
Phone Number:  +34935460135 
E-mail: mgonzalezcao@oncorosell.com 
 
Dr. Javier Martinez-Picado 
AIDS Research Institute -IrsiCaixa- 
Hospital Univ. Germans Trias i Pujol 
Address: Carretera Canyet s/n 
Badalona (Barcelona) 
Phone Number: 34 934656374   
E-mail: jmpicado@irsicaixa.es 
 
Dr. Bartomeu Massuti 
Hospital General de Alicante 
Department Oncology Department 
AddressPintor Baeza, 11 
03010 Alicante 
Phone Number:  34965933000 
E-mail: bmassutis@seom.org 
 
Dr. Bonaventura Clotet 
AIDS Research Institute -IrsiCaixa- 
Hospital Univ. Germans Trias i Pujol 
Address: Carretera Canyet s/n 
Badalona (Barcelona) 
Phone Number:  34 934656374  


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Sponsor code: GECP 16/04_ Astra Zeneca Study number: ESR 15-10869 
Version Number 4.1 
Date 14th November 2018 
 
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E-mail: bclotet@irsicaixa.es 
 
CRO 
Fundación GECP 
Avenida Meridiana 358, 6ª planta    
08027 Barcelona 
Phone Number. +34 93 430 20 06 
Fax. +34 93 419 17 68 
E-mail: secretaria@gecp.org 
 
Central lab oncology 
 
 
Central lab virology 
PangaeaBiotech 
Sabino Arana 5 
Phone Number: +34935460135 
E-mail: mamolina@oncorosell.com 
 
AIDS Research Institute -IrsiCaixa- 
Hospital Univ. Germans Trias i Pujol 
Address: Carretera Canyet s/n 
Phone Number:  +34 934656374  
E-mail: jmpicado@irsicaixa.es