A Phase II Study of Durvalumab (MEDI4736) Plus Tremelimumab for the Treatment of Patients With Advanced Neuroendocrine Neoplasms of Gastroenteropancreatic or Lung Origin (the DUNE Trial)
Phase: PHASE2
Conditions: Neuroendocrine Tumors, Neuroendocrine Neoplasm of Lung
Sponsor: Grupo Espanol de Tumores Neuroendocrinos

Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Investigational Drug Substance (s)
Durvalumab (MEDI4736) and
Tremelimumab
Study Number
ESR 15-11561-61-DUNE
Version Number
5.0
Date
JUNE 09th, 2021
A PHASE II STUDY OF DURVALUMAB (MEDI4736) PLUS TREMELIMUMAB FOR THE
TREATMENT OF PATIENTS WITH ADVANCED NEUROENDOCRINE NEOPLASMS OF
GASTROENTEROPANCREATIC OR LUNG ORIGIN (THE DUNE TRIAL)
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Sponsor:
GETNE
(Spanish Group of Neuroendocrine and Endocrine Tumors)
C/ Secretari Coloma, 64-68 esc. B entresuelo 5ª
08024 Barcelona
Phone: + 34 93 434 44 12
e-mail: getne@getne.org
Coordinating Investigator:
Dr. Jaume Capdevila
Vall d'Hebron University Hospital
Medical Oncology Service
Passeig de la Vall d'Hebron, 119-129, 08035. Barcelona
Phone: +34 93 274 60 85
Fax: +34 93 274 60 59
E-mail: jacapdevila@vhebron.net
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
SPONSOR’S SIGNATURE PAGE
Study title: A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of
patients with advanced neuroendocrine neoplasms of gastroenteropancreatic or lung origin (the
DUNE trial).
Study code: ESR 15-11561-61 – DUNE
EudraCT Number: 2016-002858-20
Version number and date: 5.0, June 09th,2021
Dr. Jaume Capdevila
______________________
________________________
_______________________
GETNE Chairman
Signature
Signature date
(DD-mm-YYYY)
Dr. Jaume Capdevila
______________________
________________________
_______________________
Coordinating Investigator
Signature
Signature date
(DD-mm-YYYY)
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
INVESTIGATOR’S SIGNATURE PAGE
Study title: A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of
patients with advanced neuroendocrine neoplasms of gastroenteropancreatic or lung origin (the
DUNE trial).
Study code: ESR 15-11561-61 – DUNE
EudraCT Number: 2016-002858-20
Version number and date: 5.0, June 09th ,2021
__________________________________________
____________________________
Principal Investigator’s signature
Signature date
(DD-mm-YYYY)
__________________________________________
Investigator's name (capital letters)
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
PROTOCOL SYNOPSIS
Clinical Protocol ESR 15-11561-61
Study Title: A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of
patients with advanced neuroendocrine neoplasms of gastroenteropancreatic or lung origin (the
DUNE trial)
Protocol Number: ESR 15-11561-61
EudraCT Number: 2016-002858-20
Clinical Phase: II
Study Duration: 3 years
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.
Tremelimumab is supplied as a sterile solution for IV infusion, filled in 20 mL clear glass vials with a
rubber stopper and aluminum seal. Each vial contains 20 mg/mL (with a nominal fill of 20 mL,
accounting to 400 mg/vial or with a nominal fill of 1.25 mL, accounting to 25 mg/vial) of
tremelimumab, in an isotonic solution at pH 5.5.
Research Hypothesis
Well-differentiated
gastroenteropancreatic
and
lung
neuroendocrine
tumors
are
generally
malignancies with a prolonged natural history. However, clinical behavior is heterogeneous and when
tumor progression is observed, treatment options are limited. The most used therapy for
neuroendocrine tumors management are somatostatin analogs, with clear evidence of antitumor
activity demonstrated by two phase III clinical trials in gastroenteropancreatic neuroendocrine
tumors. However, even the use in lung carcinoids is quite usual, no antitumoral activity has been
demonstrated in prospective clinical trials. In recent years, targeted therapies as sunitinib and
everolimus have been approved for pancreatic neuroendocrine tumors and recently everolimus have
showed a significant reduction in the risk of progression or death in patients with non-functional
neuroendocrine tumors of lung and gastrointestinal origin. After the failure of these therapies, no
drugs have demonstrated efficacy. Only Interferon alpha-2b is an option for these patients who have
worsening symptoms of carcinoid syndrome while on treatment with somatostatin analogs and have
showed some evidence of antitumoral activity in neuroendocrine tumors. The efficacy of Interferon
alpha 2-b is not fully understood, but one of its antitumoral mechanisms of action could be related via
stimulation of T cells. Tremelimumab and Durvalumab combination could be more efficient drugs to
improve immune system activation and could obtain a significantly higher clinical benefit in these
patients. We have analyzed presence of tumor-infiltrating lymphocytes (TILS) in these tumor types.
We found a high number of TILS that could be activated through Tremelimumab and Durvalumab.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
In cases of advanced high-grade G3 neuroendocrine carcinomas (NEC), regardless of the site of the
primary tumor, combination chemotherapy using cisplatin/etoposide is recommended in first-line
setting (provided that the patient has adequate organ function and performance status). There is no
established second-line therapy for poorly differentiated neuroendocrine carcinomas of the
gastroenteropancreatic origin.
The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1, PD-L2) play integral
roles in immune regulation. Expressed on activated T cells, PD-1 is activated by PD-L1 and PD-L2
expressed by stromal cells, tumor cells, or both, initiating T-cell death and localized immune
suppression, potentially providing an immune-tolerant environment for tumor development and
growth.
Conversely, inhibition of this interaction can enhance local T-cell responses and mediate
antitumor activity in nonclinical animal models.
Tremelimumab and Durvalumab would be the first immune combination agents showing efficacy in
neuroendocrine neoplasms of different origins.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Objectives:
Primary Objectives:
Primary endpoint for cohorts 1, 2 and 3:
Nine-months clinical benefit rate (CBR) by Response Evaluation Criteria In Solid Tumors (RECIST
1.1), which is defined as the percentage of patients achieving complete response (CR), partial
response (PR), or stable disease (SD) at month 9 after durvalumab plus tremelimumab was started.
Primary endpoint for cohort 4:
Nine-months overall survival rate, which is defined as the percentage of patients alive at month 9
after durvalumab plus tremelimumab was started.
Secondary Objective(s):
●
Overall response rate (ORR) by irRECIST.
●
To assess the duration of response according to irRECIST.
●
To assess the median progression-free survival time (PFS) according to irRECIST.
●
To assess the safety profile of Durvalumab and Tremelimumab in subjects with advanced
neuroendocrine neoplasms.
●
To assess the median overall survival (OS) time.
●
To assess response status according to irRECIST at 6, 9 and 12 months after start of study
treatment.
Exploratory Objective(s):
●
To evaluate biochemical response (changes in CgA and NSE levels) and its association with
response rate and progression-free survival.
●
To assess whether baseline tumor and blood biomarkers may be predictive of response to
durvalumab and tremelimumab therapy.
●
To explore additional hypotheses related to biomarkers and relationship to durvalumab and
tremelimumab efficacy and/or toxicity and neuroendocrine tumors evolution that may arise
from internal or external research activities.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Study Design:
Prospective, multi-center, open label, stratified, exploratory, phase II study evaluating the efficacy
and safety of durvalumab plus tremelimumab in different cohorts of patients with neuroendocrine
neoplasms.
The study will include patients in four different cohorts:
●
Cohort 1: Well-moderately differentiated lung neuroendocrine tumors (classically known as
typical and atypical carcinoids) after progression to somatostatin analogs and one prior
targeted therapy or chemotherapy.
●
Cohort 2: G1/G2 (WHO grade 1 and 2) gastrointestinal neuroendocrine tumors after
progression to somatostatin analogs and one prior targeted therapy.
●
Cohort 3: G1/G2 (WHO grade 1 and 2) pancreatic neuroendocrine tumors after progression
to standard therapies (chemotherapy, somatostatin analogs and target therapy), who have
received between two and four prior lines of treatment.
●
Cohort 4: Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin or
unknown primary site (excluding lung primary tumors), patients will be treated in second line
only, after progression to first-line chemotherapy with a platinum based regimen.
Number of Centers: 20
Number of Subjects: 126 patients: 31 patients for cohorts 1 to 3, and 33 for cohort 4.
Study Population:
Patients with advanced/metastatic, histologically confirmed, grade 1/2 (G1/G2) of the 2010 WHO
classification neuroendocrine tumors of the pancreas, gastrointestinal tract and lung origins and
grade 3 (G3) of gastroenteropancreatic system or unknown primary site (excluding lung primaries)
after progression to previous therapies.
Inclusion Criteria:
For inclusion in the study, patients should fulfill the following criteria:
1. Written informed consent obtained from the subject prior to performing any protocol-related
procedures.
2. Age >18 years at time of study entry.
3. Subjects
must
have
histologically
confirmed
diagnosis
of
one
of
the
following
advanced/metastatic neuroendocrine tumor types:
a) Cohort 1: Well-moderately differentiated neuroendocrine tumors of the lung ( mitotic
count ≤10 mitoses x 10 HPF), also known as typical and atypical lung carcinoids, that
have progressed to prior somatostatin analog therapy and/or one prior targeted therapy
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
or chemotherapy (only one prior systemic therapy, with the exception of patients that
have been treated with somatostatin analogues and other systemic treatment, when two
prior treatments are allowed).
b) Cohort 2: Well-moderately differentiated G1/G2 (WHO grade 1 and 2) gastrointestinal
neuroendocrine tumors after progression to somatostatin analogs and one targeted
therapy (prior targeted therapy could be everolimus or a multikinase inhibitor). Prior
therapies with interferon alpha-2b or radionucleotide therapy are allowed.
c) Cohort 3: Well-moderately differentiated neuroendocrine tumors G1/G2 (WHO grade 1
and 2) from pancreatic origin after progression to standard therapies (chemotherapy,
somatostatin analogs and target therapy); patients must be treated with at least two prior
systemic treatment lines and a maximum of four previous treatment lines.
d) Cohort 4: Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin or
unknown primary site (excluding lung primary tumors), patients will be treated in second
line only, after progression to first-line chemotherapy with a platinum based regimen.
4. For patients included in cohorts 1, 2 and 3: WHO Classification G1/G2 (mitotic count ≤10
mitoses x 10 HPF) lung typical and atypical carcinoids for cohort 1, G1/G2 (Ki67≤20% or
mitotic count ≤20 mitoses x 10 HPF) gastrointestinal for cohort 2 (including stomach, small
intestine and colorectal origins), G1/G2 (Ki67≤20% or mitotic count ≤20 mitoses x 10 HPF)
pancreatic for cohort 3.
5. For patients included in cohort 4: WHO classification G3 (Ki67>20% or mitotic count >20
mitoses x 10 HPF) gastroenteropancreatic neuroendocrine carcinomas (NEC) or liver
metastases of G3 NEC of unknown primary site.
6. Subjects must have evidence of measurable disease meeting the following criteria:
a) In case of more than one target lesion, it should be identified at least 1 lesion of ≥1.0 cm
in the longest diameter for a non lymph node, or ≥1.5 cm in the short-axis diameter for a
lymph node, which is serially measurable according to RECIST 1.1 using computerized
tomography/magnetic resonance imaging (CT/MRI). If there is only one target lesion and
it is a non-lymph node, it should have a longest diameter of ≥ 1.5 cm.
b) Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies
such as radiofrequency (RF) ablation or liver embolization must show evidence of
progressive disease based on RECIST 1.1 to be deemed a target lesion.
c) Subjects must show evidence of disease progression by radiologic image techniques within
12 months (an additional month will be allowed to accommodate actual dates of
performance of scans, i.e., within ≤13 months) prior to signing informed consent,
according to RECIST 1.1.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Life expectancy of at least 12 weeks.
9. Adequate normal organ and marrow function as defined below:
▪
Haemoglobin ≥ 9.0 g/dL.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
▪
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3).
▪
Platelet count ≥ 100 x 109/L (>100,000 per mm3).
10.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 hemolysis or hepatic pathology), who will be
allowed only in consultation with their physician.
11. 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.
12.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)
13. 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.
14.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.
Exclusion Criteria:
Subjects who meet any of the following criteria will be excluded from this study:
1.
Involvement in the planning and/or conduct of the study.
2.
Participation in another clinical study with an investigational product during the last 4 weeks.
3.
WHO Classification G3 neuroendocrine neoplasms of lung origin (oat cell/large cell lung
cancer).
4.
Prior treatment with anti-PDL-1/anti-PD-1 or anti-CTL-4 therapy.
5.
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 diathesis including
any subject known to have evidence of acute or chronic hepatitis B (e.g., HBsAg reactive),
hepatitis C (e.g., HCV RNA [qualitative] is detected) or known history of Human
Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or psychiatric illness/social situations
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
that would limit compliance with study requirements or compromise the ability of the subject
to give written informed consent.
6.
Known history of previous clinical diagnosis of tuberculosis.
7.
Current or prior use of immunosuppressive medication within 28 days before the first dose of
durvalumab or tremelimumab, 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.
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.
9.
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative
colitis).
10. History of allogeneic organ transplant.
11. History of hypersensitivity to durvalumab, tremelimumab or any excipient.
12. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid therapy or
any other form of immunosuppressive therapy within 28 days prior to the first dose of trial
treatment.
13. Knowledge of active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided they
have stable brain metastases [without evidence of progression by imaging confirmed [by
magnetic resonance imaging (MRI) if MRI was used at prior imaging, or confirmed by
computed tomography (CT) imaging if CT used at prior imaging] for at least four weeks
prior to the first dose of trial treatment; also, any neurologic symptoms must have returned to
baseline], have no evidence of new or enlarging brain metastases,and have not used steroids
for brain metastases for at least 7 days prior to trial treatment. This exception does not
include carcinomatous meningitis, as subjects with carcinomatous meningitis are excluded
regardless of clinical stability.
14. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of
receiving durvalumab or tremelimumab. Note: The killed virus vaccines used for seasonal
influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g.,
FluMist®) are live attenuated vaccines, and are not allowed.
15. Subjects having known history of, or any evidence of interstitial lung disease or active,
noninfectious pneumonitis.
16. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1.
17. Subjects who have received any anti-cancer treatment within 21 days or any investigational
agent within 30 days prior to the first dose of study drug and should have recovered from any
toxicity related to previous anti-cancer treatment. This does not apply to the use of
somatostatin analogues for symptomatic therapy.
18. Major surgery within 3 weeks prior to the first dose of study drug.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
19. Subjects having > 1+ proteinuria on urine dipstick testing will undergo 24h urine collection
for quantitative assessment of proteinuria.
Subjects with urine protein ≥1 g/24h will be
ineligible.
20. Significant cardiovascular impairment: history of congestive heart failure greater than New
York Heart Association (NYHA) Class II, unstable angina; myocardial infarction or stroke
within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical
treatment.
21. Mean
QT
interval
corrected
for
heart
rate
(QTc)
≥470
ms
calculated
from
3
electrocardiograms (ECGs) using Fredericia’s Correction.
22. Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, or similar agents
requiring therapeutic international normalized ratio (INR) monitoring. Treatment with low
molecular weight heparin (LMWH) is allowed.
23. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first
dose of study drug.
24. Patients with tumoral disease in the head and neck region, such as paratracheal or
periesophageal lymph node involvement, or with infiltration of structures in the digestive
tract, or vascular pathways that represent a risk of increased bleeding.
25. Patients of cohort 1 with neuroendocrine tumors of pulmonary origin or pulmonary
metastases with evidence of active bleeding.
26. Patients with evidence of digestive bleeding.
27. Active infection (any infection requiring treatment).
28. Active malignancy (except for differentiated thyroid carcinoma, or definitively treated
melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the
cervix) within the past 24 months.
29. Female patients who are pregnant or breastfeeding or male or female patients of reproductive
potential who are not willing to employ highly effective birth control from screening to 180
days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after
the last dose of durvalumab monotherapy, whichever is the longer time period.
30. Documented active alcohol or drug abuse.
31. Patients with a prior history of non-compliance with medical regimens.
32. Any condition that, in the opinion of the investigator, would interfere with evaluation of study
treatment or interpretation of patient safety or study results.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Investigational Product(s), Dose, and Mode of Administration:
Durvalumab, 1500 mg Q4W (equivalent to 20 mg/kg Q4W) for 12 months in patients ≥ 30kg.
Tremelimumab 75 mg Q4W (equivalent to 1 mg/kg Q4W) for up to 4 doses/cycles in patients ≥ 30kg.
Weight-based dosing should be used for patients <30 kg durvalumab 20 mg/kg Q4 and
tremelimumab 1 mg/kg Q4.
Study Assessments and Criteria for Evaluation:
Safety Assessments:
The safety objective of this trial is to characterize the safety and tolerability of durvalumab plus
tremelimumab in subjects with advanced neuroendocrine neoplasms. The primary safety analysis
will be based on subjects who experienced toxicities as defined by CTCAE, v4.03 The attribution to
drug, time-of-onset, duration of the event, its resolution, and any concomitant medications
administered will be recorded. AEs will be analyzed including but not limited to all AEs, SAEs, fatal
AEs, and laboratory changes. Furthermore, specific immune-related adverse events (irAEs) will be
collected and designated as immune related events of clinical interest (ECIs).
Efficacy Assessments:
The primary efficacy objective of this study is to evaluate the anti-tumor activity of durvalumab plus
tremelimumab in subjects with advanced neuroendocrine neoplasms. 9-months clinical benefit rate
by Response Evaluation Criteria in Solid Tumors. (RECIST 1.1), which is defined as the percentage
of patients achieving complete response, partial response (PR), or stable disease (SD) at month 9 after
durvalumab plus tremelimumab was started for cohorts 1, 2 and 3, and 9-months overall survival
rate, which is defined as the percentage of patients alive at 9 months after durvalumab plus
tremelimumab
was
started
will
be
used
as
the
primaries
endpoints
per
RECIST
1.1.
Pharmacodynamic / Pharmacokinetic Assessments (if applicable):
Correlative blood samples for pharmacodynamics studies will be obtained during the course of the
trial.
Archival tumor tissue will be required at baseline.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Statistical Methods and Data Analysis:
Strategic decisions about future development of immune therapy in neuroendocrine tumors will be
available after the results of this trial.
Summary tables (descriptive statistics and frequency tables) will be provided for all baseline
variables, efficacy variables, and safety variables, as appropriate. Continuous variables will be
summarized with descriptive statistics (mean, standard deviation, range, and median). Ninety-five
(95) percent confidence highest probability density (HPD) credible intervals (95% CI) may also be
presented, as appropriate. Frequency counts and percentage of subjects within each category will be
provided for categorical data.
The primary efficacy analysis will be performed using the binomial test procedure. Missing data will
be treated using statistical multiple random imputation.
Secondary endpoints will be summarized with descriptive statistics. Continuous variables will be
summarized with n, mean, standard deviation, and range, frequency counts and percentage of
subjects within each category will be provided for categorical data. Multivariate regression models
will be used to study relations between explanatory variables and primary endpoint. Survival analysis
will be performed to analyze PFS, Kaplan-Meier curves will be presented and possible comparisons
will be tested using the log-rank test or the Cox proportional hazard model for multivariate analysis,
hazard ratios (HR) and their 95% confidence interval (CI95%) will be provided. Patients with lost of
follow-up or treatment discontinuation will be included in the final analysis of primary endpoint if
they have at least one tumor evaluation and considered as censored data for survival endpoints.
R software version 3.2.1 will be used for all analysis.
Sample Size Determination:
Sample size has been calculated using one-sample Superiority test (function One Sample Proportion.
(NIS) of the Trial Size package of R software). According to previous knowledge, it is estimated that
the reference value for the likelihood to be progression-free at 9 months is 30% and we expect an
increase of 20% with a superiority margin of 10%. With a unilateral alpha level of 5% and 80%
power, we estimate to include 28 patients per group, with an expected lost to follow-up rate of 10%, a
final sample size in each 1, 2 and 3 cohort will include 31 patients.
For cohort 4, and according to previous knowledge, it is estimated that the reference proportion of
patients being alive at 9 months is 13% and we expect an increase of 10% with a superiority margin
of 5%. With a unilateral alpha level of 5% and 80% power, we estimate to include 30 patients per
group, with an expected lost to follow-up rate of 10%, a final sample size will include 33 patients.
Summarizing, total sample size will include 126 patients: 31 patients for cohorts 1 to 3, and 33 for
cohort 4.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
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Edition Number: 5.0 dated on June 09th, 2021
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Drug Substance DURVALUMAB/TREMELIMUMAB
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EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
SCHEDULE OF STUDY ASSESSMENTS (according to section 8)
Phase
Screening Phase
Treatment Phase
End of
treatment r
Follow-up s
Period
Screening ,b
Baselinea,b
Study Treatment
Visit
V1
-28 to -2
V2
Day -3 to
C1D1
V3
C1D1
V4
C1D15
V5
C2D1
(C1D28)
V6
C2D15
V7
C3D1
(C2D28)
V8
C3D15
V9
C4D1
(C3D28)
V10-V16
C5D1
C12D1
Informed consent
X
Inclusion/Exclusion
X
X
Allocation
X
Medical history and
demographic Data
X
ECOG PSC
X
X
X
X
X
X
X
X
X
X
X
Prior Therapies for
neuroendocrine
neoplasms
X
Vitals signsd
X
X
X
X
X
X
X
X
X
X
X
Physical examf
X
Xe
X
X
X
X
X
X
X
X
X
12/lead ECGg
X
Only
when
clinical
ly
indicat
ed
Biochemistry and
hematologyh
X
Xh
X
X
X
X
X
X
X
X
X
Hepatitis B and C;
HIV
X
Thyroid function test
(TSH and fT3 and
fT4)i
X
X
X
X
X
X
X
X
X
X
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Urinalysisj
X
X
X
X
X
X
X
X
X
X
Pregnancy testk
X
Only
when
clinical
ly
indicat
ed
Durvalumab
administration
X
X
X
X
X
Tremelimumab
administration
X
X
X
X
Tumor assessments
(CT/MRI)l
X
CT/MRI of chest/abdomen/pelvis and other areas of known disease at screening plus any areas of newly suspected disease
should be performed every 12 weeks until confirmed PD.
Octreoscan / PET/CTm
X
Survivaln
X
X
X
X
X
X
Biomarkerso
X
X
X
(end of
treatment/
progression)
Archival tumor block
or slidesp
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X
X
AEs/SAEsq
X
X
X
X
X
X
X
X
X
X
X
X
AEs = adverse events, BP = blood pressure, CT = computerized tomography, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, HR = heart rate, MRI =
magnetic resonance imaging, PET = positron-emission tomography, RECIST 1.1 = Response Evaluation Criteria in Solid Tumors , RR = respiratory rate, SAEs = serious adverse events,
surg = surgical, 99m-Tc MDP = 99m-technetium-methylene diphosphonate, w/in = within.
a)
72 hours before Cycle 1 Day 1 (C1D1). The baseline assessment can be performed on
C1D1, prior to treatment. Informed consent may be taken up to 4 weeks prior to C1D1.
b) Efforts should be made to conduct study visits on the day scheduled (± 1 day). Clinical
laboratory assessments may be conducted anytime within 72 hours prior to the scheduled visit.
c)
ECOG will be performed at the Screening and Baseline Visits and at every subsequent
treatment visit thereafter.
d)
Assessments will include vital signs (supine BP, HR, RR, and body temperature), weight, and
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
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Edition Number: 5.0 dated on June 09th, 2021
height. Height will be measured at the Screening Visit only. Elevated BP (≥140/90 mmHg) should
be confirmed by 3 measurements (at least 5 minutes apart).
If systolic BP is ≥160 mmHg or
diastolic BP ≥100 mmHg, BP should be confirmed by repeat measurements after an hour. 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
follow the principles as described above or more frequently if clinically indicated. According to
section 8.2.4.
e)  Required if screening physical examination was performed > 7 days prior C1D1.
f) A comprehensive physical examination (including a neurological examination) will be performed
at the Screening or Baseline Visit, on each visit of the Treatment phase, and at the off-treatment
assessment. A symptom-directed physical examination will be performed on Cycle 1/Day 1 and at
any time during the study, as clinically indicated.
g) Single 12-lead ECG. Subjects must be in the recumbent position for a period of 5 minutes prior
to the ECG.
h)
Assessments scheduled may be performed within 72 hours prior to the visit. Assessments
during follow up are made every 8-12 weeks, according to investigator's criteria. According to
section 8.2.5.
i) 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. Assessments
during follow up are made every 8-12 weeks, according to investigator's criteria.
j) Assessments during follow up are made every 8-12 weeks, according to investigator's criteria.
k) A serum or urine pregnancy test will be performed at the Screening Visit, at the Baseline Visit (or
within 72 hours prior to the first dose of study medication)
l) Screening tumor assessments using CT of the chest/abdomen/pelvis and other areas of known
disease or newly suspected disease should be performed within 28 days prior to C1D1. Scans of
the abdomen, pelvis and other areas of the body may be done with MRI instead of CT, but
evaluation of the chest should be done with CT. CT scans should be performed with oral and
iodinated IV contrast and MRI scans with IV gadolinium chelate unless there is a medical
contraindication to contrast. If iodinated IV contrast is contraindicated, chest CT should be done
without IV contrast.
m)
Somatostatin receptor scintigraphy (octreoscan) or PET-CT should be performed and/or
available within the previous 6 months before C1D1, only on cohort 1-3. It is not applicable on
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
cohort 4.
n)
Survival data will be collected every 4 weeks until end of treatment phase is declared. All
anticancer therapies will be collected. Survival data and other cancer treatments received will be
collected every 6 months until close of the study database. The study sponsor may elect to
discontinue survival follow-up.
o) Collection of blood sample to obtain plasma, serum, or other components to be used for
biomarker studies. Samples will be obtained at baseline, Cycle 2/Day 1, and at end-of-treatment
visit.
p) All subjects will have collection of most recent archived, tumor-biopsy sections for identification
of predictive biomarkers.
q) Throughout the study from the signature of Informed Consent. SAE irrespective of relationship
to study treatment must be reported as soon as possible but not later than one business day. AEs
and concomitant meds collected 28 days from last dose.
r) See section 8.1.3, APPENDIX 2 and APPENDIX 3.
s) See section 8.1.3, APPENDIX 2 and APPENDIX 3.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
LIST OF TABLES
¡Error! Marcador no definido.
LIST OF APPENDICES
23
ABBREVIATIONS AND DEFINITION OF TERMS
24
1. INTRODUCTION
28
1.1 Disease Background
28
1.1.1 Immunotherapies
30
1.1.2  Durvalumab
30
1.1.3 Tremelimumab
31
1.1.4 Durvalumab in combination with tremelimumab
31
1.2 Research hypothesis
32
1.3 Rationale for conducting this study
32
1.3.1 Durvalumab  + tremelimumab combination therapy dose rationale
33
1.3.2 Rationale for 4 cycles of combination therapy followed by durvalumab
monotherapy
34
1.4 Benefit/risk and ethical assessment
35
1.4.1 Potential benefits
35
1.4.1.1 Durvalumab
35
1.4.1.2  Tremelimumab
35
1.4.1.3 Durvalumab + tremelimumab
35
1.4.2 Potential risks
36
1.4.2.1   Durvalumab
36
1.4.2.3 Durvalumab + tremelimumab
39
1.4.2.4 Fixed Dosing for durvalumab and tremelimumab
41
2. STUDY OBJECTIVES
42
2.1 Primary objective(s)
42
2.2 Secondary objective(s)
43
2.3 Exploratory objective(s)
43
3. STUDY DESIGN
43
3.1 Overview of study design
43
3.2 Study schema
44
3.3 Study Oversight for Safety Evaluation
45
4. PATIENT SELECTION, ENROLLMENT, ALLOCATION, RESTRICTIONS, DISCONTINUATION
AND WITHDRAWAL
45
4.1 Inclusion criteria
45
4.2 Exclusion criteria
47
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Edition Number: 5.0 dated on June 09th, 2021
4.3 Withdrawal of Subjects from Study Treatment and/or Study
49
4.4  Replacement of subjects
50
5. INVESTIGATIONAL PRODUCT(s)
50
5.1 Durvalumab and tremelimumab
50
5.1.1         Formulation/packaging/storage
50
5.2 Dose and treatment regimens
51
5.2.1  Treatment regimen
51
5.2.2  Duration of treatment and criteria for retreatment
51
5.2.3 Study drug preparation of durvalumab and tremelimumab
52
5.2.4  Monitoring of dose administration
54
5.2.5   Accountability and dispensation
54
5.2.6 Disposition of unused investigational study drug
54
6. TREATMENT PLAN
56
6.1      Subject enrollment and allocation
56
6.1.1         Procedures for allocation
56
6.1.2        Procedures for handling subjects incorrectly enrolled
56
6.2       Dose Modification and Toxicity Management
56
6.2.1         Durvalumab and tremelimumab
56
7. RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENT(s)
57
7.1 Restrictions during the study
57
7.2 Concomitant treatment(s)
58
7.2.1       Permitted concomitant medications
58
7.2.2      Excluded Concomitant Medications
58
8. STUDY PROCEDURES
59
8.1     Schedule of study procedures
59
8.1.1 Screening Phase
59
8.1.2 Treatment Phase
60
8.1.3 End of Treatment
63
8.2 Description of study procedures
64
8.2.1  Medical history and physical examination, electrocardiogram, weight and vital
signs
64
8.2.2  Physical examination
64
8.2.3  Electrocardiograms
64
8.2.4  Vital signs
64
8.2.5   Clinical laboratory tests
65
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8.3 Biological sampling procedures
66
8.3.1  Biomarker/Pharmacodynamic sampling and evaluation methods
67
8.3.2  Estimate of volume of blood to be collected
68
8.3.3  Archival tumor samples
68
8.3.3.1  Archival tumor samples
68
8.3.4  Withdrawal of informed consent for donated biological samples
69
9. DISEASE EVALUATION AND METHODS
70
Primary Objective
70
Secondary objectives (irRECIST)
70
9.1 Efficacy variable
71
10. ASSESSMENT OF SAFETY
71
10.1 Safety Parameters
71
10.1.1  Definition of adverse events
71
10.1.2 Definition of serious adverse events
72
10.1.3 Durvalumab + tremelimumab adverse events of special interest
72
10.2 Assessment of safety parameters
75
10.2.1   Assessment of severity
75
10.2.2   Assessment of relationship
75
10.3 Recording of adverse events and serious adverse events
75
10.3.1   Study recording period and follow-up for adverse events and serious adverse
events
76
10.3.2    Reporting of serious adverse events
77
10.3.2.1   Reporting of deaths
78
10.3.3  Other events requiring reporting
78
10.3.3.1  Overdose
78
10.3.3.2  Hepatic function abnormality
78
10.3.3.3   Pregnancy
79
11. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION
80
11.1. Description of analysis sets
80
11.2. Methods of statistical analyses
81
11.3. Determination of sample size
81
12. ETHICAL AND REGULATORY REQUIREMENTS
82
12.1. Ethical conduct of the study
82
12.2. Ethics and regulatory review
82
12.3. Informed consent
82
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Edition Number: 5.0 dated on June 09th, 2021
12.4. Changes to the protocol and informed consent form
83
12.5. Audits and inspections
83
12.6. Confidentiality
83
12.7. Insurance
84
12.8. Publications
84
13.1. Training of study site personnel
84
13.2. Monitoring of the study
84
13.3. Source data
85
13.4. Retention of Records
85
13.5. Quality assurance
85
13.6. Study timetable and end of study
86
14. DATA MANAGEMENT
86
15. INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
87
15.1. Identity of investigational product(s)
87
16. LIST OF REFERENCES
87
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)
96
Appendix 2 Schedule of study procedures follow-up for subjects who have completed
durvalumab and tremelimumab treatment and achieved disease control (until confirmed
progression of disease) and subjects who have discontinued durvalumab or
tremelimumab due to toxicity in the absence of confirmed progression of disease.
¡Error! Marcador no definido.
Appendix 3 Schedule of study procedures: follow-up for subjects who have
discontinued durvalumab or tremelimumab treatment due to confirmed progression of
disease at the investigator discretion
140
Appendix 4 Durvalumab dose calculations
141
Appendix 5  Durvalumab Dose Volume Calculations
142
Appendix 6 Tremelimumab Dose Calculations
143
Appendix 7 Tremelimumab Dose Volume Calculations
145
Appendix 8 Contact Details
146
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
LIST OF TABLES
Table 1. Groups of neuroendocrine neoplasms following the WHO classification
Table 2. Effective methods of contraception (2 methods must be used)
Table 3. Prohibited and Rescue Medications
Table 4. Hematology Laboratory Tests
Table 5. Clinical chemistry (Serum or Plasma) Laboratory Tests
Table 6. Urinalysis Testsa
Tabla 7. List of investigational products for this study.
LIST OF APPENDICES
Appendix 1. Dosing Modification and Toxicity Management Guidelines for Immune-Mediated,
Infusion-Related, and Non-Immune–Mediated Reactions
Appendix 2. Schedule of study procedures: follow-up for subjects who have completed durvalumab
and tremelimumab treatment and achieved disease control (until confirmed progression of disease)
and subjects who have discontinued durvalumab or tremelimumab due to toxicity in the absence of
confirmed progression of disease.
Appendix 3. Schedule of study procedures: follow-up for subjects who have discontinued
nivolumab or tremelimumab treatment due to confirmed progression of disease at the investigator
discretion.
Appendix 4. Durvalumab DOSE CALCULATIONS
Appendix 5. Durvalumab VOLUME CALCULATIONS
Appendix 6. Tremelimumab DOSE CALCULATIONS
Appendix 7. Tremelimumab VOLUME CALCULATIONS
Appendix 8. Contact details.
Appendix 9. Sites and Investigators participants.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
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Edition Number: 5.0 dated on June 09th, 2021
ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation
Explanation or special term
AchE
Acetylcholinesterase
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
APF12
Proportion of patients alive and progression free at 12 months from randomization
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC0-28day
Area under the plasma drug concentration-time curve from time zero to Day 28
post-dose
AUCss
Area under the plasma drug concentration-time curve at steady state
BoR
Best objective response
BP
Blood pressure
C
Cycle
CD
Cluster of differentiation
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
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Edition Number: 5.0 dated on June 09th, 2021
CI
Confidence interval
CL
Clearance
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CSA
Clinical study agreement
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T–lymphocyte-associated antigen 4
Ctrough,ss
Trough concentration at steady state
CXCL
Chemokine (C-X-C motif) ligand
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board and Independent
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
EdoR
Expected duration of response
EGFR
Epidermal growth factor receptor
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HR
Hazard Ratio
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IFN
Interferon
IgE
Immunoglobulin E
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
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Edition Number: 5.0 dated on June 09th, 2021
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IL
Interleukin
ILS
Interstitial lung disease
IM
Intramuscular
IMT
Immunomodulatory therapy
IP
Investigational product
irAE
Immune-related adverse event
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Regulatory Activities
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
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Edition Number: 5.0 dated on June 09th, 2021
MHLW
Minister of Health, Labor, and Welfare
miRNA
Micro-ribonucleic acid
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non–small-cell lung cancer
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PDx
Pharmacodynamic(s)
PFS
Progression-free survival
PFS2
Time to second progression
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
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Edition Number: 5.0 dated on June 09th, 2021
PGx
Pharmacogenetic research
PK
Pharmacokinetic(s)
PR
Partial response
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q8w
Every 8 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
Ribonucleic acid
RR
Response rate
RT-QPCR
Reverse transcription quantitative polymerase chain reaction
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Safety analysis set
SD
Stable disease
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
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Edition Number: 5.0 dated on June 09th, 2021
SNP
Single nucleotide polymorphism
SoC
Standard of Care
sPD-L1
Soluble programmed cell death ligand 1
T3
Triiodothyronine
T4
Thyroxine
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
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Edition Number: 5.0 dated on June 09th, 2021
1.
INTRODUCTION
Neuroendocrine neoplasms constitute a heterogeneous group of tumors derived from the
Kultchitzky cells of the diffuse neuroendocrine system located in the gastrointestinal tract (origin of
classical carcinoid tumors), pancreatic islet cells (origin of pancreatic endocrine tumors) and lung
(origin of typical and atypical carcinoids). Advanced disease is common at diagnosis leading to
limited options of curative strategies, so general prognosis is poor. Neuroendocrine neoplasms are
considered rare diseases, however, taken all together into account and the natural history of
well-differentiated tumors, their prevalence is increasing. Systemic treatment options have been
limited for several years. However, in the last decade, the better knowledge of molecular biology of
neuroendocrine neoplasms has increased the interest to develop targeted agents in this field,
changing the scenario of possible therapies for advanced disease. Even though, treatment options
are still limited.
Immune
balance
has
always
been
related
with
neuroendocrine
neoplasms.
Prolonged
stabilizations have often been described without treatment and initial immune modulators, such as
interferon,
have
demonstrated
antitumoral
effects
in
these
tumors.
Recent
advances
in
immunotherapy have permitted the development of new targeted agents with higher efficacy and
lower toxicity that opens a new treatment option for patients with advanced neuroendocrine
tumors.
​
1.1
Disease Background
Well-differentiated
gastroenteropancreatic
and
lung
neuroendocrine
tumors
are
generally
malignancies with a prolonged natural history. However, clinical behavior is heterogeneous and
when
tumor
progression
is
observed,
treatment
options
are
limited.
Although advanced
neuroendocrine neoplasms represent less than 2% of all gastrointestinal cancers, they constitute
the second most prevalent advanced tumor of the gastrointestinal tract after colorectal cancer (Yao
et al, 2008). The biological behavior of neuroendocrine neoplasms depends mainly on their
histological characteristics, defined by the differentiation grade and Ki67 expression. The most
recent 2010 WHO classification divides neuroendocrine neoplasms in three groups regarding Ki67
value and mitotic count: neuroendocrine tumors that include grade 1 (G1) and grade 2 (G2) with
Ki67 value ≤20% and mitotic count ≤20 mitoses x 10 HPF, and neuroendocrine carcinomas that
include grade 3 (G3) with Ki67>20% and/or mitotic count >20 mitoses x 10 HPF.
Table 1. Groups of neuroendocrine neoplasms following the WHO classification
Lung and Thymus
GEP-NETs
Grade
Mitotic count
(10 HPF)
Mitotic count
(10 HPF)
Ki-67
(%)
G1
< 2
<2
≤2
G2
2-10
2-20
3-20
G3
>10
>20
>20
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Drug Substance DURVALUMAB/TREMELIMUMAB
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EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
The medical treatment of advanced well-moderately differentiated (G1/G2) neuroendocrine
neoplasms has included somatostatin analogs, interferon and cytotoxic agents. The lack of
effectiveness of conventional cytotoxic agents has prompted exploration of new targeted drugs
exploiting phenotypical features of neuroendocrine neoplasms. Neuroendocrine neoplasms are
characterized by being remarkably vascular and expressing several growth factors, including
vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like
growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor
(TGF)-α and -β. In addition, expression of several receptors of these growth factors and ligands
has been described, including stem cell factor receptor (c-KIT), epidermal growth factor receptors
(EGFR), VEGF receptors (VEGFR)-2 and 3, IGF receptors (IGF-R), and PDGF receptors
(PDGFR). The (over)expression of some of these factors has been associated with poor prognosis
and decreased progression-free survival (PFS), as well as with tumor growth, aggressiveness, and
disease extent in patients with gastroenteropancreatic neuroendocrine neoplasms. Several
targeted agents have been studied in the treatment of neuroendocrine neoplasms including
antiangiogenic compounds (such as bevacizumab), inhibitors of multiple receptors with kinase
activity (such as sunitinib), and inhibitors of intracellular downstream effector proteins such as the
mammalian target of rapamycin (mTOR) everolimus. Three phase III studies with everolimus and
sunitinib
have
demonstrated
efficacy
in
G1/G2
neuroendocrine
tumors
of
the
gastroenteropancreatic system becoming new treatment options in the management of these
patients (Raymond et al 2011; Yao et al 2011; Yao et al 2015). Everolimus has also demonstrated
efficacy in G1/G2 lung neuroendocrine tumors (typical and atypical carcinoids), becoming the first
drug that has demonstrated a significant increase in progression-free survival in this setting (Yao et
al 2015).
For advanced high-grade neuroendocrine carcinomas (G3), regardless of the site of the primary
tumor, combination chemotherapy using cisplatin-based regimens is recommended early (provided
that the patient has adequate organ function and performance status). Responses are frequently
seen, however impact in overall survival is limited and life expectancy of these patients is around
12-16 months. There is no established second-line therapy for G3 neuroendocrine carcinomas of
the gastroenteropancreatic system.
Immune responses directed against tumors are one of the body’s natural defense 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 (Mu et al, 2011), renal (Krambeck et al,
2007), pancreatic (Nomi et al, 2007; Loos et al, 2008), ovarian cancer (Hamanishi et al, 2007), and
hematologic malignancies (Andorsky et al, 2011; Brusa et al, 2013) 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 used 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 (Keir et al, 2008;
Park et al, 2010). This results in reduced T-cell activation and fewer activated T cells in circulation.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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 (Zou and
Chen, 2008).
Immune responses directed against tumors are one of the body’s natural defenses against the
growth and proliferation of cancer cells. T cells play a critical role in antitumor immunity and their
infiltration and activity have been linked to improved prognosis in a number of cancers (Pagès et
al, 2010; Suzuki et al, 2011). Immune evasion, primarily through suppression of T-cell activity, is
now recognized as one of the hallmarks of cancer. Such evasion can occur via a range of
mechanisms including production of suppressive cytokines such as IL-10, secretion of chemokines
and growth factors that recruit and sustain suppressive regulatory T cells (Tregs) and inflammatory
macrophages, and expression of inhibitory surface molecules such as B7-H1. Tumor types
characterized as being responsive to immunotherapy-based approaches include melanoma, renal
cell carcinoma (RCC), bladder cancer , and malignant mesothelioma (Bograd et al, 2011).
Inhibition of CTLA-4 signaling is a validated approach to cancer therapy, as shown by the approval
in 2011 of ipilimumab for the treatment of metastatic melanoma based on statistically significant
and clinically meaningful improvement in OS (Robert et al, 2011).
In general, tumor response rates to anti-CTLA-4 therapy are low (~10%). However, in patients who
respond, the responses are generally durable, lasting several months even in patients with
aggressive tumors such as refractory metastatic melanoma. Because these agents work through
activation of the immune system and not by directly targeting the tumor, responses can occur late
and some patients may have perceived progression of their disease in advance of developing
disease stabilization or a tumor response. In some cases, early growth of pre-existing lesions or
the appearance of new lesions may have been due to immune-cell infiltration into the tumor and
not due to proliferation and extension of neoplastic cells, per se (Wolchok et al, 2009). Overall,
although the impact on conventionally-defined PFS can be small, durable response or stable
disease seen in a proportion of patients can lead to significant prolongation of OS. The melanoma
data with ipilimumab clearly demonstrate that a small proportion of patients with an objective
response had significant prolongation of OS, supporting the development of this class of agents in
other tumors. Although Phase 2 and Phase 3 studies of tremelimumab in metastatic melanoma did
not meet the primary endpoints of response rate and OS, respectively, the data suggest activity of
tremelimumab in melanoma (Ribas et al, 2013). In a large Phase 3 randomized study comparing
tremelimumab with dacarbazine (DTIC)/temozolomide in patients with advanced melanoma, the
reported median OS in the final analysis was 12.58 months for tremelimumab versus 10.71 months
for DTIC/temozolomide (HR = 1.1416, p = 0.1272; Ribas et al, 2013).
​
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 (Dunn et al, 2004).
Studies in mouse models of transplantable tumors have demonstrated that manipulation of
co-stimulatory or co-inhibitory signals can amplify T-cell responses against tumors (Peggs et al
2009). This amplification may be accomplished by blocking co-inhibitory molecules, such as
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death 1 (PD-1), from
binding with their ligands, B7 or B7-H1 (programmed cell death ligand 1 [PD-L1]).
1.1.2
Durvalumab
The non-clinical and clinical experience is fully described in the last version of the durvalumab
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Investigator’s Brochure .
Durvalumab 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.
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some types of
cancers. In a number of these cancers, including lung, the expression of PD-L1 is associated with
reduced survival and an unfavorable prognosis. In lung cancer, only 12% of patients with tumors
expressing PD-L1 survived for more than 3 years, compared with 20% of patients with tumors
lacking PD-L1 (Mu et al, 2011).
Based on these findings, an anti-PD-L1 antibody could be used
therapeutically to enhance anti-tumor immune responses in patients with cancer. Results of several
non-clinical studies using mouse tumor models support this hypothesis, where antibodies directed
against PD-L1 or its receptor PD-1 showed anti-tumor activity (Hirano et al 2005, Iwai et al 2002,
Okudaira et al 2009, Zhang et al 2008).
Durvalumab has been given to humans as part of ongoing studies as a single drug or in
combination with other drugs.
As of the data cut-off date (12 July 2017) across the entire clinical development program, an
estimated
4067
patients
have
been
exposed
to
1
or
more
doses
of
durvalumab
in
AstraZeneca-sponsored Phase I to III studies, either as monotherapy or in combination, and 5911
patients where the treatment arm is blinded. Additionally, approximately 4000 patients have been
exposed to 1 or more doses of durvalumab in ESR/IITs.
Estimates of overall cumulative patient exposure based on actual exposure data from any
completed clinical trials and the enrolment/randomisation schemes for ongoing open label and
blinded trials are: 3723 patients received durvalumab monotherapy, 3372 patients received
durvalumab in combination with tremelimumab.Details on the safety profile of durvalumab
monotherapy, tremelimumab monotherapy and durvalumab plus tremelimumab are summarized in
Section 1.4.2. Refer to the current durvalumab Investigator’s Brochure for a complete summary of
non-clinical and clinical information including safety, efficacy and pharmacokinetics.
​
1.1.3
Tremelimumab
The non-clinical and clinical experience is fully described in the last version of the tremelimumab
Investigator’s Brochure.
Tremelimumab
is
an
IgG-2
kappa
isotype
mAb
directed
against
the
cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152).
This is an immunomodulatory therapy (IMT) that is being developed by AstraZeneca for use in the
treatment of cancer.
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory signal,
which limits T-cell activation.
Anti-CTLA-4 inhibitors antagonize the binding of CTLA-4 to B7
ligands and enhance human T-cell activation as demonstrated by increased cytokine (interleukin
[IL]-2 and interferon [IFN] gamma) production in vitro in whole blood or peripheral blood
mononuclear cell (PBMC) cultures (Tarhini and Kikwood 2008). In addition, blockade of CTLA-4
binding to B7 by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
anti-tumor activity in animal models, including killing of established murine solid tumors and
induction of protective anti-tumor immunity. See the last version of tremelimumab IB, , for more
information.
Therefore, it is expected that treatment with an anti-CTLA-4 antibody, such as
tremelimumab, will lead to increased activation of the human immune system, increasing
anti-tumor activity in patients with solid tumors.
An extensive program of non-clinical and clinical studies has been conducted for tremelimumab
both as monotherapy and combination therapy with conventional anticancer agents to support
various cancer indications using different dose schedules.
To date Nov/2017 tremelimumab has been given to more than 1000 patients as part of ongoing
studies either as monotherapy or in combination with other anticancer agents. Refer to the current
tremelimumab Investigator’s Brochure for a complete summary of non-clinical and clinical
information including safety, efficacy and pharmacokinetics.
​
1.1.4
Durvalumab in combination with tremelimumab
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012)
because
the
mechanisms
of
action
of
CTLA-4
and PD-1 are non-redundant; therefore,
AstraZeneca is also investigating the use of durvalumab + tremelimumab combination therapy for
the treatment of cancer.
Durvalumab + tremelimumab: Study D4190C00006: As of 28 February 2017, durvalumab PK
(n=347) and tremelimumab PK (n=353) data were available from the dose-escalation and
dose-expansion phases following durvalumab Q4W (3, 10, 15, or 20 mg/kg) or Q2W (10 mg/kg) in
combination with tremelimumab Q4W (1, 3, or 10 mg/kg). An approximately dose-proportional
increase in PK exposure (C max and AUC 0 to 28 days [AUC 0-28 ]) of both durvalumab and
tremelimumab was observed over the dose range of 3 to 20 mg/kg durvalumab Q4W and 1 to 10
mg/kg tremelimumab Q4W. Exposures following multiple doses demonstrated accumulation
consistent with PK parameters estimated from the first dose. The observed PK exposures of
durvalumab
and
tremelimumab
following
combination
were
consistent
with
respective
monotherapy data, indicating no PK interaction between these 2 agents.
As of DCO of28 February 2017, ADA data were available from 99 patients for durvalumab and 95
patients for tremelimumab in Study D4190C00006. The ADA incidence was 2.0% (2/99 patients)
for durvalumab and 5.3% (5/95 patients) for tremelimumab. There was no clear relationship
between ADA and the dose of either durvalumab or tremelimumab, and no apparent association
between ADA and safety or efficacy.
Durvalumab has also been combined with other anticancer agents, including gefitinib, dabrafenib,
and trametinib. To date, no PK interaction has been observed between durvalumab and these
agents.
​
1.2
Research hypothesis
The most used therapy for neuroendocrine tumors are somatostatin analogs, with clear evidence
of antitumor activity demonstrated by two phase III clinical trials in gastroenteropancreatic
neuroendocrine tumors. However, even the use in lung carcinoids is quite usual, no antitumoral
activity has been demonstrated in prospective clinical trials. In recent years, target therapy as
sunitinib and everolimus have been approved for pancreatic neuroendocrine tumors and recently
everolimus have showed a significant reduction in the risk of progression or death in patients with
nonfunctional neuroendocrine tumors of lung or gastrointestinal origin. After the failure of these
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
therapies, no other drugs have demonstrated efficacy. Only Interferon alpha-2b is an option for
these patients who have worsening symptoms of carcinoid syndrome while on treatment with
somatostatin analogs and have showed some evidence of antitumoral activity in neuroendocrine
tumors. The efficacy of Interferon alpha 2-b is not fully understood, but one of its antitumoral
mechanisms of action could be related via stimulation of T cells. Tremelimumab and Durvalumab
are much more efficient drugs to improve immune system activation and could obtain a significantly
higher clinical benefit in these patients. The presence of tumor-infiltrating lymphocytes (TILS) in
these type of tumors have been described enhancing the hypothesis of immunotherapy in this
setting.
Following the knowledge of increased tumor-specific antigens with the presence of more
mutational load, dedifferentiation process and treatments previously received we hypothesize that
immunotherapy could have a higher effect in the setting of refractory neuroendocrine neoplasms,
when tumor behavior is more aggressive and the probability of immune escape process is higher.
​
1.3
Rationale for conducting this study
Well and moderately differentiated neuroendocrine tumors of the gastroenteropancreatic tract and
lung are orphan tumors after progression a targeted therapy. For gastrointestinal origin tumors,
somatostatin analogues have been the cornerstone of antihormonal therapy during decades.
During the last 5 years, antiproliferative effects have also been demonstrated in this setting.
Recently, for neuroendocrine tumors of the lung (typical and atypical carcinoids), everolimus has
demonstrated impact in tumor growth control and improvement in progression-free survival.
However, after progression to a targeted therapy, no other drugs are approved.
Within the lack of treatment options, combinations of somatostatin analogues and interferon alpha
have widely been used, mainly for their effect in tumor hormone release and for the evidence of
tumor growth control in many retrospective analyses.
The hypothesis of efficacy of interferon alpha in these settings could be via stimulation of T cells.
Recently, PD-L1 expression has been observed in neuroendocrine tumors such as small cell
neuroendocrine carcinomas of the lung and Merkel cell carcinoma. These facts could provide a
timely opportunity to develop specific studies with targeted therapies that stimulate the immune
system against the tumor. Currently, several clinical trials are ongoing in these G3 high grade
neuroendocrine tumors of the lung (small cell lung cancer) and skin (Merkel Cell carcinomas).
However, there are no clinical trials ongoing in G3 gastroenteropancreatic neuroendocrine
neoplasms (which is the most frequent site of G3 neuroendocrine carcinomas after the lung origin)
and well-moderately differentiated (G1/G2) neuroendocrine tumors, which are the ones where
immunotherapy with interferon alpha has demonstrated some activity.
Tremelimumab and Durvalumab would be the first immune combination agents showing efficacy in
G1/G2/G3 advanced neuroendocrine neoplasms of gastroenteropancreatic or lung origin.
As an antibody that blocks the interaction between PD-L1 and its receptors, durvalumab may
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic activity
of anti-tumor T-cells.
This hypothesis is supported by emerging clinical data from other mAbs
targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical activity and a
manageable safety profile (Brahmer et al 2012, Topalian et al 2012).
Responses have been
observed in patients with PD-L1-positive tumors and patients with PD-L1-negative tumors.
In
addition, durvalumab monotherapy has shown durable responses in NSCLC in Study 1108 (see
Section 1.4.1.1).
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
The rationale for combining durvalumab and tremelimumab is that the mechanisms of CTLA-4 and
PD-1 are non-redundant, suggesting that targeting both pathways may have additive or synergistic
activity (Pardoll 2012).
In fact, combining immunotherapy agents has been shown to result in
improved
response
rates
(RRs)
relative
to
monotherapy.
For
example,
the
concurrent
administration of nivolumab and ipilimumab to patients with advanced melanoma induced higher
objective response rates (ORRs) than those obtained with single-agent therapy.
Importantly,
responses appeared to be deep and durable (Wolchok et al 2013).
Similar results have been
observed in an ongoing study of durvalumab + tremelimumab in NSCLC (Antonia et al 2014), with
further updated details presented in this clinical study protocol.
​
1.3.1
Durvalumab  + tremelimumab combination therapy dose rationale
The durvalumab + tremelimumab doses and regimen selected for this study are based on the goal
of selecting an optimal combination dose of durvalumab and tremelimumab that would yield
sustained target suppression (sPD-L1), demonstrate promising efficacy, and have an acceptable
safety profile.
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were
narrowed to 15 and 20 mg/kg durvalumab q4w. PK simulations from the durvalumab monotherapy
data indicated that a similar area under the plasma drug concentration-time curve at steady state
(AUCss; 4 weeks) was expected following both 10 mg/kg q2w and 20 mg/kg q4w durvalumab. The
observed durvalumab PK data from the D4190C00006 study were well in line with the predicted
monotherapy PK data developed preclinically. This demonstrates similar exposure of durvalumab
20 mg/kg q4w and 10 mg/kg q2w, with no alterations in PK when durvalumab and tremelimumab
(doses ranging from 1 to 3 mg/kg) are dosed together.
While the median Cmax at steady state
(Cmax,ss) is expected to be higher with 20 mg/kg q4w (approximately 1.5 fold) and median trough
concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg q2w (approximately
1.25 fold), this is not expected to impact the overall safety and efficacy profile, based on existing
preclinical and clinical data.
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab relative
to the activity observed in patients treated with durvalumab monotherapy. There was evidence of
augmented PDx activity relative to durvalumab monotherapy with combination doses containing 1
mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab plus 1 mg/kg
tremelimumab combinations.
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the
10
mg/kg
durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg
tremelimumab cohorts treated at the q2w schedule, the number of patients reporting any AE,
Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg
tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A similar
pattern was noted in the q4w regimens, suggesting that, as the dose of tremelimumab increased
above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, the SAEs
frequently attributed to immunotherapy, pneumonitis and colitis, were more commonly seen in
cohorts using either 3 or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts.
Together, these data suggest that a combination using a tremelimumab dose of 1 mg/kg appeared
to minimize the rate of toxicity when combined with durvalumab. As a result, all combination doses
utilizing either the 3 or 10 mg/kg doses of tremelimumab were eliminated in the final dose
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
selection.
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab
did not show an increase in the rate of AEs.
The data suggested that increasing doses of
durvalumab may not impact the safety of the combination as much as the tremelimumab dose.
Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in
safety events with increasing dose of durvalumab.
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 20 mg/kg
durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥3 AEs, SAEs, and
treatment discontinuations due to AEs, but still showed strong evidence of clinical activity. This
cohort had a lower number of treatment-related Grade ≥3 AEs or treatment-related SAEs.
No
dose-limiting toxicities were reported.
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to
change with increasing doses of tremelimumab. The 15- and 20-mg/kg durvalumab q4w cohorts
demonstrated objective responses at all doses of tremelimumab, and increasing doses of
tremelimumab did not provide deeper or more rapid responses.
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort may
demonstrate equivalent clinical activity to another dose combinations. Of the 45 patients, full
analysis set,, there were 7 patients (15,6%) with PR, 19 patients (42,2%) with SD, and 15 patients
(33,3%) with PD. Four patients were not evaluable for response .
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort had the
fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still showed
some evidence of clinical activity. All together, the data suggested that a 20 mg/kg durvalumab + 1
mg/kg tremelimumab dose combination should be selected for further development.
Refer to the current durvalumab Investigator’s Brochure for a complete summary of non-clinical
and clinical information on the durvalumab + tremelimumab combination, including safety, efficacy
and pharmacokinetics.
​
1.3.2
Rationale for 4 cycles of combination therapy followed by durvalumab
monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 targeting
antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that patients
responding to ipilimumab derive long-term benefit, with a 3-year OS rate of approximately 22%.
Furthermore, the survival curve in this population reached a plateau at 3 years and was maintained
through 10 years of follow up (Schadendorf et al, 2013).
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies:
Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I dose-escalation and
expansion study, and showed responses were maintained for a median of 22.94 months for
melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 1, 3, and 10 mg/kg), and
12.9 months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the time of data analysis
(Hodi et al 2014, Bramer et al 2014, Drake et al 2013). Furthermore, responses were maintained
beyond treatment discontinuation in the majority of patients who stopped nivolumab treatment
(either due to protocol specified end of treatment, complete response [CR], or toxicity) for up to 56
weeks at the time of data analysis (Topalian et al 2014).
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in which patients
were dosed for a finite time period and responses maintained beyond treatment discontinuation
have been reported (Herbest et al 2013, Wolchok et al 2013).
Similar long term results may be expected with use of other immune-mediated cancer therapeutics
including
anti-CTLA-4
antibodies
such
as
tremelimumab,
anti PD-L1 antibodies such as
durvalumab, or the combination of the two.
​
1.4
Benefit/risk and ethical assessment
Natural history of neuroendocrine tumors is usually prolonged. G1/G2 neoplasms are slowing
growing tumors that require continued therapy to control tumor growth, increasing the risk of
long-term side effects. The prolonged effect of immunotherapy could be of especial interest in this
setting, reducing the risk of chronic toxicity and maintaining the long-term benefit.
​
1.4.1
Potential benefits
1.4.1.1 Durvalumab
The majority of the safety and efficacy data currently available for durvalumab are based on the
first time in-human, single-agent study (Study 1108) in patients with advanced solid tumors. Data
from Study 1108 were presented at the European Society for Medical Oncology 2014 Congress.
Overall, 456 of 694 subjects treated with durvalumab 10 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%)(Antonia et al 2014b).
1.4.1.2  Tremelimumab
In a single-arm, Phase II study (Study A3671008) of tremelimumab administered at 15 mg/kg every
90 days to patients with refractory melanoma, an RR of 7% and a median OS of 10 months in the
second-line setting (as compared to approximately 6 months with best supportive care reported
from a retrospective analysis; Korn et al 2008) were observed (Kirkwood et al 2010).
In a
randomized, open-label, first-line Phase III study of tremelimumab (administered at 15 mg/kg every
90 days) versus chemotherapy (dacarbazine or temozolomide) in advanced melanoma (Study
A3671009), results of the final analysis showed an RR of 11% and a median OS of 12.58 months
in this first-line setting as compared to 10.71 months with standard chemotherapy; however, these
results were not statistically significant (Ribas et al 2013). Additionally, a Phase II maintenance
study (Study A3671015) in patients with Stage IIIB or IV NSCLC who had responded or remained
stable failed to achieve statistical significance. The primary endpoint of PFS at 3 months was
22.7% in the tremelimumab arm (15 mg/kg) compared with 11.9% in the best supportive care arm
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Edition Number: 5.0 dated on June 09th, 2021
(Study A3671015).
1.4.1.3 Durvalumab + tremelimumab
The preclinical and clinical justification for this combination as noted in Section 1.1.4 also supports
the synergy of this combination. Available data, such as those presented by Wolchok et al, suggest
that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may have profound and durable
benefits in patients with melanoma (Wolchok et al 2013). Of the 102 subjects with advanced
NSCLC treated with durvalumab in combination with tremelimumab in Study D4190C00006, 63
subjects with at least 16 weeks of follow-up were evaluable for response (defined as measurable
disease at baseline and at least 1 follow-up scan; this included discontinuations due to disease
progression or death without follow-up scan). Of the 63 evaluable subjects, 17 (27%) had a best
overall response of PR,14 (22%) had SD,22 (35%) had PD, and 10 (16%) were not evaluable. The
ORR(confirmed and unconfirmed CR or PR) was 27% and the DCR (CR, PR, or SD) was 49% as
assessed by RECIST v1.1.
Current experience with single-agent IMT studies suggests that clinical responses may be
restricted to a subset of any given patient population and that it might be beneficial to enrich the
patient population by selecting patients likely to respond to therapy. To date, no assay has been
established or validated, and no single approach has proven accurate, for patient enrichment for
IMTs.
However, independent data from multiple sources using different assays and scoring
methods suggests that PD-L1 expression on tumor cells and/or tumor infiltrating cells may be
associated with greater clinical benefit.
Data from ongoing studies with durvalumab and other agents targeting the PD-1/PD-L1 pathway
suggest, as shown in a number of tumor types (eg, NSCLC, renal cell carcinoma, and melanoma),
that monotherapy may be more efficacious (in terms of ORR) in patients who are PD-L1-positive.
Given these findings, a number of ongoing studies are assessing the activity of agents in patients
with PD-L1–positive tumors. There is also an unmet medical need in patients with PD-L1–negative
tumors that needs to be addressed. Data, as of 27 January 2015 from Study 006 show that with
the addition of tremelimumab to durvalumab, the ORR can be increased to 25% in patients with
PD-L1 negative NSCLC.
​
1.4.2 Potential risks
1.4.2.1   Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis, abdominal pain,
pneumonitis/ILD, endocrinopathies (hypo- and hyperthyroidism, type I diabetes mellitus,
hypophysitis and adrenal insufficiency, Thyroiditis) hepatitis/increases in transaminases,
nephritis/increases
in
creatinine,
pancreatitis/increases
in
amylase
and
lipase,
rash/pruritus/dermatitis,
pemphigoid,
myocarditis,
myositis/polymyositis,
inflammatory
events including neuromuscular toxicities (myasthenia gravis), infusion-related reactions,
immune thrombocytopenia, hypersensitivity reactions and infections/serious infections.
For information on all identified and potential risks with durvalumab please always refer to
the current version of the durvalumab IB.
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Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
In monotherapy clinical studies AEs (all grades) reported very commonly (≥10% of
patients) are cough/productive cough, diarrhoea, abdominal pain, hypothyroidism, rash
pruritus, pyrexia, and upper respiratory tract infections
Approximately 9% of patients experienced an AE that resulted in permanent discontinuation of
durvalumab and approximately 6% of patients experienced an SAE that was considered to be
related to durvalumab by the study investigator.
ImAEs: immune-mediated pneumonitis, hepatitis, colitis, hypothyroidism, hyperthyroidism, adrenal
insufficiency,
Type
1
diabetes
mellitus,
hypophysitis/hypopituitarism,
nephritis,
rash
and
pemphigoid.
Other
immune-mediated
adverse
reactions
including
myocarditis
and
myositis/polymyositis.
These
imAEs
should
be
managed
based
on
dosing
and
Toxicity
Management Guidelines described in appendix 1 of this protocol.
Infusion-related reactions: as with the administration of any Ig, infusion-related reactions may occur
and may be severe and should be managed according to Toxicity Management Guidelines and
study protocol.
As patients with previous history of bleeding and/or who are taking anticoagulant medications may
have a higher risk of subsequent bleeding, the investigator should devote special attention to
monitoring of these patients in the context of possible bleeding.
Further information on these risks can be found in the current version of the durvalumab IB.
In monotherapy clinical studies AEs (all grades) reported very commonly (≥10% of patients) are
fatigue, cough , decreased appetite , dyspnoea , nausea , constipation , diarrhoea , pyrexia , back
pain, anaemia, vomiting, pruritus, arthralgia, headache, asthenia, oedema peripheral and rash.
A total of 178 patients (9.4%) discontinued from study treatment due to an AE.  A total of 108
patients (5.7%) had serious AEs (SAEs) that were considered by the investigator as related to
durvalumab.
Most treatment-related AEs were manageable by delaying or interrupting the durvalumab dose,
symptomatic treatment, and in the case of events suspected to have an immune basis, the use of
established treatment guidelines for immune-mediated toxicity (see the Dosing Modification and
Toxicity Management Guidelines).
Serious adverse reactions for durvalumab monotherapy considered expected
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Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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 (please see Appendix 1)
A detailed summary of durvalumab monotherapy AE data can be found in the current version of
the durvalumab IB.
1.4.2.2 Tremelimumab
Potential risks, based on the mechanism of action of tremelimumab and related molecules
(ipilimumab)
include
potentially
immune-mediated
gastrointestinal
(GI)
events
including
enterocolitis,, abdominal pain, dehydration, nausea and vomiting, and decreased appetite
(anorexia); dermatitis including urticaria, skin exfoliation, and dry skin; endocrinopathies including
hypophysitis, adrenal insufficiency, and hyperthyroidism and hypothyroidism; pancreatitis including
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
autoimmune pancreatitis and lipase and amylase elevation; respiratory tract events including
pneumonitis and interstitial lung disease (ILD); nervous system events including encephalitis,
peripheral motor and sensory neuropathies, and Guillain-Barré syndrome; cytopenias including
thrombocytopenia, anemia, and neutropenia; infusion-related reactions; anaphylaxis; and serious
allergic reactions. The profile of AEs and the spectrum of event severity have remained stable
across the tremelimumab clinical program and are consistent with the pharmacology of the target.
To date, no tumor type or stage appears to be associated with unique AEs (except for vitiligo that
appears to be confined to patients with melanoma). Overall, 944 of the 973 patients (97.0%)
treated with tremelimumab monotherapy as of the data cutoff date of 1 November 2015 (not
including
569 patients who have been treated in the ongoing blinded Phase IIb Study
D4880C00003) experienced at least 1 AE. The events resulted in discontinuation of tremelimumab
in 10.0% of patients, were serious in 36.5%, were Grade ≥3 in severity in 49.8%, were fatal in
67.7%, and were considered to be treatment related in 79.1% of patients. The frequency of any
AEs and Grade ≥3 AEs was generally similar across the tremelimumab dose groups. However, a
higher percentage of patients in the 10 mg/kg every 28 days and 15 mg/kg every 90 days groups
compared with the All Doses <10 mg/kg group experienced treatment-related AEs, SAEs, AEs
resulting in discontinuation of investigational product (IP), and deaths.
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Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Serious adverse reactions for the tremelimumab monotherapy pool considered expected
A detailed summary of tremelimumab monotherapy AE data can be found in the current version of
the tremelimumab IB.
1.4.2.3 Durvalumab + tremelimumab
Safety data have been pooled for 5 durvalumab and tremelimumab combination studies
(D4190C00002, D4190C00006, D4190C00010, D4190C00011 and D4193C00003 [CONDOR]) for
patients who received a dose of 20 mg/kg Q4W durvalumab plus 1 mg/kg tremelimumab Q4W, or
equivalent durvalumab 10 mg/kg Q2W + tremelimumab 1 mg/kg Q4W; a total of 1088 patients are
included in the pooled data set with a DCO of the 12 July 2017.
In durvalumab+tremelimumab combination studies at the dose of durvalumab 20 mg/kg and
tremelimumab 1 mg/kg AEs (all grades) reported very commonly (≥10% of patients) are
cough/productive cough, alteration of hepatic enzymes ALT/AST, diarrhoea, abdominal pain,
hypothyroidism, rash, pruritus, pyrexia, peripheral oedema, and upper respiratory tract infections-
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation of
study drug and approximately 15% of patients experienced an SAE that was considered to be
related to durvalumab and tremelimumab by the study investigator.
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Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
●
Potential imAEs for durvalumab and durvalumab in combination with tremelimumab
include:
•
immune-mediated pneumonitis, hepatitis, diarrhoea/colitis, intestinal perforation,
hypothyroidism, adrenal insufficiency, hypophysitis/hypopituitarism, type I diabetes
mellitus, nephritis, rash/dermatitis (including pemphigoid)
•
Pancreatitis
•
Other rare or less frequent events with a potential immune-mediated aetiology, eg,
pericarditis, sarcoidosis, uveitis, and other events involving the eye (eg, keratitis and
optic
neuritis),
skin
(eg,
scleroderma
and vitiligo), and haematological (eg,
haemolytic anaemia and immune thrombocytopenic purpura), rheumatological
events
(polymyalgia
rheumatic
and
autoimmune
arthritis)
and
neuropathy/neuromuscular
toxicities
(eg,
myasthenia
gravis,
Guillain
Barre
syndrome).
●
Hypersensitivity reactions including
•
Anaphylaxis and allergic reaction
•
Cytokine release syndrome
•
Immune complex disease
●
Other infections
Infusion-related reactions: as with the administration of any Ig, infusion-related reactions may occur
and may be severe and should be managed according to Toxicity Management Guidelines and
study protocol.
Serious adverse reactions for durvalumab plus tremelimumab combination considered expected.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the
current version of the durvalumab IB.
1.4.2.4 Fixed Dosing for durvalumab and tremelimumab
A population PK model was developed for durvalumab using monotherapy data from a Phase 1
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors).
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab
(coefficient of ≤0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th,
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was selected
to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 patients were
simulated using body WT distribution of 40–120 kg. Simulation results demonstrate that body
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Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
WT-based and fixed dosing regimens yield similar median steady state PK concentrations with
slightly less overall between-subject variability with fixed dosing regimen.
Similarly, a population PK model was developed for tremelimumab using data from Phase 1
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) [Wang et
al. 2014]. Population PK model indicated minor impact of body WT on PK of tremelimumab
(coefficient of ≤0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on
median body WT of ~75 kg) regimens were compared using predicted PK concentrations (5th,
median and 95th percentiles) using population PK model in a simulated population of 1000 patients
with body weight distribution of 40 to 120 kg. Similar to durvalumab, simulations indicated that both
body WT-based and fixed dosing regimens of tremelimumab yield similar median steady state PK
concentrations with slightly less between-subject variability with fixed dosing regimen.
Similar findings have been reported by others [Ng 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 750 mg Q2W MEDI4736 (equivalent to 10 mg/kg Q2W), 1500 mg Q4W durvalumab
(equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is
included in the current study.
Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with more or
equal than 30kg body weight due to endotoxin exposure. Patients with a body weight less than 30
kg should be dosed using a weight-based dosing schedule.
2.
STUDY OBJECTIVES
​
2.1
Primary objective(s)
The study will include patients with advanced neuroendocrine neoplasms in four different cohorts
with the following primary endpoints:
Primary endpoint for cohorts 1, 2 and 3:
Nine-months clinical benefit rate (CBR) by Response Evaluation Criteria In Solid Tumors (RECIST
1.1), which is defined as the percentage of patients achieving complete response (CR), partial
response (PR), or stable disease (SD) at month 9 after durvalumab plus tremelimumab was
started.
Primary endpoint for cohort 4:
Nine-months overall survival rate, which is defined as the percentage of patients alive at month 9
after durvalumab plus tremelimumab was started.
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EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
​
2.2
Secondary objective(s)
●
Overall response rate (ORR) by irRECIST.
●
To assess the duration of response according to irRECIST.
●
To assess the median progression-free survival time (PFS) according to irRECIST.
●
To assess the safety profile of Durvalumab and Tremelimumab in subjects with advanced
neuroendocrine neoplasms.
●
To assess the median overall survival (OS) time.
●
To assess response status according to irRECIST at 6 and 12 months after start of study
treatment.
2.3
Exploratory objective(s)
●
To evaluate biochemical response (changes in CgA and NSE levels) and its association
with response rate and progression-free survival.
●
To assess whether baseline tumor and blood biomarkers may be predictive of response to
durvalumab and tremelimumab therapy.
●
To explore additional hypotheses related to biomarkers and relationship to durvalumab and
tremelimumab efficacy and/or toxicity and neuroendocrine tumors evolution that may arise
from internal or external research activities.
3.
STUDY DESIGN
​
3.1
Overview of study design
This is a prospective, multi-center, open label, stratified, exploratory phase II study evaluating the
efficacy and safety of durvalumab plus tremelimumab in different cohorts of patients with
neuroendocrine neoplasms.
The study will include patients in four different cohorts:
●
Cohort 1: Well-moderately differentiated lung neuroendocrine tumors (classically known as
typical and atypical carcinoids) after progression to somatostatin analogs and one prior
targeted therapy or chemotherapy.
●
Cohort 2: G1/G2 (WHO grade 1 and 2) gastrointestinal neuroendocrine tumors after
progression to somatostatin analogs and one prior targeted therapy.
●
Cohort
3: G1/G2 (WHO grade 1 and 2) pancreatic neuroendocrine tumors after
progression
to
standard therapies (chemotherapy, somatostatin analogs and target
therapy), who have received between two and four prior lines of treatment.
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Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
●
Cohort 4: Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin or
unknown primary site (excluding lung primary tumors), patients will be treated in second
line only, after progression to first-line chemotherapy with a platinum based regimen.
The patient recruitment period of the study will last approximately 24 months. The maximum
treatment period for each subject on study is anticipated to be approximately 12 months (13
administrations of durvalumab). However, subjects will continue on active follow-up to determine
secondary endpoints of duration of response, median progression-free survival, median overall
survival and safety profile.
This study will be conducted in 3 phases: a screening phase, a treatment phase stratified by tumor
origin (four different cohort) and a follow up phase.
​
3.2
Study schema
Screening phase
Screening will occur between Day -28 and Day -1. The purpose of the screening period is to
establish protocol eligibility. Informed consent will be obtained up to 4 weeks prior to Cycle 1 Day 1
and after the study has been fully explained to each subject and prior to the conduct of any
screening procedures or assessments.
The purpose of the baseline visit is to establish disease characteristics prior to allocation and
treatment and to confirm protocol eligibility as specified in the inclusion/exclusion criteria. Results
of baseline assessments must be obtained prior to the first dose of study drug (Cycle 1/Day 1).
Baseline assessments may be performed on Day -1 or on Cycle 1/Day 1 prior to dosing. Clinical
laboratory tests including pregnancy test (where applicable) can be performed within 72 hours of
the first dose of study drug. Subjects who complete the baseline visit and continue to meet the
criteria for inclusion/exclusion will begin the treatment phase of this study.
Determinations performed by routine clinical practice before signing the informed consent will be
valid, provided they are carried out following this protocol requirements and date of baseline TC is
performed within the previous 4 weeks from treatment initiation. It should be clearly stated that
patient consented her/his participation to ESR 15-11561-61–DUNE trial in patient record.
Treatment phase
The treatment phase will begin at the time of allocation of the first patient and will consist of the
study treatment cycles. The treatment phase will end when the last patient discontinue the study
drug.
The treatment phase will include two stages for each cohort. The first stage will dose the first
patient in each cohort in a safety run period for one cycle (4 weeks). If no unexpected side effects
are observed in the first patient treated in each cohort during the safety run period, recruitment will
continue up to 31 patients for cohorts 1 to 3, and 33 for cohort 4.
Subjects will be allocated in each primary tumor cohort to receive durvalumab 1500 mg Q4W for
12 months plus tremelimumab 75 mg Q4W for up to 4 doses during the first 4 cycles of combined
therapy. Cycles are defined by 4 weeks or 28 days. Subjects will undergo safety and efficacy
assessment as defined per protocol.
If a toxicities pause occurs, cycles not administered for that toxicity can be delayed for a maximum
of 4 weeks, after that time that cycle will be considered lost and the next cycle will be administered.
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EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Remember no restarts are allowed after a delay of more than 12 weeks due to toxicity or more
than 4 weeks of delay if the reason is different from toxicity without consulting the Coordinating
Investigator.
Follow-up phase
Patients will finish the treatment phase after the administration of 12 months (13 cycles) of
durvalumab or after disease progression during the treatment phase. For patients that complete all
scheduled treatment, the follow-up phase will begin to determine survival endpoints. Tumor
assessments will continue every 12 weeks and clinical appointments will start monthly during the
first 3 months of follow-up, every 2 months until first year, and continue every 6 months until
disease progression.
3.3
Study Oversight for Safety Evaluation
A subject may elect to discontinue study drug at any time for safety, medical, or personal reasons.
Patients who choose to discontinue study drug prior to disease progression will be followed in the
post study treatment follow up period and continue to undergo regularly scheduled disease
assessment until documentation of disease progression or start of an alternative anticancer
treatment. All subjects who discontinue study drug will be followed for overall survival and all post
progression cancer treatments administered will be recorded. Subjects may at any time withdraw
consent for further study participation. No further data will be collected on subjects once consent
has been withdrawn. The investigator will promptly explain to the subject involved that the study
drug will be discontinued for that subject and provide appropriate medical treatment and other
necessary measures for the subject. A subject who has ceased to return for visits will be followed
up by mail, phone, or other means as much as possible to gather information such as the reason
for failure to return and the status of treatment compliance, presence or absence of adverse
events, and clinical courses of signs and symptoms, and the information will be recorded in the
CRF.
Subjects who discontinue early from the study or treatment will be discontinued for 1 of these
primary reasons: adverse event(s), lost to follow-up, subject choice, progressive disease, or
administrative/other. In addition to the primary reason, the subject may have indicated 1 or more of
these reasons as secondary reasons for discontinuation. Study disposition information will be
collected on the appropriate CRF. A subject removed from the study for any reason may not be
replaced.
Safety will be assessed by monitoring and recording all AEs including all CTCAE grades (for both
increasing and decreasing severity) and serious adverse events (SAEs); regular monitoring of
hematology, clinical chemistry, and urine values; physical examinations; and regular measurement
of vital signs, and electrocardiograms (ECGs) as detailed in the schedule of visits and procedures.
4.
PATIENT
SELECTION,
ENROLLMENT,
ALLOCATION,
RESTRICTIONS,
DISCONTINUATION AND WITHDRAWAL
Approximately 126 patients will be enrolled and allocated in a balanced manner into either the four
cohorts of patients at approximately 20 sites in Spain. Each patient must meet all of the inclusion
criteria (Section 4.1) and none of the exclusion criteria (Section 4.2) for this study. Under no
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Edition Number: 5.0 dated on June 09th, 2021
circumstances, will there be exceptions to this rule.
​
4.1
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
1.
Written informed consent obtained from the subject prior to performing any protocol-related
procedures.
2.  Age > 18 years at time of study entry.
3.
Subjects
must
have
histologically
confirmed
diagnosis
of
one
of
the
following
advanced/metastatic neuroendocrine tumor types:
a)
Cohort 1: Well-moderately differentiated neuroendocrine tumors of the lung ( mitotic
count ≤10 mitoses x 10 HPF), also known as typical and atypical lung carcinoids, that have
progressed to prior somatostatin analog therapy and/or one prior targeted therapy or
chemotherapy (only one prior systemic therapy, with the exception of
patients
that
have been treated with somatostatin analogues and other systemic treatment, when two
prior treatments are allowed).
b) Cohort 2: Well-moderately differentiated neuroendocrine tumors G1/G2 (WHO grade 1
and 2) gastrointestinal neuroendocrine tumors after progression to somatostatin analogs
and one targeted therapy (prior targeted therapy could be everolimus or a multikinase
inhibitor). Prior therapies with interferon alpha-2b or radionucleotide therapy are allowed.
c) Cohort 3: Well-moderately differentiated neuroendocrine tumors G1/G2 (WHO grade 1
and 2) from pancreatic origin after progression to standard therapies (chemotherapy,
somatostatin analogs and target therapy); patients must be treated with at least two prior
systemic treatment lines and a maximum of four previous treatment lines.
d) Cohort 4: Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin or
unknown primary site (excluding lung primary tumors), patients will be treated in second line
only, after progression to first-line chemotherapy with a platinum based regimen. Patients
will be treated in second line.”
4. For patients included in cohorts 1, 2 and 3: WHO Classification G1/G2 (mitotic count ≤10
mitoses x 10 HPF) lung typical and atypical carcinoids for cohort 1, G1/G2 (Ki67≤20% or mitotic
count ≤20 mitoses x 10 HPF) gastrointestinal for cohort 2 (including stomach, small intestine and
colorectal origins), G1/G2 (Ki67≤20% or mitotic count ≤20 mitoses x 10 HPF) pancreatic for cohort
3.
5. For patients included in cohort 4: WHO classification G3 (Ki67≥20% or mitotic count >20 mitoses
x 10 HPF) gastroenteropancreatic neuroendocrine carcinomas (NEC) or liver metastases of G3
NEC of unknown primary site.
6.  Subjects must have evidence of measurable disease meeting the following criteria:
a) In case of more than one target lesion, it should be identified at least 1 lesion of ≥1.0 cm
in the longest diameter for a non lymph node, or ≥1.5 cm in the short-axis diameter for a
lymph node, which is serially measurable according to RECIST 1.1 using computerized
tomography/magnetic resonance imaging (CT/MRI). If there is only one target lesion and it
is a non-lymph node, it should have a longest diameter of ≥ 1.5 cm.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
b) Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such
as radiofrequency (RF) ablation or liver embolization must show evidence of progressive
disease based on RECIST 1.1 to be deemed a target lesion.
c)
Subjects must show evidence of disease progression by radiologic image techniques
within 12 months (an additional month will be allowed to accommodate actual dates of
performance of scans, i.e., within ≤13 months) prior to signing informed consent,
according to RECIST 1.1.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Life expectancy of at least 12 weeks.
9.  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).
10. 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 hemolysis or hepatic pathology), who will be allowed only in
consultation with their physician.
11. 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.
12. 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)
13. 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.
14. 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.
​
4.2
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Involvement in the planning and/or conduct of the study.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
2. Participation in another clinical study with an investigational product during the last 4 weeks.
3. WHO Classification G3 neuroendocrine neoplasms of lung origin (oat cell/large cell lung cancer).
4. Prior treatment with anti-PDL-1/anti-PD-1 or anti-CTL4 therapy.
5. 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 diathesis including any subject
known to have evidence of acute or chronic hepatitis B (e.g., HBsAg reactive), hepatitis C (e.g.,
HCV RNA [qualitative] is detected) or known history of Human Immunodeficiency Virus (HIV) (HIV
1/2 antibodies), or psychiatric illness/social situations that would limit compliance with study
requirements or compromise the ability of the subject to give written informed consent.
6. Known history of previous clinical diagnosis of tuberculosis.
7. Current or prior use of immunosuppressive medication within 28 days before the first dose of
durvalumab or tremelimumab, 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. 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.
9. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative
colitis).
10. History of allogeneic organ transplant.
11. History of hypersensitivity to durvalumab, tremelimumab or any excipient.
12. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid therapy or
any other form of immunosuppressive therapy within 28 days prior to the first dose of trial
treatment.
13. Knowledge of active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided they have
stable brain metastases [without evidence of progression by imaging confirmed [by magnetic
resonance imaging (MRI) if MRI was used at prior imaging, or confirmed by computed tomography
(CT) imaging if CT used at prior imaging] for at least four weeks prior to the first dose of trial
treatment; also, any neurologic symptoms must have returned to baseline], have no evidence of
new or enlarging brain metastases, and have not used steroids for brain metastases for at least 7
days prior to trial treatment. This exception does not include carcinomatous meningitis, as subjects
with carcinomatous meningitis are excluded regardless of clinical stability.
14. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of
receiving durvalumab or tremelimumab. Note: The killed virus vaccines used for seasonal influenza
vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live
attenuated vaccines, and are not allowed.
15. Subjects having known history of, or any evidence of interstitial lung disease or active,
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
noninfectious pneumonitis.
16. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1.
17. Subjects who have received any anti-cancer treatment within 21 days or any investigational
agent within 30 days prior to the first dose of study drug and should have recovered from any
toxicity related to previous anti-cancer treatment. This does not apply to the use of somatostatin
analogues for symptomatic therapy.
18. Major surgery within 3 weeks prior to the first dose of study drug.
19. Subjects having > 1+ proteinuria on urine dipstick testing will undergo 24h urine collection for
quantitative assessment of proteinuria.  Subjects with urine protein ≥ 1 g/24h will be ineligible.
20. Significant cardiovascular impairment: history of congestive heart failure greater than New York
Heart Association (NYHA) Class II, unstable angina; myocardial infarction or stroke within 6
months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment.
21. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms
(ECGs) using  Fredericia’s Correction.
22. Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, or similar agents
requiring therapeutic international normalized ratio (INR) monitoring. Treatment with low molecular
weight heparin (LMWH) is allowed.
23. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first
dose of study drug.
24. Patients with tumoral disease in the head and neck region, such as paratracheal or
periesophageal lymph node involvement, or with infiltration of structures in the digestive tract, or
vascular pathways that represent a risk of increased bleeding.
25. Patients of cohort 1 with neuroendocrine tumors of pulmonary origin or pulmonary metastases
with evidence of active bleeding.
26.  Patients with evidence of digestive bleeding.
27. Active infection (any infection requiring treatment).
28. Active malignancy (except for differentiated thyroid carcinoma, or definitively treated melanoma
in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the
past 24 months.
29. Female patients who are pregnant or breastfeeding or male or female patients of reproductive
potential who are not willing to employ highly effective birth control from screening to 180 days
after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last
dose of durvalumab monotherapy, whichever is the longer time period.
30. Documented active alcohol or drug abuse.
31. Patients with a prior history of non-compliance with medical regimens.
32. Any condition that, in the opinion of the investigator, would interfere with evaluation of study
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
treatment or interpretation of patient safety or study results.
​
4.3
Withdrawal of Subjects from Study Treatment and/or Study
Permanent discontinuation of investigational product/study treatment
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.
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 a safety risk.
4. Pregnancy or intent to become pregnant.
5. Any AE that meets criteria for discontinuation as defined in Section 10.3.
6. Grade ≥ 3 infusion reaction.
7. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal;
eg, refusal to adhere to scheduled visits.
8. Initiation of alternative anticancer therapy including another investigational agent.
9. Confirmed PD by RECIST 1.1 (CT scan or MRI at 4-6 weeks that confirms progression) and
investigator determination that the subject is no longer benefiting from treatment with durvalumab +
tremelimumab. Patients with documented tumor progression by image (all time-points but
especially at 12 weeks), the progression should be confirmed with an additional imaging test (same
characteristics) within 4-6 weeks. Treatment should continue according to protocol, until disease
progression is confirmed, according the aforementioned procedure.
10. No restarts are allowed after a delay of more than 12 weeks due to toxicity or more than 4
weeks of delay if the reason is different from toxicity without consulting the Coordinating
Investigator.
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 as having
permanently discontinued treatment.
Subjects who are permanently discontinued from receiving investigational product will be followed
for safety per Section 10.0 and Appendix 1 or 2, 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
If consent is withdrawn, the subject will not receive any further investigational product or further
study observation.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
4.4
Replacement of subjects
If a patient withdraws from participation in the study, then his or her enrollment/allocation code
cannot be reused.  Withdrawn patients will not be replaced.
5.
INVESTIGATIONAL PRODUCT(s)
​
5.1
Durvalumab and tremelimumab
The sponsor will supply durvalumab and tremelimumab to the site pharmacies as a solution for
infusion after dilution.
​
5.1.1         Formulation/packaging/storage
The trial medication (i.e., Durvalumab and Tremelimumab) and its packaging will be labeled in
accordance with annex 13 of EU to Good Manufacturing Practice.
Durvalumab
Durvalumab will be supplied 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.
Tremelimumab
Tremelimumab will be supplied as a 400-mg vial or 25 mg solution for infusion after dilution. The
solution contains 20 mg/mL of tremelimumab, 20 mM histidine/histidine hydrochloride, 222 mM
trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM disodium edetate dihydrate
(EDTA);it has a pH of 5.5.The nominal fill volume is 20 mL. Investigational product vials are stored
at 2°C to 8°C (36°F to 46°F) and must not be frozen. Tremelimumab must be used within the
individually assigned expiry date on the label.
​
5.2
Dose and treatment regimens
​
5.2.1  Treatment regimen
Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg
tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 1500 mg
durvalumab q4w starting on Week 16 for up to 8 months (9 doses). Dosing outside the window
should be discussed with the Study Physician. Tremelimumab will be administered first.
Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The
duration will be approximately 1 hour for each infusion. A 1-hour observation period is required
after the first infusion of durvalumab and tremelimumab. If no clinically significant infusion reactions
are observed during or after the first cycle, subsequent infusion observation periods can be at the
Investigator’s discretion (suggested 30 minutes after each durvalumab and tremelimumab
infusion).
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
​
5.2.2  Duration of treatment and criteria for retreatment
Retreatment is allowed (once only) for patients meeting the retreatment criteria below. The same
treatment guidelines followed during the initial 12-month treatment period will be followed during
the retreatment period, including the same dose and frequency of treatments and the same
schedule of assessments.
Patients receiving the combination of durvalumab and tremelimumab may undergo retreatment in 2
clinical scenarios, described below:
1. Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the end of the
12-month treatment period may restart treatment with the combination upon evidence of PD, with
or without confirmation according to RECIST 1.1, during follow-up.
2. Patients who complete the 4 dosing cycles of the combination of durvalumab and tremelimumab
portion of the regimen (with clinical benefit per Investigator judgment), but subsequently have
evidence of PD during the durvalumab monotherapy portion of the combination regimen, with or
without confirmation according to RECIST 1.1, may restart treatment with the combination.
Before restarting their assigned treatment, the Investigator should ensure that the patient:
1. Does not have any significant, unacceptable, or irreversible toxicities that indicate continuing
treatment will not further benefit the patient.
2. Still fulfills the eligibility criteria for this study, including re-consenting to restart durvalumab and
tremelimumab.
3. Has not had received an intervening systemic anticancer therapy after their assigned treatment
discontinuation.
4. Has had a baseline tumor assessment within 28 days of restarting their assigned treatment; all
further scans should occur with the same frequency as during the initial 12 months of treatment
(relative to the date of randomization) until study treatment is stopped (maximum of 12 months of
further treatment).
During the retreatment period, patients receiving durvalumab + tremelimumab may resume
durvalumab dosing at 1500 mg q4w with 75 mg of tremelimumab q4w for 4 doses each. Patients
will then continue with durvalumab monotherapy at 1500 mg q4w, beginning at Week 16, 4 weeks
after the last dose of combination therapy (a total of 9 additional doses).
Treatment through progression is at the Investigator’s discretion, and the Investigator should
ensure that patients do not have any significant, unacceptable, or irreversible toxicities that indicate
that continuing treatment will not further benefit the patient. A patient with a confirmed progression
receiving durvalumab + tremelimumab cannot continue therapy or obtain retreatment if dosing is
ongoing in the combination portion of therapy (q4w dosing) and progression occurs in a target
lesion that has previously shown a confirmed response.
Patients who the sponsor and/or the Investigator determine may not continue treatment will enter
follow-up.
​
5.2.3
Study drug preparation of durvalumab and tremelimumab
Based on average body WT of 75 kg, a fixed dose of 750 mg Q2W durvalumab (equivalent to 10
mg/kg Q2W), 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg Q4W
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
tremelimumab (equivalent to 1 mg/kg Q4W) is included in the current study.
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
●
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 1500mg durvalumab for patients ≥30 kg will be administered using an IV bag
containing 0.9% (w/v) saline (compatibility with dextrose has been established and may be used as
a diluent option, if preferred), 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 30.0
mL of IV solution from the IV bag prior to addition of durvalumab. Next, 30.0 mL of durvalumab (ie,
1500 mg of durvalumab) is added to the IV bag such that final concentration is within 1 to 20
mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently inverting to ensure homogeneity of
the dose in the bag.
Patient weight at baseline should be used for dosing calculations 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 tremelimumab and number of
vials needed for the subject to achieve the accurate dose.
Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion
via an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the
entire contents of the IV bag should be administered as an IV infusion over approximately 60
minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes is considered a
deviation.
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline equal to the priming
volume of the infusion set used after the contents of the IV bag are fully administered, or complete
the infusion according to institutional policy to ensure the full dose is administered and document if
the line was not flushed.
Standard infusion time is 1 hour.
However, if there are interruptions during infusion, the total
allowed time should not exceed 8 hours at room temperature. The table below summarizes time
allowances and temperatures.
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
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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 in the
table, a new dose must be prepared from new vials. Durvalumab does not contain preservatives,
and any unused portion must be discarded.
Preparation of tremelimumab doses for administration with an IV bag
The dose of tremelimumab 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
tremelimumab vial to the start of administration should not exceed:
●
24 hours at 2°C to 8°C
●
4 hours at room temperature
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C until needed. If
storage time exceeds these limits, a new dose must be prepared from new vials. The refrigerated
infusion solutions in the prepared final IV bag should be equilibrated at room temperature for about
2 hours prior to administration. Tremelimumab does not contain preservatives and any unused
portion must be discarded.
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have been
observed. Doses of 75 mg tremelimumab for patients ≥30 kg will be administered using an IV bag
containing 0.9% (w/v) saline, with a final tremelimumab concentration ranging from 0.1 mg/mL to
10 mg/mL, and delivered through an IV administration set with a 0.2 μm or 0.22 μm in-line filter.
Remove 3.8 mL of IV solution from the IV bag prior to addition of tremelimumab. Next, 3.8 mL of
tremelimumab (ie, 75 mg of tremelimumab) is added to the IV bag such that final concentration is
within 0.1 mg/mL to 10 mg/mL (IV bag volumes 50 to 500 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 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 <30 kg, Calculate the dose volume for tremelimumab and number of vials needed for
subject to achieve the accurate dose.
Tremelimumab 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
tremelimumab, the entire contents of the IV bag should be administered as an IV infusion over
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes
is considered a deviation.
The IV line will be flushed with a volume of 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
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
allowed time should not exceed 8 hours at room temperature. The table below summarizes time
allowances and temperatures.
Tremelimumab hold and infusion times
Maximum time from needle puncture to start of administration
4 hours at room temperature, 24 hours at 2ºC to 8ºC
Maximum time for IV bag infusion, including interruptions.
8 hours at room temperature
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
In the event that either preparation time or infusion time exceeds the time limits outlined in the
table,
a
new dose must be prepared from new vials. Tremelimumab does not contain
preservatives, and any unused portion must be discarded.
​
5.2.4  Monitoring of dose administration
Patients will be monitored during and after the infusion with assessment of vital signs at the times
specified in the Study Protocol.
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 and re-initiated at 50% of the initial
rate until completion of the infusion. For patients with a ≤Grade 2 infusion-related reaction,
subsequent infusions may be administered at 50% of the initial rate.
Acetaminophen and/or an
antihistamine (eg, 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.
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 patients to an intensive care unit if necessary.
​
5.2.5   Accountability and dispensation
The trial medication will be sent to the investigator's site pharmacy preceded by the Regulatory
Green Light. The medication is to be used exclusively in the clinical trial according to the
instructions of this trial protocol.
When a drug shipment is received, the Investigator or designee will check the amount and
condition of the delivery, drug expiration date, and sign the Receipt of Shipment Form provided.
The Receipt of Shipment Form should be faxed or emailed to the CRO (see appendix 8). The
original form will preliminarily be retained at the site and will be collected at the next monitoring visit
by the monitor and stored in the Trial Master File at CRO. A copy remains in the Investigator File at
the site. In case of shipment problems the Investigator or designee shall contact the CRA as soon
as possible.
An Investigational Product Accountability Log will be provided for the trial medication. The record
must be continuously updated and contain the dates, quantities and compounds of drugs received,
medication identification number(s), the patient identification number to whom the trial medication
was dispensed, date and quantity of medication dispense and the initials of the dispenser.
​
5.2.6
Disposition of unused investigational study drug
Trial medication will be monitored by the CRA at the respective hospital pharmacy prior to
destruction after having completed a final inventory. Local or institutional regulations may require
immediate destruction of the study drug used for safety reasons, e.g., cytotoxicity or to maintain
the storage capacity and functionality of the storage at the site. In these cases, it may be
acceptable to destroy it by the research staff, including partially used and empty vials, dispensed
before a monitoring inspection, if the verification of original documents of empty boxes that indicate
the information of batch number and dispensing date to the patient on the label. This
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
documentation will be verified against the quantity shipped, dispensed, returned and destroyed.
Prior to the destruction a final trial medication reconciliation statement must be completed. Drug
supplies will be destroyed according to the legal requirements in Spain.
All trial medication inventory forms must be made available for inspection by a Sponsor authorized
representative or designee and regulatory agency inspectors. The Investigator is responsible for
the accountability of all used and unused study supplies at the site.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
6.
TREATMENT PLAN
​
6.1      Subject enrollment and allocation
​
6.1.1         Procedures for allocation
Patients will be allocated in one of the following cohorts regarding primary tumor site and WHO
grading classification:
●
Cohort 1: Well-moderately differentiated lung neuroendocrine tumors (classically known as
typical and atypical carcinoids) after progression to somatostatin analogs and one prior
targeted therapy or chemotherapy.
●
Cohort 2: G1/G2 (WHO grade 1 and 2) gastrointestinal neuroendocrine tumors after
progression to somatostatin analogs and one prior targeted therapy.
●
Cohort 3: G1/G2 (WHO grade 1 and 2) pancreatic neuroendocrine tumors after progression
to standard therapies (chemotherapy, somatostatin analogs and target therapy), who have
received between two and four prior lines of treatment.
●
Cohort 4: Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin or
unknown primary site (excluding lung primary tumors) after progression to first-line
chemotherapy with a platinum based regimen. Patients will be treated in second line.
​
6.1.2        Procedures for handling subjects incorrectly enrolled
Patients incorrectly enrolled in the trial will be considered as protocol deviations. If investigator
considerer that the patient is obtaining benefit of the investigational treatment, patients could
continue on therapy. They will not be considered for the primary endpoint of the trial, neither for
efficacy nor biomarker secondary and exploratory analyses. Patients incorrectly enrolled that
continue on treatment can be assessed for safety profile endpoint.
​
6.2       Dose Modification and Toxicity Management
​
6.2.1         Durvalumab and tremelimumab
For adverse events (AEs) that are considered at least partly due to administration of durvalumab
and/or tremelimumab the following dose adjustment guidance may be applied:
●
Treat each of the toxicities with maximum supportive care (including holding the agent
suspected of causing the toxicity where required).
●
If the symptoms promptly resolve with supportive care, consideration should be given to
continuing the same dose of durvalumab or tremelimumab along with appropriate
continuing supportive care. If medically appropriate, dose modifications are permitted for
durvalumab and tremelimumab (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 or tremelimumab should be
permanently discontinued.
Following the first dose of durvalumab or tremelimumab, subsequent administration of durvalumab
or tremelimumab can be modified based on toxicities observed (see Appendix 1).
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Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Based on the mechanism of action of durvalumab or tremelimumab 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/hepatotoxicity, endocrinopathy, pneumonitis, nephritis, pancreatitis and neuropathy or
neurologic events. 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/hepatotoxicity, endocrinopathy, pneumonitis, nephritis, pancreatitis and neuropathy or
neurologic events 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.
7.
RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENT(s)
​
7.1
Restrictions during the study
The following restrictions apply while the patient is receiving study treatment and for the specified
times before and after:
●
Female subjects of childbearing potential who are sexually active with a non-sterilized male
partner must use one highly effective method of contraception (Table 2) from the time of
screening and must agree to continue using such precautions for 180 days after the last
dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of
durvalumab monotherapy, whichever is the longer time period. Male partners of a female
subject must use male condom plus spermicide throughout this period. Cessation of birth
control after this point should be discussed with a responsible physician. Not engaging in
sexual activity for the total duration of the trial and the drug washout period is an acceptable
practice; however, occasional abstinence, the rhythm method, and the withdrawal method
are not acceptable methods of contraception..
●
Females of childbearing potential are defined as those who are not surgically sterile (ie,
bilateral
tubal
ligation,
bilateral
oophorectomy,
or
complete
hysterectomy)
or
post-menopausal (defined 12 months with no menses without an alternative medical
cause).
●
Non-sterilized male subjects who are sexually active with a female partner of childbearing
potential must use male condom plus spermicide from screening through 180 days after
receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days
after receipt of the final dose of durvalumab monotherapy, whichever is the longer time
period. Female partners of a male subject must use a highly effective method of
contraception throughout this period.
●
Highly effective methods of contraception are described in Table 2. A highly effective
method of contraception is defined as one that results in a low failure rate (i.e. less than 1%
per year) when used consistently and correctly. Note that some contraception methods are
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
not considered highly effective (e.g. male or female condom with or without spermicide;
female cap, diaphragm, or sponge with or without spermicide; non-copper containing
intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of
ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is
considered highly effective]; and triphasic combined oral contraceptive pills).
●
Restrictions relating to concomitant medications are described in Section 7.2.
Table 2. Highly Effectivea Methods of Contraception
Barrier/ Intrauterine
Hormonal Methods
●
Copper T intrauterine
●
Levonorgestrel-relasing
intrauterine system
(eg, Mirema)b
●
Etonogestrel
implants:
e.g.
Implanon
or
Norplan
●
Intravaginal device; e.g. ethinylestradiol and
etonogestrel
●
Medroxyprogesterone
injection:
e.g.
Depo-Provera
●
Normal
and
low
dose
combined
oral
contraceptive pill
●
Norelgestromin/ethinylestradiol
transdermal
system
●
Cerazette (desogestrel)
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Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
a Highly effective (i.e. failure rate of <1% per year) b This is also considered a hormonal method
Blood donation
Subjects should not donate blood while participating in this study, or for at least 90 days following
the last infusion of durvalumab or tremelimumab, whichever occurs longest.
​
7.2
Concomitant treatment(s)
The Principal Investigator must be informed as soon as possible about any medication taken from
the time of screening until the end of the clinical phase of the study (final study visit). Any
concomitant medication(s), including herbal preparations, taken during the study will be recorded in
the CRF.
Restricted, prohibited, and permitted concomitant medications are described in the following
tables.
​
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.
Concomitant treatment with somatostatin analogues (octreotide or lanreotide) are allowed for
hormonal symptom control.
​
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
noncancer-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
not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α
blockers.
Use
of
immunosuppressive
medications
for
the
management
of
investigational
product-related AEs or in subjects with contrast allergies is acceptable. In addition, use of inhaled
and intranasal corticosteroids is permitted. A temporary period of steroids will be allowed for
different indications, at the discretion of the principal investigator (e.g., chronic obstructive
pulmonary disease, radiation, nausea, etc).
4. Live attenuated vaccines within 30 days of durvalumab and tremelimumab dosing (ie, 30 days
prior to the first dose, during treatment with durvalumab and tremelimumab for 30 days post
discontinuation of durvalumab and tremelimumab.
Inactivated vaccines, such as the injectable
influenza vaccine, are permitted.
Table 3. Prohibited and Rescue Medications
Prohibited medication/class of drug
Usage
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Edition Number: 5.0 dated on June 09th, 2021
Additional investigational anticancer therapy concurrent with
those under investigation in this study
Should not be given whilst the patient is on IP treatment
mAbs against CTLA-4, PD-1, or PD-L1
Should not be given whilst the patient is on IP treatment
through 90 days after the last dose of IP.
Any
concurrent
chemotherapy,
local
therapy
(except
palliative
radiotherapy
for
non-target
lesions,
eg,
radiotherapy,
surgery,
radiofrequency
ablation), biologic
therapy, or hormonal therapy for cancer treatment
Should not be given whilst the patient is on IP treatment
(including
SoC).
(Concurrent
use
of
hormones for
non-cancer-related conditions [eg, insulin for diabetes and
hormone replacement therapy] is acceptable.)
Immunosuppressive medications, including, but not limited
to, systemic corticosteroids at doses exceeding 10 mg/day of
prednisone or its equivalent, methotrexate, azathioprine, and
tumor necrosis factor α blockers
Should not be given whilst the patient is on IP treatment
(including SoC).
(Use of immunosuppressive medications
for the management of IP-related AEs or in patients with
contrast allergies is acceptable. In addition, use of inhaled,
topical, and intranasal corticosteroids is permitted.
Live attenuated vaccines
Should not be given through 30 days after the last dose of
IP (including SoC) during the study.
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 after the Protocol Synopsis.
​
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 performed
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Drug Substance DURVALUMAB/TREMELIMUMAB
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Edition Number: 5.0 dated on June 09th, 2021
prior to the signing of the ICF are considered standard of care and 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
●
Review of eligibility criteria
●
Medical history and demographics
●
Complete physical exam
●
ECOG Performance Status
●
Vital signs, weight and height
●
12-lead ECG (in triplicate [2-5 minutes apart])
●
Review of prior/concomitant medications
●
Record any Aes or SAEs (since ICF signature)
●
Imaging by CT/MRI
●
Review of octreoscan/PET (up to 6 months prior inclusion) only on cohorts 1 to 3.
●
Collect blood samples for biomarkers analysis
●
Archival tumor block or slides
●
Clinical laboratory tests for:
◦
Hematology (see Table 4)
◦
Clinical chemistry (see Table 5)
◦
TSH, fT3 and fT4
◦
Coagulation (PT, PTT, INR)
◦
Creatinine Clearance
◦
Serum pregnancy test (for women of childbearing potential only)
◦
Hepatitis and HIV serologies
◦
Urinalysis (see Table 6)
◦
Disease-specific tumor markers
​
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.
Efforts should be made to conduct study visits on the day scheduled (± 1 day). Clinical laboratory
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Edition Number: 5.0 dated on June 09th, 2021
assessments may be conducted anytime within 72 hours prior to the scheduled visit, unless
otherwise specified in the Schedule of Visits and Procedures. Results of the laboratory
assessments should be reviewed always prior each cycle dose administration. Whenever possible,
subjects should be evaluated at approximately the same time of the day (e.g., morning or
afternoon) at each visit, and reasonable efforts should be made to conduct all evaluations in the
same test order at each visit.
Tumor assessments should be performed at time points indicated in the Schedule of Visits and
Procedures.
Cycle 1/Day 1
●
Obtain vital signs (resting BP, HR, RR, body temperature) and weight.
●
Physical examination is not mandatory if performed at baseline (day -1) however a
symptom-directed physical examination will be performed on Cycle 1/Day 1 and at any time
during the study, as clinically indicated.
●
Administer study drug:
◦
Record all concomitant medication use.
◦
Record any AEs or SAEs.
Cycle 1/Day 15
●
Obtain vital signs (resting BP, HR, RR, body temperature) and weight.
●
Evaluate ECOG performance status.
●
Perform a comprehensive physical examination (including a neurological evaluation). A
symptom-directed physical examination will be performed at any time during the study, as
clinically indicated.
●
Collect blood samples for biochemistry and hematology analyses (see Tables 4 and 5),
including TSH, fT3 and fT4.
●
Urinalysis (see  Table 6)
●
Record all concomitant medication use.
●
Record any AEs or SAEs.
Cycle 2/Day 1
●
Evaluate ECOG performance status.
●
Obtain vital signs (supine BP, HR, RR, body temperature) and weight.
●
Perform a comprehensive physical examination (including a neurological evaluation). A
symptom-directed physical examination will be performed at any time during the study, as
clinically indicated.
●
Collect blood samples for biochemistry and hematology analyses (see Tables 4 and 5),
including TSH, fT3 and fT4.
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Drug Substance DURVALUMAB/TREMELIMUMAB
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Edition Number: 5.0 dated on June 09th, 2021
●
Urinalysis (see Table 6)
●
Administer study drug.
●
Collect blood samples for biomarker analysis.
●
Record all concomitant medication use.
●
Record any AEs or SAEs.
●
Record survival data.
Cycle 2/Day 15
●
Evaluate ECOG performance status.
●
Obtain vital signs (supine BP, HR, RR, body temperature) and weight.
●
Perform a comprehensive physical examination (including a neurological evaluation). A
symptom-directed physical examination will be performed at any time during the study, as
clinically indicated.
●
Collect blood samples for biochemistry and hematology analyses (see Tables 4 and 5),
including TSH, fT3 and fT4.
●
Urinalysis (see  Table 6)
●
Record all concomitant medication use.
●
Record any AEs or SAEs.
Cycle 3/Day 1
●
Evaluate ECOG performance status.
●
Obtain vital signs (supine BP, HR, RR, body temperature) and weight.
●
Perform a comprehensive physical examination (including a neurological evaluation). A
symptom-directed physical examination will be performed at any time during the study, as
clinically indicated.
●
Collect blood samples for biochemistry and hematology analyses (see Tables 4 and 5),
including TSH, fT3 and fT4.
●
Urinalysis (see  Table 6)
●
Administer study drugs.
●
Record all concomitant medication use.
●
Record any AEs or SAEs.
●
Record Survival data
Cycle 3/Day 15
●
Evaluate ECOG performance status.
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Drug Substance DURVALUMAB/TREMELIMUMAB
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Edition Number: 5.0 dated on June 09th, 2021
●
Obtain vital signs (supine BP, HR, RR, body temperature) and weight.
●
Perform a comprehensive physical examination (including a neurological evaluation). A
symptom-directed physical examination will be performed at any time during the study, as
clinically indicated.
●
Collect blood samples for biochemistry and hematology analyses (see Tables 4 and 5),
including TSH, fT3 and fT4.
●
Urinalysis (see  Table 6)
●
Record all concomitant medication use.
●
Record any AEs or SAEs.
Cycle 4 Through Last Cycle (cycle 12)/Day 1
●
Evaluate ECOG performance status.
●
Obtain vital signs (supine BP, HR, RR, body temperature) and weight.
●
Perform a comprehensive physical examination (including a neurological evaluation). A
symptom-directed physical examination will be performed at any time during the study, as
clinically indicated.
●
Collect blood samples for biochemistry and hematology analyses (see Tables 4 and 5),
including TSH, fT3 and fT4
●
Urinalysis (see  Table 6)
●
Administer study drugs. (from C5D1 to C12D1 tremelimumab no longer administered, only
durvalumab).
●
Record all concomitant medication use.
●
Record any AEs or SAEs.
●
Record survival data.
●
Tumor assessment every 12 weeks until confirmed PD.
​
8.1.3 End of Treatment
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. For
subjects who discontinue durvalumab or tremelimumab prior to 12 months, 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.
Blood samples for biomarker analysis are collected.
Assessments for subjects who have completed durvalumab and tremelimumab treatment and
achieved disease control, or have discontinued durvalumab or tremelimumab due to toxicity in the
absence of confirmed progressive disease are provided in APPENDIX 2.
Assessments for subjects who have discontinued durvalumab or tremelimumab treatment due to
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Edition Number: 5.0 dated on June 09th, 2021
confirmed PD are presented in APPENDIX 3.
All subjects will be followed for survival until the end of the study regardless of further treatments,
or until the sponsor ends the study.
Follow-up period
TC/MRI every 12 weeks until progression. Monthly visits during the first 3 months after end of
treatment, every 2 months until one year, and therefore every 6 months. Determinations to be done
are listed in appendix 2 and 3.
​
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.
​
8.2.2  Physical examination
Physical examinations will be performed according to the assessment schedule.
Full physical
examinations will include assessments of the head, eyes, ears, nose, and throat and the
respiratory,
cardiovascular,
GI,
urogenital,
musculoskeletal,
neurological,
dermatological,
hematologic/lymphatic, and endocrine systems.
Height will be measured at Screening only.
Targeted physical examinations are to be used by the Investigator on the basis of clinical
observations and symptomatology. Situations in which physical examination results should be
reported as AEs are described in Section 10.
​
8.2.3  Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the
study. ECGs should be obtained after the patient has been in a supine position for 5 minutes and
recorded while the patient remains in that position.
At Screening, a single ECG will be obtained on which QTcF must be <470 ms.
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional
12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm the finding.
Situations in which ECG results should be reported as AEs are described in Section 10.0.
​
8.2.4  Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated
according to the assessment schedules.
On infusion days, patients receiving durvalumab + tremelimumab treatment will be monitored
during and after infusion of IP as presented in the bulleted list below.
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Edition Number: 5.0 dated on June 09th, 2021
Supine BP will be measured using a semi-automatic BP recording device with an appropriate cuff
size, after the patient has rested for at least 5 minutes.
BP and pulse will be collected from
patients receiving durvalumab + tremelimumab treatment before, during, and after each infusion at
the following times (based on a 60-minute infusion):
Prior to the beginning of the infusion (measured once from approximately 30 minutes before up to
0 minutes [ie, the beginning of the infusion]).
Approximately 30 minutes during the infusion (halfway through infusion).
At the end of the infusion (approximately 60 minutes ±5 minutes).
A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab.
If no clinically significant infusion reactions are observed during or after the first cycle, subsequent
infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after
each durvalumab and tremelimumab infusion).
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the
principles as described above or be taken more frequently if clinically indicated. The date and time
of collection and measurement will be recorded on the appropriate eCRF. Additional monitoring
with assessment of vital signs is at the discretion of the Investigator per standard clinical practice
or as clinically indicated.
Body weight is also recorded along with vital signs.
Situations in which vital signs results should be reported as AEs are described in Section 10.3. A
complete physical examination will be performed and will include an assessment of the following
(as clinically indicated): general appearance, respiratory, cardiovascular, abdominal, skin, head
and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including
spine and extremities), genital/rectal, and neurological systems and at screening only, height.
​
8.2.5   Clinical laboratory tests
The following clinical laboratory tests will be performed in local hospitals (see the Schedule of
Assessments):
●
Coagulation parameters: Activated partial thromboplastin time and International normalised
ratio to be assessed at baseline and as clinically indicated
●
Pregnancy test (female subjects of childbearing potential only)
◦
Urine human chorionic gonadotropin
◦
Serum beta-human chorionic gonadotropin (at screening only)
●
Thyroid Stimulating Hormone
◦
Free T3 and free T4 only if TSH is abnormal
●
Other laboratory tests
◦
Hepatitis B surface antigen, hepatitis C antibody
◦
HIV antibody
Table 4. Hematology Laboratory Tests
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Basophils
Eosinophils
Hematocrit
Hemoglobin
Lymphocytes
Mean corpuscular volume
Monocytes
Neutrophils
Platelet count
Red blood cell count
Total white cell count
Mean corpuscular
hemoglobin concentration
Mean corpuscular
hemoglobin
Table 5. Clinical chemistry (Serum or Plasma) Laboratory Tests
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipase
Amylase
Magnesium
Aspartate aminotransferase
NSE (Enolase)
Bicarbonate
Potassium
Calcium
Sodium
CgA (Chromogranine)
Total bilirubina
Chloride
Total protein
Creatinine
Urea or blood urea nitrogen, depending on local
practice
Gamma glutamyltransferaseb
Uric acid
a If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fraction into direct and indirect bilirubin
b At baseline and as clinically indicated.
Table 6. Urinalysis Tests a
Bilirubin
pH
Blood
Protein
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Edition Number: 5.0 dated on June 09th, 2021
Glucose
Specific gravity
Ketones
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
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Edition Number: 5.0 dated on June 09th, 2021
​
8.3
Biological sampling procedures
Blood samples for the development of exploratory predictive biomarkers will be collected from all
subjects prior to the first dose of study drug, and on Cycle 2/Day 1 and at end-of treatment visit or
after documented disease progression, whichever occurs first. Biomarker discovery and validation
will be performed to identify blood or tumor biomarkers which may be useful to predict subject
response, as determined by evaluation of primary or secondary efficacy endpoints. Plasma
samples from study subjects will undergo global proteomic and/or enzyme-linked immunosorbent
assay (ELISA)-based analyses or multiplex bead-based immunoassay in an effort to identify
protein biomarkers. In addition, DNA and RNA analyses will be performed in search of predictive or
prognostic biomarkers and also biomarkers identified in other durvalumab+trametinib clinical
studies may also be assessed in samples collected from subjects enrolled in this study.
Archived, fixed tumor tissue from will be collected for all subjects for confirmation of histology and
assessment of somatic mutations of genes which may be important in the development and
progression
of
neuroendocrine
tumors.
Gene-expression
profiling
(GEP),
proteomic,
or
immunohistochemical (IHC) analysis will be performed based on the amount of tumor tissue
available for analysis. All analyses will be limited to correlations relevant to neuroendocrine tumors
and clinical outcomes related to treatment with durvalumab and tremelimumab.
Blood and tumor samples collected during the study will be stored at the study sites until the initial
primary efficacy and safety analyses of the study will be completed and results will be available.
Then,
the
study
Sponsor
will
decide
whether
to
perform
all
or
part
of
the
pharmacogenetic/pharmacogenomics assessments.
Data obtained will only be used for research, to assist in developing safer and more effective
treatments, and will not be used to change the diagnosis of the subject or alter the therapy of the
subject. Any DNA derived from the sample may be stored for up to 15 years to assist in any
research scientific questions related to durvalumab or tremelimumab. Sample collection will be
registered in Spanish National Registry and will be used in research projects in the particular
research line foresee in the informed consent. Samples cannot be transferred to third parties, and
studies in the future with these samples will require EC approval. Instructions for the processing,
storage, and shipping of samples will be provided in the Laboratory Manual.
​
8.3.1  Biomarker/Pharmacodynamic sampling and evaluation methods
PD-L1 Testing
Retrospectively, PD-L1 assessment will be performed using Ventana SP263 assay in accordance
with the package insert on the Ventana Benchmark platform (Ultra or XT) within the GETNE
translational working group to ensure comparability of data across all studies of durvalumab and/or
tremelimumab.
Sample collection for PD-L1 testing
●
The preferred tumor sample for the determination of a patient’s PD-L1 status is the one
taken following the completion of the most recent prior line of therapy. Samples taken at
this time reflect the current PD-L1 status of the tumor and considered clinically most
relevant.
●
The preferred sample for PD-L1 testing was less than or equal to 3 months old. In cases
where a sample a less than 3 months old was not available, patients were asked to
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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. The provision of 2 cores is advised in order to provide
sufficient tissue for PD-L1 assessment and processed to FFPE in a single block. 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 PD-L1 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 5 years of age. When archival samples
are used to assess PD-L1 status, the age of the sample / date of collection should be
captured.
●
Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin.
Samples from fine needle aspirates (FNA) or decalcified bone are not appropriate for
PD-L1 analysis.
Sample data collection for PD-L1 testing
The following fields of data should be collected from the site/institution collecting and if, indicated
shipping of the samples:
Patient identifier (e-code or unique identifier)
●
Specimen identifier (written on the specimen)
●
Site identifier
●
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 PD-L1 testing laboratory:
●
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
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●
PD-L1 status (positive, negative or NA) in tumor cells
●
Total percent positivity of PD-L1 in infiltrating immune cells
Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing.
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 PD-L1
testing and they are used within 90 days of being cut to obtain PD-L1 status
​
8.3.2  Estimate of volume of blood to be collected
The total of two blood samples will be drawn from each subject in this study (at baseline, C2D1,
end of treatment/progression) will be managed according the laboratory manual and stored -80ºC
(-20ºC if not available) in the investigators centers. At the end of the study treatment period and
follow-up up, and regarding results obtained, the sponsor and investigators will decide if biomarker
analyses will be performed.
​
8.3.3  Archival tumor samples
8.3.3.1  Archival tumor samples
Archival tumor samples in formalin-fixed paraffin-embedded tissue block will be identified at
screening period. Samples will only be used at the end of the study treatment and always
regarding results obtained with the investigational drugs.
8.3.4  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.
Participation in biological samples analyses are optional, and patients can participate in the study
without giving the consent to use their biological samples.
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.
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Edition Number: 5.0 dated on June 09th, 2021
9.
DISEASE EVALUATION AND METHODS
Primary Objective
Disease evaluation according RECIST 1.1.
A copy of the RECIST 1.1 guideline will be included in the ISF.
RECIST 1.1 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 + tremelimumab would continue between the initial
assessment of progression and confirmation for progression.
Secondary objectives (irRECIST)
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
●
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 1.1 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 + tremelimumab would
continue between the initial assessment of progression and confirmation for progression.
●
In addition, subjects may continue to receive durvalumab + tremelimumab beyond
confirmed PD in the absence of clinically significant deterioration and if investigators
consider that subjects continue to receive benefit from treatment.
Progression would be considered confirmed if the following criteria are met:
●
≥20% increase in the sum diameters of target lesions compared with the nadir at 2
consecutive visits with an absolute increase of 5 mm, and/or
●
Clinically significant progression (worsening) of non-target lesions or new lesions at the
confirmatory PD time point compared with the first time point where progression of
non-target lesions or new lesions was identified, and/or
●
Additional new unequivocal lesions at the confirmatory PD time point compared with the
first time point at which new lesions were identified.
In the absence of clinically significant deterioration, the Investigator should continue study
treatment until progression is confirmed.
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Edition Number: 5.0 dated on June 09th, 2021
If progression is not confirmed, then the patient should continue on study treatment and on
treatment assessments.
Modification of RECIST as described may discourage the early discontinuation of durvalumab +
tremelimumab 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 + tremelimumab 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
Efficacy variable
The RECIST 1.1 criteria will be used to assess patient response to treatment by determining
progression-free survival rates at 6, 9 and 12 months, median progression-free survival, overall
response rate and median overall survival using Investigator assessments. The management of
patients will be based in part upon the results of the RECIST 1.1 assessment conducted by the
Investigator.
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
Safety Parameters
​
10.1.1  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,
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 pre planned 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
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Edition Number: 5.0 dated on June 09th, 2021
from baseline, is not considered an AE (serious or non serious). An untoward medical event
occurring during the pre scheduled 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:
1- Results in death
2- Is immediately life-threatening
3- Requires inpatient hospitalization or prolongation of existing hospitalization
4- Results in persistent or significant disability or incapacity
5- Is a congenital abnormality or birth defect in offspring of the subject
6- Is an important medical event that may jeopardize the patient or may require medical
intervention to prevent one of the outcomes listed above:
7- 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 the sponsor.
​
10.1.3
Durvalumab + tremelimumab adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to
understanding of the Investigational Product and may require close monitoring 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. A report is required
using the SAE form, indicating an event of special interest.
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential
inflammatory or immune-mediated mechanism and which may require more frequent monitoring
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy.
These AESIs 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 alternative 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.
Events with an inflammatory or immune mediated mechanism could occur in nearly all organs.
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Potential risks with an immune-mediated aetiology that are rare or less frequent include, but are
not limited to, Guillain-Barre Syndrome, myasthenia gravis, pericarditis, sarcoidosis, uveitis, and
other events involving the eye (eg, keratitis and optic neuritis), skin (eg, scleroderma, vitiligo and
pemphigoid), haematological (eg, haemolytic anaemia and immune thrombocytopenic purpura),
rheumatological
events
(polymyalgia
rheumatic
and
autoimmune
arthritis),
vasculitis,
non-infectious meningitis and non-infectious encephalitis.
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 and tremelimumab include:
●
●
Diarrhea / Colitis and intestinal perforation
●
Pneumonitis / ILD
●
hepatitis / transaminase increases
●
Endocrinopathies
(i.e.
events
of
hypophysitis/hypopituitarism,
thyroiditis,
adrenal
insufficiency, hyper- and hypothyroidism and type I diabetes mellitus)
●
Rash / Dermatitis
●
Nephritis / Blood creatinine increases
●
Pancreatitis / serum lipase and amylase increases
●
Myocarditis
●
Myositis / Polymyositis
●
Intestinal Perforations
●
Other inflammatory responses that are rare/less frequent with a potential immune-mediated
etiology include, but are not limited to:
●
Pericarditis
●
Neuromuscular toxicities (such as Guillain-Barre syndrome and myasthenia gravis)
●
Sarcoidosis
●
Uveitis
●
Other events involving the eye and skin
●
Hematological events
●
Rheumatological events
●
Vasculitis
●
Non-infectious meningitis
●
Non-infectious encephalitis.
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Edition Number: 5.0 dated on June 09th, 2021
It is possible that events with an inflammatory or immune mediated mechanism could occur in
nearly all organs.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different
underlying pharmacological etiology are also considered AESIs.
Further information on these risks (e.g. presenting symptoms) can be found in the current version
of the durvalumab and tremelimumab Investigator Brochure.
Guidelines for the management of patients with immune-related AEs (irAEs) are provided in
Appendix 1. In addition to the dose modification guidelines provided in Appendix 1, it is
recommended that irAEs are managed according to the general treatment guidelines outlined for
ipilimumab (Weber et al, 2012).  These guidelines recommend the following:
●
Patients should be evaluated to identify any alternative etiology.
●
In the absence of a clear alternative etiology, all events of an inflammatory nature should be
considered immune related.
●
Symptomatic and topical therapy should be considered for low-grade events.
●
Systemic corticosteroids should be considered for a persistent low-grade event or for a
severe event.
●
More potent immunosuppressives should be considered for events not responding to
systemic steroids (eg, infliximab or mycophenolate).
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should
immediately contact the Study Physician.
Infusion reactions
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to
AstraZeneca and are defined, for the purpose of this protocol, as all AEs occurring from the start of
IP infusion up to 48 hours after the infusion start time. For all infusion reactions, SAEs should be
reported to the sponsor as described in Section 10.3.
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 (IgE-mediated) and anaphylactoid reactions against the
mAbs 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 the
management of patients with hypersensitivity (including anaphylactic reaction) and infusion-related
reactions are provided in Appendix 1.
Hepatic function abnormalities (hepatotoxicity)
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
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Edition Number: 5.0 dated on June 09th, 2021
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 (eg, cholelithiasis and bile duct obstruction with distended
gallbladder) or an agent other than the IP.
Guidelines for management of patients with hepatic
function abnormality are provided in section 10.3.3.2.
For the consultation of the complete list of adverse events see the last version of IB provided in the
ISF.
​
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 9.2.1. 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.
​
10.2.2   Assessment of relationship
Relationship of adverse events with study drugs will be assessed by investigators based on toxicity
profile described for each study drug (see investigator brochure).
​
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 and not later than 24 h, to the Sponsor.
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Edition Number: 5.0 dated on June 09th, 2021
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 or tremelimumab (yes or no)
●
Action taken with regard to durvalumab + tremelimumab
●
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 + tremelimumab).
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
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Edition Number: 5.0 dated on June 09th, 2021
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.
The sponsor and AstraZeneca/MedImmune retain 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 + tremelimumab.
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, who will
inform 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).. Sponsor is responsible for informing the Health Authorities of the
SAE as per local requirements.
After the initial notification of an AE or SAE, the investigator is required to follow up each case and
obtain more data on the patient’s state. All the AEs and SAEs documented in previous visits must
be reviewed in subsequent visits. All AEs and SAEs must be monitored until their resolution,
stabilization, explanation of the event by another cause, or until the follow-up period ends. This is
applicable to all the patients, including those who withdraw early.
The investigator will include in the follow-up any additional research that may clarify the nature
and/or causality of the AE or SAE. This might include additional laboratory tests or studies,
histopathologic
examinations,
or
the
consultation
of
other
healthcare
professionals.
Any
co-investigator can ask the investigator to carry out additional evaluations to definitively clarify the
nature and/or the causality of AEs or SAEs. If the patient dies while participating in the study or
during a follow-up period agreed upon mutually, the investigator will provide a copy of any
postmortem finding requested, including histopathology.
The sponsor is responsible for notifying all serious or unexpected AEs potentially related to the
treatments being investigated that occur during the study to the AEMPS, competent bodies of the
autonomous communities where the clinical trial is being conducted within the time frame
established by Spanish law and will concurrently forward all such reports to AstraZeneca. A copy
of the SAE report must be sent by e-mail to AstraZeneca at the time the event is reported to the
Health Authorities (AEMailboxClinicalTrialTCS@astrazeneca.com). It is the responsibility of the
sponsor to compile all necessary information and ensure that the Health Authorities receives a
report according to the reporting requirement timelines and to ensure that these reports are also
submitted to AstraZeneca at the same time.
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Edition Number: 5.0 dated on June 09th, 2021
SAE report and accompanying cover page will be sent by way of email to
DEPARTAMENTO DE INVESTIGACIÓN, MFAR Clinical Research.
Fax: +34 93 253 11 68
Email: investigacion@mfar.net
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Edition Number: 5.0 dated on June 09th, 2021
If a non-serious AE becomes serious, this and other relevant follow-up information must also be
provided to AstraZeneca and the Health Authorities.
Serious adverse events that do not require expedited reporting to the 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.
10.3.2.1   Reporting of deaths
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of
durvalumab + tremelimumab 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.
●
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.
​
10.3.3  Other events requiring reporting
10.3.3.1  Overdose
An overdose is defined as a subject receiving a dose of durvalumab + tremelimumab in excess of
that specified in the Investigator’s Brochure, unless otherwise specified in this protocol.
Any overdose of a study subject with durvalumab + tremelimumab, with or without associated
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the sponsor
,who will send a copy to AstraZeneca/MedImmune Patient Safety, or designed 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 10.3 and Section 10.3.2). There is currently no specific treatment in the event of
an overdose of durvalumab or tremelimumab.
The investigator will use clinical judgment to treat any overdose.
10.3.3.2  Hepatic function abnormality
Hepatic function abnormality (as defined in Section 10.1.3.) 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
,who
will
send
a
copy
to
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.,
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cholelithiasis or bile duct obstruction) that is unrelated to investigational product has been
confirmed.
●
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.
Grade 1-2 events should be considered AEs, not SAEs. However, Grade 1-2 events should be
reported as SAEs if requires hospitalization or if they are medically important events based on the
investigator judgement.
Grade 3 events, should be reported as SAE if requires hospitalization or if they are medically
important events based on the investigator judgement.
All grade 4 events should be reported as SAEs.
Cases where a patient shows elevations in liver biochemistry may require further evaluation and
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be
reported as SAEs.
Each reported event of hepatic function abnormality will be followed by the investigator and
evaluated by the sponsor.
10.3.3.3   Pregnancy
a) 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 sponsor representatives within 1 day, ie, immediately, but no later
than 24 hours of when he or she becomes aware of it.
The designated sponsor representative will work with the Investigator to ensure that all relevant
information is provided to the sponsor, who will inform AstraZeneca Patient Safety data entry site.
The same timelines apply when outcome information is available.
b) Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 180
days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the
last dose of durvalumab monotherapy, whichever is the longer time period.
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Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose
should, if possible, be followed up and documented.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the
Investigator must obtain the consent of the patient’s partner.
Therefore, the local study team
should adopt the generic ICF template in line with local procedures and submit it to the relevant
Ethics Committees (ECs) prior to use.
11.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION
​
11.1.
Description of analysis sets
The statistical analyses described in this section will be performed as further outlined in the
Statistical Analysis Plan, which will be included in the clinical study report for this protocol.
Analysis Sets
The analysis sets will be defined as follows:
●
Full Analysis Set will include all allocated subjects. This will be primary analysis set for the
efficacy endpoints.
●
Per Protocol Analysis Set will include those subjects who were allocated and received at
least one dose of the assigned study drug and had no major protocol deviations. The
subjects will complete both baseline and at least one post-baseline tumor assessments
(week 12).
●
Safety Analysis Set will include all subjects who were allocated and received at least one
dose of the study drug and had at least one post-baseline safety evaluation (week 12). This
will be the analysis set for all safety evaluations.
●
Pharmacodynamic Analysis Set: All the subjects who have received at least one dose of
study drug and have evaluable pharmacodynamic data.
Demographic and other baseline characteristics
Demographic and other baseline characteristics will be summarized and listed. For continuous
demographic/baseline variables including age, weight, and vital signs, results will be summarized
and presented as n, number of not available data (NA), mean, standard deviation, median, and
minimum and maximum values. For categorical variables such as race/ethnicity, the number and
percentage of subjects will be used.
Prior and concomitant medications
Concomitant medications will be assigned an 11-digit code using the World Health Organization
Drug Dictionary (WHO DD) drug codes. Concomitant medications will be further coded to the
appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic classification.
Prior and concomitant medications will be summarized and listed by drug and drug class.
Efficacy Analyses
All efficacy analyses will be based primarily on the Full Analysis Set and secondarily on the Per
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Protocol Analysis Set.
Data cut-off for the primary study analysis will happen following after the last patient included in the
study has performed the first tumor evaluation (week 12 after first dose of study drug).The
following tumor evaluations will take place every 12 weeks until documentation of disease
progression or start of another anticancer therapy.
Analysis of primary efficacy variable
The analysis of clinical benefit rate and overall survival rate will be performed independently for
each study cohort when the last patient included in the corresponding cohort of the study will
arrived to 9 months after inclusion in the study or have progressed. The primary objective of the
study will be based on the investigator assessment.
​
11.2.
Methods of statistical analyses
Strategic decisions about future development of immune therapy in neuroendocrine tumors will be
available after the results of this trial.
Summary tables (descriptive statistics and frequency tables) will be provided for all baseline
variables, efficacy variables, and safety variables, as appropriate. Continuous variables will be
summarized with descriptive statistics (mean, standard deviation, range, and median). Ninety-five
(95) percent confidence intervals (95% CI) may also be presented, as appropriate. Frequency
counts and percentage of subjects within each category will be provided for categorical data.
The primary efficacy analysis will be performed using the binomial test procedure. Missing data will
be treated using statistical multiple random imputation.
Secondary endpoints will be summarized with descriptive statistics. Continuous variables will be
summarized with n, mean, standard deviation, and range, frequency counts and percentage of
subjects within each category will be provided for categorical data. Multivariate regression models
will be used to study relations between explanatory variables and primary endpoint. Survival
analysis will be performed to analyze PFS, Kaplan-Meier curves will be presented and possible
comparisons will be tested using the log-rank test or the Cox proportional hazard model for
multivariate analysis, hazard ratios (HR) and their 95% confidence interval (CI95%) will be
provided. Patients with lost of follow-up or treatment discontinuation will be included in the final
analysis of primary endpoint if they have at least one tumor evaluation and considered as censored
data for survival endpoints.
R software version 3.2.1 will be used for all analysis.
Safety Analyses
Safety analyses will be based on the Safety Analysis Set. All safety analyses will be summarized
separately by cohort. Adverse events and serious adverse events, laboratory test results, physical
examination findings and vital signs, and their changes from baseline will be summarized using
descriptive statistics. Abnormal values will be flagged.
​
11.3.
Determination of sample size
Sample size has been calculated using one-sample Superiority test (function One Sample
Proportion. NIS of the Trial Size package of R software). According to previous knowledge, it is
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estimated that the reference value for the likelihood to be progression-free at 9 months is 30% and
we expect an increase of 20% with a superiority margin of 10%. With a unilateral alpha level of 5%
and 80% power, we estimate to include 28 patients per group, with an expected lost to follow-up
rate of 10%, a final sample size in each 1, 2 and 3 cohort will include 31 patients.
For cohort 4, and according to previous knowledge, it is estimated that the reference proportion of
patients being alive at 9 months is 13% and we expect an increase of 10% with a superiority
margin of 5%. With a unilateral alpha level of 5% and 80% power, we estimate to include 30
patients per group, with an expected lost to follow-up rate of 10%, a final sample size will include
33 patients. Summarizing, total sample size will include 126 patients: 31 patients for cohorts 1 to 3,
and 33 patients for cohort 4.
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 including those related to Subject data protection.
​
12.2.
Ethics and regulatory review
The protocol, ICF, and appropriate related documents must be reviewed and approved by an EC
constituted and functioning in accordance with ICH E6, Section 3, and any local regulations,. Any
protocol amendment and/or revision to the ICF will be resubmitted to the EC for review and
approval, except for changes involving only logistical or administrative aspects of the study (e.g.,
change in CRA[s] or change of telephone number[s]). Documentation of EC compliance with ICH
and any local regulations regarding constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the EC Chairman must be obtained prior to study start and
the release of any study drug to the site by the sponsor or its designee. If the EC decides to
suspend or terminate the study, the sponsor will immediately send the notice of study suspension
or termination by the EC to the investigators. Study progress is to be reported to the EC annually
(or as required) by the sponsor. If the investigator is required to report to the EC, he/she will
forward a copy to the sponsor at the time of each periodic report. The sponsor will submit periodic
reports and inform the EC of any reportable adverse events according to local legislation. Upon
completion of the study, the investigator will provide the EC with a brief report of the outcome of the
study, if required.
​
12.3.
Informed consent
As part of administering the informed consent document, the investigator must explain to each
subject (or guardian/legally authorized representative) the nature of the study, its purpose, the
procedures involved, the expected duration, the
potential risks and benefits involved, and any
potential discomfort. Each subject must be informed that participation in the study is voluntary and
that he/she may withdraw from the study at any time and that withdrawal of consent will not affect
his/her subsequent medical treatment or relationship with the treating physician. This informed
consent should be given by means of a standard written statement, written in non-technical
language. The subject should understand the statement before signing and dating it and will be
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given a copy of the signed document. If a subject is unable to read or if a legally acceptable
representative is unable to read, an impartial witness should be present during the entire informed
consent discussion. After the written informed consent form and any other written information to be
provided to subjects is read and explained to the subject or the subject’s legally acceptable
representative, and after the subject or the subject’s legally acceptable representative has orally
consented to the subject’s participation in the trial and, if capable of doing so, has signed and
personally dated the ICF, the witness should sign and personally date the consent form. The
subject will be asked to sign an informed consent at the Screening Visit prior to any study-specific
procedures being performed. No subject can enter the study before his/her informed consent has
been obtained. The form must be signed and dated by the appropriate parties. The original, signed
ICF for each subject will be verified by the sponsor and kept on file, according to local procedure,
at the study center.
The subject or the subject’s legally authorized representative should be informed in a timely
manner if new information becomes available that may be relevant to the subject’s willingness to
continue participation in the trial. The communication of this information should be documented.
​
12.4.
Changes to the protocol and informed consent form
There are to be no changes to the protocol without written approval from the sponsor. Protocols will
be followed as written. Any change to the protocol requires a written protocol amendment or
administrative change that must be approved by the sponsor before implementation. Amendments
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the study
require submission to Health Authorities as well as additional approval by the EC. These
requirements should in no way prevent any immediate action from being taken by the investigator,
or by the sponsor, in the interest of preserving the safety of all subjects included in the study. If an
immediate change to the protocol is felt by the investigator to be necessary for safety reasons, the
sponsor’s appropriate study team member must be notified promptly and the EC for the site must
be informed immediately. A protocol change intended to eliminate an immediate hazard may be
implemented immediately, provided that the Health Authorities and EC are subsequently notified by
protocol amendment.
Changes affecting only administrative aspects of the study do not require formal protocol
amendments or EC approval, but the EC (if regionally required, the heads of the medical
institutions) must be kept informed of such changes. In these cases, the sponsor will send a letter
to the EC (if regionally required, the heads of the medical institutions) detailing such changes.
​
12.5.
Audits and inspections
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance department
conducts audits of clinical research activities in accordance with the sponsor’s Standard Operating
Procedures (SOPs) to evaluate compliance with the principles of ICH GCP and all applicable local
regulations. A government regulatory authority may also wish to conduct an inspection (during the
study or after its completion). If an inspection is requested by a regulatory authority, the investigator
must inform the sponsor immediately that this request has been made.
​
12.6.
Confidentiality
The contents of this protocol and any amendments and results obtained during the course of this
study will be kept confidential by the investigator, the investigator’s staff, and the EC and will not be
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disclosed in whole or in part to others or used for any purpose other than reviewing or performing
the study without the written consent of the sponsor. No data collected as part of this study will be
utilized in any written work, including publications, without the written consent of the sponsor.
These obligations of confidentiality and non-use shall in no way diminish such obligations as set
forth in the Confidentiality Agreement between the sponsor and the investigator.
All persons assisting in the performance of this study must be bound by the obligations of
confidentiality and non-use set forth in the Confidentiality Agreement between the investigator and
sponsor (provided by the sponsor).
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner
designed to maintain subject confidentiality. Each patient will be given a Unique Patient Number
(UPN) for this study, provided by the Sponsor. The investigator will custody a log matching the
UPN with personal data of patients. All data will be recorded i the appropriate CRFs using this
identification number. This number will be provided to the central laboratory to ensure traceability
of study samples. Each Investigator will ensure that all site personnel involved will respect the
confidentiality of any information about trial subjects. Management of personal data from subjects
participating in the trial, particularly as regards consent, will comply with European Directive on
Data Privacy (2016/679) and the Spanish Organic Law 3/2018 of 5th December on the protection
of personal data.
At each site, all records will be kept in a secure storage area with limited access.
Clinical
information will not be released without the written permission of the subject. Subject identity is
confidential and may only be known by the Investigator, trial personnel, appointed auditors and
monitors, and Health Authorities.
Each Investigator and all employees and coworkers involved with this trial may not disclose or use
for any purpose other than performance of the trial, any data, record, or other unpublished,
confidential information disclosed to those individuals for the purpose of the trial. Prior written
agreement from the sponsor or its designee must be collected for the disclosure of any said
confidential information to other parties.
​
12.7.
Insurance
The sponsor has contracted 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: CHUBB Insurance Company of Europe SE.
Policy Number: 9950243799502437
​
12.8.
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
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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.
​
13.2.
Monitoring of the study
The sponsor’s or representative (e.g., CRO’s CRA) will maintain contact with the investigator and
designated staff by telephone, and/or letter, and/or email between study visits. Monitoring visits to
each investigational site will be conducted by the assigned CRA as described in the monitoring
plan. The investigator (if regionally required, the heads of the medical institutions) will allow the
CRA to inspect the clinical, laboratory, and pharmacy facilities to assure compliance with Good
Clinical Practices and local regulatory requirements. The eCRFs and subject’s corresponding
original medical records (source documents) are to be fully available for review by the sponsor’s
representatives at regular intervals. These reviews verify adherence to the study protocol and data
accuracy in accordance with federal regulations. All records at the investigational site, including
source documents, are subject to inspection by the regulatory authorities and to review by the
Ethical Committee.
​
13.3.
Source data
In accordance with ICH E6, Section 6.10, source documents include but are not limited to the
following:
●
Clinic, office, hospital charts;
●
Copies or transcribed healthcare provider notes which have been certified for accuracy
after production;
●
Recorded data from automated instruments such as x-rays, and other imaging reports:
e.g.,
sonograms,
CT scans, MRIs, nuclear medicine scans, ECGs, rhythm strips,
electroencephalograms
(EEGs),
polysomnography,
and
pulmonary
function
tests
(regardless of how these images are stored, including microfiche and photographic
negatives);
●
Records of telephone contacts;
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●
Drug distribution and accountability logs maintained in pharmacies or by research
personnel;
●
Laboratory results and other laboratory test outputs: e.g., urine pregnancy test result
documentation;
●
Correspondence regarding a study subject’s treatment between physicians or memoranda
sent to the EC;
​
13.4.
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the investigator (if
regionally required, the heads of the medical institutions) has the responsibility to retain all study
documents, including but not limited to the protocol, the Investigator's Brochure, regulatory agency
registration documents, ICFs, and EC correspondence. The investigational site should retain study
documents until at least 25 years after the finalization of the study.
It is requested that at the completion of the required retention period or, should the investigator
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of
permanently retaining the study records.
​
13.5.
Quality assurance
This study will be organized, performed, and reported in compliance with the protocol, standard
operating
practices
(SOPs),
working
practice
documents,
and applicable regulations and
guidelines. Site visit audits will be made periodically by the sponsor’s or CRO’s qualified
compliance auditing team, which is an independent function from the study conduct team.
​
13.6.
Study timetable and end of study
End of study is defined as Last Subject Last Visit.
●
Recruitment period will be:
33 months
●
Research Agreement executed:
Nov 2016
●
Projected IRB/IEC approval:
Feb 2017
●
First Subject In:
Apr 2017
●
50% Enrollment:
Dec 2017
●
Last Subject In (100% enrollment):
Dec 2019
●
Last Subject Last Visit:
Dec 2021
●
Clinical Study Report
Dec 2022
14.
DATA MANAGEMENT
All software applications used in the collection and validation of data must be properly validated
following
standard
computer
system
validation
and
must
be
compliant
to all regulatory
requirements.
The Data Management Plan (DMP) defines and documents the procedures necessary to ensure
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data quality. These activities must be followed to ensure data are properly entered, validated,
coded, integrated, reconciled and reviewed.
Data required by the protocol are collected on an electronic Case Report Form (eCRF) and
entered
into
a
validated
data
management
system which is compliant to all regulatory
requirements. As defined by ICH Guidelines, the Case Report Form (CRF) is a printed, optical, or
electronic document designed to record all of the protocol required information to be reported to
the sponsor on each trial subject’. In this study, CRF should refer to electronic data collection form.
Data collected on the CRF must follow the instructions described in the CRF Completion
Guidelines. The Investigator has ultimate responsibility for the collection and reporting of all
clinical, safety and laboratory data entered on the CRF.
Any corrections to entries made on the CRF must be documented in a valid audit trail where the
corrections must be dated, initialed, the reason for change stated, and original data not obscured.
Only data required by the protocol for the purposes of the study should be collected.
The primary objective of the study will be clinical benefit rate at 9 months and survival rate at 9
months by investigator. Images of tumor evaluations will be anonymized correctly identified with
trial number patient. 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.
15.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
​
15.1.
Identity of investigational product(s)
Table 7. List of investigational products for this study
Investigational product
Dosage form and strength
Manufacturer
Durvalumab
1500 mg, solution, IV
MedImmune
Tremelimumab
75 mg, solution, IV
MedImmune
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16.
LIST OF REFERENCES
Andorsky et al 2011
Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, and Timmerman JM.
Programmed
death
ligand
1
is
expressed
by
non-hodgkin
lymphomas
and
inhibits
the
activity
of
tumor-associated T cells.  Clin Cancer Res. 2011. 17(13):4232-4244
Antonia et al 2014b
Antonia S, Ou SI, Khleif SN, Brahmer J, Blake-Haskins A, Robbins PB, et al. Clinical activity and
safety of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody in patients with
NSCLC. Poster presented at the European Society for Medical Oncology (ESMO) Meeting; 2014
Sep 26-30; Madrid, Spain.
Antonia et al 2014a
Antonia S, Goldberg S, Balmanoukian A, Narwal R, Robbins P, D’Angelo G, et al. A Phase 1
open-label study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell
death-ligand 1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced
non-small cell lung cancer (NSCLC). Poster presented at European Society of Medical Oncology
(ESMO) Meeting; 2014 Sep 26-30; Madrid, Spain.
Antonia et al 2015
Antonia et al.
Phase ib study of medi4736 in combination with treme in patients with advanced
NSCLC.  Chicago, Il ASCO May30-June4,ASCO 2015, poster #3014.
Berry et al 1991
Berry G, Kitchin RM, Mock PA. A comparison of 2 simple hazard ratio estimators based on the log
rank test. Stat Med 1991;10(5):749-55.
Bograd et al 2011
Bograd AJ, Suzuki K, Vertes E, Colovos C, Morales EA, Sadelain M, et al. Immune responses and
immunotherapeutic interventions in malignant pleural mesothelioma. Cancer Immunol Immunother.
2011;60:1509-27.
Bonomi 2010
Bonomi
PD.
Implications
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Appendix
1.Dosing
Modification
and
Toxicity
Management
Guidelines
(TMGs)
for
Durvalumab
Monotherapy,
Durvalumab
in
Combination
with
other
Products,
or
Tremelimumab Monotherapy. 17 November 2020.
Note: Annex is to be used in any clinical trial protocol within which patients are treated with
Durvalumab Monotherapy, Durvalumab in Combination with other Products, or Tremelimumab
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1.
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1.
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General Considerations Regarding Immune-Mediated Reactions
General Considerations Regarding Immune-Mediated Reactions
These guidelines are provided as a recommendation to support investigators in the management of potential
immune-mediated adverse events (imAEs).
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all
the possible immune-mediated reactions. Investigators are advised to take into consideration the appropriate
practice guidelines and other society guidelines (e.g., NCCN, ESMO) in the management of these events.  Refer
to the section of the table titled “Other -Immune-Mediated Reactions” for general guidance on imAEs not noted
in the “Specific Immune-Mediated Reactions” section.
Early identification and management of immune-mediated adverse events (imAEs) are essential to ensure safe
use of the study drug.  Monitor patients closely for symptoms and signs that may be clinical manifestations of
underlying immune-mediated adverse events. Patients with suspected imAEs  should be thoroughly evaluated to
rule out any alternative etiologies (e.g., disease progression, concomitant medications, infections). In the absence
of a clear alternative etiology, all such events should be managed as if they were immune-mediated.  Institute
medical management promptly, including specialty consultation as appropriate. In general, withhold study
drug/study regimen  for severe (Grade 3) imAEs. Permanently discontinue study drug/study regimen for
life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic immunosuppressive
treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day
within 12 weeks of initiating corticosteroids.
Based on the severity of the imAE, durvalumab should be withheld and corticosteroids administered. Upon
improvement to Grade ≤ 1, corticosteroid should be tapered over ≥ 28 days.  More potent immunosuppressive
agents such as TNF inhibitors (e.g., infliximab) should be considered for events not responding to systemic
steroids. Alternative immunosuppressive agents not listed in this guideline may be considered at the discretion of
the investigator based on clinical practice and relevant guidelines. 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.
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities
graded per NCI CTCAE version in the applicable study protocol.
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events;
imAE immune-mediated adverse event; NCI National Cancer Institute; NCCN  National Comprehensive Cancer
Network; ESMO European Society for Medical Oncology
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Pediatric Considerations Regarding Immune-Mediated Reactions
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 of initiating corticosteroids.
−         All recommendations for specialist consultation
should occur with a pediatric specialist in the
specialty recommended.
−         The recommendations for steroid dosing (i.e.,
mg/kg/day) provided for adult patients should
also be used for pediatric patients.
−         The recommendations for IVIG and
plasmapheresis use provided for adult patients
may be considered for pediatric patients.
−         The infliximab 5 mg/kg IV one time dose
recommended for adults is the same as
recommended for pediatric patients ≥ 6 years old.
For subsequent dosing and dosing in children < 6
years old, consult a pediatric specialist.
−         For pediatric dosing of mycophenolate mofetil,
consult 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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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of
the Event
Dose Modifications
Toxicity Management
Pneumonitis/Interstiti
al Lung Disease
(ILD)
Any Grade
(Refer to NCI
CTCAE applicable
version in study
protocol for
defining the CTC
grade/severity)
General Guidance
For Any Grade
−         Monitor patients for signs and
symptoms of pneumonitis or ILD
(new onset or worsening shortness of
breath or cough). Evaluate patients
with imaging and pulmonary
function tests, including other
diagnostic procedures as described
below.
−         Suspected pneumonitis should
be confirmed with radiographic
imaging and other infectious and
disease-related aetiologies excluded,
and managed 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.
−         Consider Pulmonary and
Infectious Diseases consults.
Grade 1
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
−         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.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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.
●
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
−         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,
consider chest CT with contrast and
repeat in 3-4 weeks.
−         If no improvement within 2 to 3
days, additional workup should be
considered and prompt treatment with
IV methylprednisolone 2 to 4
mg/kg/day started.
−         If no improvement within 2 to 3
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 IV once, may be repeated at 2
and 6 weeks after initial dose at the
discretion of the treating provider).
Caution: It is important to rule out
sepsis and refer to infliximab label for
general guidance before using
infliximab. Consider, as necessary,
discussing with study physician.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 3 or 4
Permanently discontinue
study drug/study
regimen.
For Grade 3 or 4
−         Promptly initiate empiric IV
methylprednisolone 1 to 4 mg/kg/day
or equivalent.
−         Obtain Pulmonary and
Infectious Diseases Consults;
consider discussing with study
physician, as needed.
−         Hospitalize the patient.
−         Supportive care (e.g., oxygen).
−         If no improvement within 2 to
3 days, additional workup should be
considered and prompt treatment
with additional immunosuppressive
therapy such as TNF inhibitors (e.g.,
infliximab at 5 mg/kg IV, may be
repeated at 2 and 6 weeks after
initial dose at the discretion of the
treating provider). Caution: rule out
sepsis and refer to infliximab label
for general guidance before using
infliximab.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Diarrhea/Colitis
Any Grade
(Refer to NCI
CTCAE
applicable
version in
study protocol
for defining
the CTC
grade/severity
)
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).
−         WHEN SYMPTOMS OR
EVALUATION INDICATE AN
INTESTINAL PERFORATION IS
SUSPECTED, CONSULT A
SURGEON EXPERIENCED IN
ABDOMINAL SURGERY
IMMEDIATELY WITHOUT ANY
DELAY.
−         PERMANENTLY
DISCONTINUE STUDY DRUG
FOR ANY GRADE OF
INTESTINAL PERFORATION.
−         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 events,
including intestinal perforation.
−         Use analgesics carefully; they
can mask symptoms of perforation
and peritonitis.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 1
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), loperamide,
and other supportive care measures.
−         If symptoms persist,consider
checking lactoferrin; if positive, treat
as Grade 2 below. If negative and no
infection, continue Grade 1
management.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 2
Hold study drug/study
regimen until resolution
to Grade ≤1
·         If toxicity worsens,
then treat as Grade 3 or
Grade 4.
·         If toxicity improves
to Grade ≤1, then study
drug/study regimen can
be resumed after
completion of steroid
taper.
For Grade 2
−         Consider symptomatic
treatment, including hydration,
electrolyte replacement, dietary
changes (e.g., American Dietetic
Association colitis diet), and
loperamide and/or budesonide.
−         Promptly start prednisone 1 to 2
mg/kg/day PO or IV equivalent.
−         If event is not responsive within
2 to 3 days or worsens despite
prednisone at 1 to 2 mg/kg/day PO or
IV equivalent, consult a GI specialist
for consideration of further workup,
such as imaging and/or colonoscopy, to
confirm colitis and rule out
perforation.
−         If still no improvement within 2
to 3 days despite 1 to 2 mg/kg IV
methylprednisolone, promptly start
immunosuppressants such as
infliximab at 5 mg/kg IV, may be
repeated at 2 and 6 weeks after initial
dose at the discretion of the treating
provider. a 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.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 3 or 4
Grade 3
·         For patient treated
with PDL-1 inhibitors,
hold study drug/study
regimen until resolution
to Grade ≤1; study
drug/study regimen can
be resumed after
completion of steroid
taper. Permanently
discontinue study
drug/study regimen for
Grade 3 if toxicity does
not improve to Grade ≤1
within 14 days.
·         Permanently
discontinue study drug
for 1) Grade 3 colitis in
patients treated with
CTLA-4 inhibitors or 2)
Any grade of intestinal
perforation in any patient
treated with ICI.
Grade 4
Permanently discontinue
study drug/study
regimen.
For Grade 3 or 4
−         Promptly initiate empiric IV
methylprednisolone 1 to 2 mg/kg/day
or equivalent.
−         Monitor stool frequency and
volume and maintain hydration.
−         Urgent GI consult and
imaging and/or colonoscopy as
appropriate.
−         If still no improvement within
2 days, continue steroids and
promptly add further
immunosuppressants (e.g.,
infliximab at 5 mg/kg IV, may be
repeated at 2 and 6 weeks after
initial dose at the discretion of the
treating provider). Caution: Ensure
GI consult to rule out bowel
perforation and refer to infliximab
label for general guidance before
using infliximab.
−         If perforation is suspected,
consult a surgeon experienced in
abdominal surgery immediately
without any delay.
Hepatitis
(elevated LFTs)
PLEASE SEE
shaded area
immediately below
this section to find
guidance for
management of
“Hepatitis (elevated
LFTS)” in HCC
patients
Infliximab should
not be used for
management of
immune-related
hepatitis.
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTC
grade/severity)
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
·         No dose
modifications.
·         If it worsens, then
treat as Grade 2.
For Grade 1
−         Continue LFT monitoring per
protocol.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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.
·        If toxicity improves
to Grade ≤1 or
baseline, resume
study drug/study
regimen after
completion of
steroid taper.
·         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 2
−         Regular and frequent
checking of LFTs (e.g., every 1 to 2
days) until LFT elevations improve
or resolve.
−         If no resolution to Grade ≤1 in
1 to 2 days, consider discussing with
study physician, as needed.
−         If event is persistent (>2 to 3
days) or worsens, promptly start
prednisone 1 to 2 mg/kg/day PO or
IV equivalent.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 3 or 4
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 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.
For Grade 4
Permanently
discontinue study
drug/study regimen.
For Grade 3 or 4
−         Promptly initiate empiric IV
methylprednisolone at 1 to 2
mg/kg/day or equivalent.
−         If still no improvement
within 2 to 3 days despite 1 to 2
mg/kg/day methylprednisolone IV
or equivalent, promptly start
treatment with an
immunosuppressants (e.g.,
mycophenolate mofetil 0.5 – 1 g
every 12 hours then taper in
consultation with hepatology
consult). Discuss with study
physician if mycophenolate is not
available. Infliximab should NOT
be used.
−         Perform Hepatology
Consult, abdominal workup, and
imaging as appropriate.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Hepatitis
(elevated LFTs)
THIS shaded area is
guidance only for
management of
“Hepatitis (elevated
LFTs)” in HCC
patients
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
Any Elevations of
AST, ALT, or TB
as Described
Below
General Guidance
For Any Elevations Described
−         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 Hepatology
or Infectious Diseases specialists
regarding changing or starting
antiviral HBV medications if HBV
viral load is >2000 IU/ml.
−         Consider consulting Hepatology
or Infectious Diseases specialists
regarding changing or starting
antiviral HCV medications if HCV
viral load has increased by ≥2-fold.
−         For HCV+ with HBcAb+:
Evaluate for both HBV and HCV as
above.
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  described for
elevations in the row
below.
·         For all
transaminase
elevations , see
instructions at bottom
of shaded area if
transaminase rise is
not isolated but (at
any time) occurs in
setting of either
increasing bilirubin
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
or signs of DILI/liver
decompensation
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  resolution
to AST or ALT
≤5.0×ULN .
·         If toxicity worsens,
then treat as
described for
elevations in the rows
below.If toxicity
improves to  AST or
ALT ≤5.0×ULN ,
resume study
drug/study regimen
after completion of
steroid taper.
·         Permanently
discontinue study
drug/study regimen
for any case meeting
Hy’s law criteria, in
the absence of any
alternative cause.b
−         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 (>2 to 3
days) or worsens, and
investigator suspects toxicity to
be an imAE, start prednisone 1
to 2 mg/kg/day PO or IV
equivalent.
−         If still no improvement within
2 to 3 days despite 1 to 2
mg/kg/day of prednisone PO or
IV equivalent, consider
additional workup. If still no
improvement within 2 to 3 days
despite 2mg/kg/day of IV
methylprednisolone, consider
additional abdominal workup
(including liver biopsy) and
imaging (i.e., liver ultrasound),
and consider starting
immunosuppressants (e.g.,.,
mycophenolate mofetil 0.5 – 1 g
every 12 hours then taper in
consultation with hepatology
consult).a Discuss with study
physician if mycophenolate
mofetil is not available.
Infliximab should NOT be
used.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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  AST or ALT
≤5.0×ULN Resume
study drug/study
regimen if elevations
downgrade to  AST
or ALT ≤5.0×ULN
within 14 days and
after completion of
steroid taper.
·      Permanently
discontinue study
drug/study regimen if
the elevations do not
downgrade to  AST
or ALT ≤5.0×ULN
within 14 days
−         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 discussing with
study physician, as needed.
−         If investigator suspects
toxicity to be immune-mediated,
promptly initiate empiric IV
methylprednisolone at 1 to 2
mg/kg/day or equivalent.
−         If no improvement within 2 to
3 days despite 1 to 2 mg/kg/day
methylprednisolone IV or equivalent,
obtain liver biopsy (if it has not been
done already) and promptly start
treatment with an
immunosuppressant (e.g.,.,
mycophenolate mofetil 0.5 – 1 g
every 12 hours then taper in
consultation with a hepatologist).
Discuss with study physician if
mycophenolate is not available.
Infliximab should NOT be used.
Isolated
AST or ALT
>20×ULN,
whether
normal or
elevated at
baseline
Permanently
discontinue study
drug/study regimen.
Same as above
(except would recommend obtaining
liver biopsy early)
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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 each level of transaminase rise as instructed for the next highest level of
transaminase rise
-          For example, manage dosing for second level of transaminase rise (i.e., AST or ALT
>5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT >2.0×baseline and
≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise
(i.e., AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT
>12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline)
-          For the third and fourth levels of transaminase rises, permanently discontinue study
drug/study regimen
Nephritis or renal
dysfunction
(elevated serum
creatinine)
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTC
grade/severity)
General Guidance
For Any Grade
−         Consult a 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, decreased urine output,
or proteinuria).
−         Patients should be
thoroughly evaluated to rule out
any alternative etiology (e.g.,
disease progression, infections,
recent IV contrast, medications,
fluid status).
−         Consider using steroids in the
absence of a clear alternative
etiology even for low-grade events
(Grade 2), in order to prevent
potential progression to higher
grade events.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 1
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
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 beyond 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, consider additional
workup.When event returns to
baseline, resume study drug/study
regimen and routine serum
creatinine monitoring per study
protocol.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 3 or 4
Permanently
discontinue study
drug/study regimen.
For Grade 3 or 4
−         Carefully monitor serum
creatinine daily.
−         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, consider additional
workup and prompt treatment with
an immunosuppressant in
consultation with a nephrologist.
Rash or Dermatitis
(Including
Pemphigoid)
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol 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).
−         HOLD STUDY DRUG IF
STEVENS-JOHNSON
SYNDROME (SJS), TOXIC
EPIDERMAL NECROLYSIS
(TEN),  OR OTHER  SEVERE
CUTANEOUS ADVERSE
REACTION (SCAR) IS
SUSPECTED.
−         PERMANENTLY
DISCONTINUE STUDY DRUG
IF SJS, TEN, OR SCAR IS
CONFIRMED.
Grade 1
No dose
modifications.
For Grade 1
−         Consider symptomatic
treatment, including oral antipruritic
(e.g., diphenhydramine or
hydroxyzine) and topical therapy (e.g.
emolient, lotion, or institutional
standard).
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 2
For persistent (>1 week)
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
−         Consider moderate-strength
topical steroid.
−         If no improvement of rash/skin
lesions occurs within 3 days or is
worsening despite symptomatic
treatment and/or use of moderate
strength topical steroid, consider
discussing with study physician, as
needed, and promptly start systemic
steroids such as prednisone 1 to 2
mg/kg/day PO or IV equivalent.
−         Consider skin biopsy if the
event persists for >1 week or recurs.
Grade 3 or 4
For Grade 3
·         Hold study
drug/study regimen
until resolution to
Grade ≤1 or baseline.
·         If toxicity
improves to Grade ≤1 or
baseline, then resume
drug/study regimen
after completion of
steroid taper.
·         If toxicity
worsens, then treat as
Grade 4.
For Grade 4
Permanently
discontinue study
drug/study regimen.
For Grade 3 or 4
−         Consult dermatology.
−         Promptly initiate empiric
IV methylprednisolone 1 to 2
mg/kg/day or equivalent.
−         Consider hospitalization.
−         Monitor extent of rash
[Rule of Nines].
−         Consider skin biopsy
(preferably more than 1) as
clinically feasible. Consider, as
necessary, discussing with study
physician.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Endocrinopathy
(e.g.,
hyperthyroidism,
thyroiditis,
hypothyroidism,
type 1 diabetes
mellitus,
hypophysitis,
hypopituitarism,
and adrenal
insufficiency)
Any Grade
(Depending on
the type of
endocrinopath
y, refer to NCI
CTCAE
applicable
version in
study protocol
for defining the
CTC
grade/severity)
General Guidance
For Any Grade
−         Consider consulting an
endocrinologist for endocrine events.
−         Consider discussing with
study physician, as needed.
−         Monitor patients for signs
and symptoms of endocrinopathies.
Non-specific symptoms include
headache, fatigue, behaviour
changes, mental status changes,
photophobia, visual field cuts,
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).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.
−         Investigators should ask
subjects with endocrinopathies who
may require prolonged or continued
hormonal replacement, to consult
their primary care physicians or
endocrinologists about further
monitoring and treatment after
completion of the study.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 1
No dose
modifications.
For Grade 1
−         Monitor patient with
appropriate endocrine function
tests.
−         For suspected
hypophysitis/hypopituitarism,
consider consulting 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.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 2, 3, or
4
·         For Grade 2-4
endocrinopathies
other than
hypothyroidism
and type 1 diabetes
mellitus, consider
holding study
drug/study regimen
dose until acute
symptoms resolve.
·         Study drug/study
regimen can be
resumed once
patient 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 if the
patient is clinically
stable as per
investigator or
treating physician’s
clinical judgement.
·         If toxicity
worsens, then treat
based on severity.
For Grade 2, 3, or 4
−         Consult endocrinologist to
guide evaluation of endocrine
function and, as indicated by
suspected endocrinopathy and as
clinically indicated, consider
pituitary scan.
−         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, and
without corticosteroids. Only hold
study drug/study regimen in setting
of hyperglycemia when diagnostic
workup is positive for diabetic
ketoacidosis.
−         For patients with normal
endocrine workup (laboratory
assessment or MRI scans), repeat
laboratory assessments/MRI as
clinically indicated.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Amylase/Lipase
increased
Any Grade
(Refer to NCI
CTCAE
applicable
version in
study protocol
for defining
the CTC
grade/severity
)
General Guidance
For Any Grade
−         For modest asymptomatic
elevations in serum amylase and
lipase, corticosteroid treatment is
not indicated as long as there are no
other signs or symptoms of
pancreatic inflammation.
−         Assess for signs/symptoms of
pancreatitis
−         Consider appropriate
diagnostic testing (e.g., abdominal
CT with contrast, MRCP if clinical
suspicion of pancreatitis and no
radiologic evidence on CT)
−         If isolated elevation of
enzymes without evidence of
pancreatitis, continue
immunotherapy.  Consider other
causes of elevated amylase/lipase
−         If evidence of pancreatitis,
manage according to pancreatitis
recommendations
Grade 1
No dose
modifications.
Grade 2, 3, or
4
For Grade 2, 3, or 4
In consultation with
relevant pancreatic
specialist consider
continuing study
drug/study regimen
if no
clinical/radiologic
evidence of
pancreatitis ±
improvement in
amylase/lipase.
Acute Pancreatitis
Any Grade
(Refer to NCI
CTCAE
applicable
version in
study protocol
for defining
the CTC
grade/severity
)
General Guidance
For Any Grade
−         Consider Gastroenterology
referral
Grade 1
No dose
modifications.
For Grade 1
−         IV hydration
−         Manage as per
amylase/lipase increased
(asymptomatic)
Grade 2, 3, or
4
For Grade 2
Hold study
drug/study regimen
dose until resolution
to Grade ≤1.
For Grade 3 or 4
For Grade 2, 3, or 4
−         Promptly start systemic
steroids prednisone 1 to 2
mg/kg/day PO or IV equivalent.
−         IV hydration
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Permanently
discontinue study
drug/study regimen.
Neurotoxicity
(to include but not
limited to
non-infectious
meningitis,
non-infectious
encephalitis, and
autonomic
neuropathy,
excluding
Myasthenia Gravis
and Guillain-Barre)
Any Grade
(Depending on
the type of
neurotoxicity,
refer to NCI
CTCAE
applicable
version in
study protocol
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).
−         Perform symptomatic
treatment with neurological consult
as appropriate.
−         FOR TRANSVERSE
MYELITIS, PERMANENTLY
DISCONTINUE FOR ANY
GRADE.
Grade 1
No dose
modifications.
For Grade 1
−         See “Any Grade”
recommendations above.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 2
·         For acute motor
neuropathies or
neurotoxicity,
hold study
drug/study
regimen dose
until resolution to
Grade ≤1.
·         For sensory
neuropathy/neur
opathic pain,
consider holding
study drug/study
regimen dose
until resolution to
Grade ≤1.
·         Permanently
discontinue study
drug/study
regimen if Grade
2 imAE does not
resolve to Grade
≤1 within 30
days.
·         If toxicity
worsens, then
treat as Grade 3
or 4.
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 2
to 3 days despite 1 to 2 mg/kg/day
prednisone PO or IV equivalent,
consider additional workup and
promptly treat with an additional
immunosuppressant (e.g., IV IG or
other immunosuppressant
depending on the specific imAE).
Grade 3 or 4
For Grade 3 or 4
Permanently
discontinue study
drug/study regimen.
For Grade 3 or 4
−         Consider, as necessary,
discussing with study physician.
−         Obtain neurology consult.
−         Consider hospitalization.
−         Promptly initiate empiric IV
methylprednisolone 1 to 2
mg/kg/day or equivalent.
−         If no improvement within 2
to 3 days despite IV corticosteroids,
consider additional workup and
promptly treat with an additional
immunosuppressant (e.g., IV IG or
other immunosuppressant
depending on the specific imAE).
−         Once stable, gradually taper
steroids over ≥28 days.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Peripheral
neuromotor
syndromes
(such as
Guillain-Barre and
myasthenia gravis)
Any Grade
(Refer to NCI
CTCAE
applicable
version in
study protocol
for defining
the CTC
grade/severity
)
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 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.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 1
No dose
modifications.
For Grade 1
−         Consider discussing with the
study physician, as needed.
−         Care should be taken to
monitor patients for sentinel
symptoms of a potential
decompensation as described above.
−         Consult a neurologist.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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 discussing with the
study physician, as needed.
−         Care should be taken to
monitor patients for sentinel
symptoms of a potential
decompensation as described above.
−         Consult a neurologist.
−         Sensory
neuropathy/neuropathic pain may
be managed by appropriate
medications (e.g., gabapentin or
duloxetine).
MYASTHENIA GRAVIS:
o    Steroids may be successfully
used to treat myasthenia gravis. It is
important to consider that steroid
therapy (especially with high doses)
may result in transient worsening of
myasthenia and should typically be
administered in a monitored setting
under supervision of a consulting
neurologist.
o    Patients unable to tolerate
steroids may be candidates for
treatment with plasmapheresis or
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.
o    Avoid medications that can
worsen myasthenia gravis.
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.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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 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.
For Grade 3 or 4
−         Consider discussing with
study physician, as needed.
−         Recommend hospitalization.
−         Monitor symptoms and
consult a neurologist.
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.
o    Avoid medications that can
worsen myasthenia gravis.
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.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Myocarditis
Any Grade
(Refer to NCI
CTCAE
applicable
version in
study protocol
for defining
the CTC
grade/severity
)
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.
−         Consider discussing with the
study physician, as needed.
−         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). Consult a cardiologist
early, to promptly assess 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)
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 1
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
-          Monitor and closely follow
up in 2 to 4 days for clinical
symptoms,  BNP, cardiac enzymes,
ECG, ECHO, pulse oximetry
(resting and exertion), and
laboratory work-up as clinically
indicated.
-          Consider using steroids if
clinical suspicion is high.
Grade 2, 3
or 4
·         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 2
to 3 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 IV, may be repeated at 2 and
6 weeks after initial dose at the
discretion of the treating provider).
Caution: It is important to rule out
sepsis and refer to infliximab label
for general guidance before using
infliximab.  Infliximab is
contraindicated for patients who
have heart failure.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Myositis/
Polymyositis
Any Grade
(Refer to NCI
CTCAE
applicable
version in
study protocol
for defining
the CTC
grade/severity
)
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 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,
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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
modificatio
ns.
For Grade 1
−         Monitor and closely follow
up in 2 to 4 days for clinical
symptoms and initiate evaluation as
clinically indicated.
−         Consider Neurology consult.
−         Consider, as necessary,
discussing with the study physician.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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.
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 2 to 3 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 2 to 3 days, consider starting
another immunosuppressive
therapy such as a TNF inhibitor
(e.g., infliximab at 5 mg/kg  IV, may
be repeated at 2 and 6 weeks after
initial dose at the discretion of the
treating provider). Caution: It is
important to rule out sepsis and
refer to infliximab label for general
guidance before using infliximab.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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 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
−         Monitor symptoms closely;
recommend hospitalization.
−         Obtain Neurology consult
−         Consider discussing with the
study physician, as needed.
−         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 2 to 3 days, consider starting
another immunosuppressive
therapy such as a TNF inhibitor
(e.g., infliximab at 5 mg/kg  IV, may
be repeated at 2 and 6 weeks after
initial dose at the discretion of the
treating provider). 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.
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.
cNCCN Clinical Practice Guidelines in Oncology “Management of Immunotherapy-Related Toxicities” Version
1.2020 – December  2019
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; 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.
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Other–Immune-Mediated Reactions
Severity Grade of the
Event (Refer to NCI
CTCAE applicable
version in study protocol
for defining the CTC
grade/severity)
Dose Modifications
Toxicity Management
Any Grade
Note: It is possible that events with
an inflammatory or immune
mediated mechanism could occur in
nearly all organs, some of them are
not noted specifically in these
guidelines (e.g. immune
thrombocytopenia, haemolytic
anaemia, uveitis, vasculitis).
−         The study physician may be
contacted for
immune-mediated reactions
not listed in the “specific
immune-mediated reactions”
section
−         Thorough evaluation to rule
out any alternative etiology
(e.g., disease progression,
concomitant medications, and
infections)
−         Consultation with relevant
specialist
−         Treat accordingly, as per
institutional standard.
Grade 1
No dose modifications.
Monitor as clinically indicated
Grade 2
·         Hold study drug/study
regimen until resolution to
≤Grade 1 or baseline.
·         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.
·         Consider whether study
drug/study regimen should be
permanently discontinued in
Grade 2 events with high
likelihood for morbidity and/or
mortality when they do not
rapidly improve to Grade <1
upon treatment with systemic
steroids and following full
taper
For Grade 2, 3, or 4
Treat accordingly, as per
institutional standard, appropriate
clinical practice guidelines, and
other society guidelines (e.g.,
NCCN, ESMO)
Grade 3
Hold study drug/study regimen
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Grade 4
Permanently discontinue study
drug/study regimen
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.
Infusion-Related Reactions
Severity Grade of the
Event (Refer to NCI
CTCAE applicable
version in study
protocol for defining
the CTC
grade/severity)
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.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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 famotidine, and IV
glucocorticoid).
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National
Cancer Institute.
Non-Immune-Mediated Reactions
Severity Grade of the
Event (Refer to NCI
CTCAE applicable
version in study protocol
for defining the CTC
grade/severity)
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.”
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer
Institute.
Appendix 2 Schedule
of
study
procedures
follow-up
for
subjects
who
have
completed
durvalumab
and
tremelimumab
treatment
and
achieved
disease
control
(until
confirmed progression of disease) and subjects who have discontinued durvalumab
or tremelimumab due to toxicity in the absence of confirmed progression of disease.
Evaluation
Time Since Last Dose
Day
(±3)
Months (±1 week)
12 Months and every
6 Months (±2 weeks)
30
2
3
4
6
8
10
Physical examinationa
x
x
x
x
x
x
x
Vital signs (temperature,
respiratory rate, blood, pressure,
pulse)
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
Urine hCG or serum βhCG
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
x
x
x
x
x
x
x
(every 2 months)
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
contacted
Hematology
x
Every 8-12 weeks, according to investigator's criteria
x
Serum chemistry
x
Every 8-12 weeks, according to investigator's criteria
Thyroid function tests )TSH, and
fT3 and fT4)b
x
Every 8-12 weeks, according to investigator's criteria
SPD-L1 concentration )to assess
target engagement)
x
Tumour assessment (CT or MRI)
For subjects who achieve disease control following 12 months of treatment, tumour assessments
should be performed every 12 weeks relative to the date of first infusion thereafter until
confirmed PD by RECIST 1.1 by investigational site review. Please refer to SCHEDULE OF
STUDY ASSESSMENTS for timings of confirmatory scans.
For subjects who discontinue study drug due to toxicity (or symptomatic deterioration), tumour
assessments should be performed relative to the relative to the date of first infusion as follows:
every 12 weeks until confirmed PD by RECIST 1.1 by investigational site review. Please refer to
SCHEDULE OF STUDY ASSESSMENTS for timings of confirmatory scans.
Upon confirmed PD, scans should be conducted according to local standard clinical practice 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.
Appendix 3
Schedule of study procedures: follow-up for subjects who have
discontinued durvalumab or tremelimumab treatment due to confirmed progression of
disease at the investigator discretion
Evaluation
Time Since Last Dose
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
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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
Pharmacokinetic assessment, if
applicable
x
SPD-L1 concentration )to assess
target engagement)
x
Tumour assessment (CT or MRI)
For subjects who continue on MEDI4736 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 STUDY ASSESSMENTS until study drug
is stopped.
For subjects who discontinue study drug following confirmed progression, scans should be
conducted according to local clinical practice  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.
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Appendix 4
Durvalumab dose calculations
For durvalumab done depending on subject weight:
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X(mg/kg) x 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 are 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) / 10.0 (mL/vial)
Example:
1. Cohort dose: 10 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 300 mg = 10 (mg/kg) x 30(kg)
4. Dose to be added into infusion bag:
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL
5. The theoretical number of vials required for dose preparation:
Number of vials = 6.0(mL) / 10.0 (mL/vial) = 1 vials
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Appendix 5
Durvalumab Dose Volume Calculations
For durvalumab flat dosing:
1. Cohort dose: X g
2. Dose to be added into infusion bag:
Dose (mL) = X g x 1000/50 (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)
3. 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) / 10.0 (mL/vial)
Example:
1. Cohort dose: 1.5 g
2. Dose to be added into infusion bag:
Dose (mL) = 1.5 g x 1000 / 50 (mg/mL) = 30.0 mL
3. The theoretical number of vials required for dose preparation:
Number of vials = 30.0 (mL) / 10.0 (mL/vial) = 3 vials
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Appendix 6
Tremelimumab Dose Calculations
For tremelimumab dosing done depending on subject weight:
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X(mg/kg) x Y(kg)
4. Dose to be added into infusion bag:
Dose (mL) = XY mg / 20 (mg/mL)
Where 20 mg/mL is tremelimumab nominal concentration.
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL
(0.1 mL). Dose adjustments for each cycle are only needed for greater then 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) / 20.0 (mL/vial)
Or
Number of vials = Dose (mL) / 1.25 (mL/vial)
Example:
1. Cohort dose: 1 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 30 mg = 1 (mg/kg) x 30(kg)
4. Dose to be added into infusion bag:
Dose (mL) = 30 mg / 20 (mg/mL) = 1.5 mL
5. The theoretical number of vials required for dose preparation:
Number of vials = 1.5(mL) / 20.0 (mL/vial) = 1 vials
or
Number of vials = 1.5(mL) / 1.25 (mL/vial) = 2 vials
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Appendix 7
Tremelimumab Dose Volume Calculations
For tremelimumab flat dosing:
1. Cohort dose: X mg
2. Dose to be added into infusion bag:
Dose (mL) = X mg /20 (mg/mL)
where 20 mg/mL is tremelimumab nominal concentration.
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL
(0.1 mL)
3. 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) / 20 (mL/vial)
or
Number of vials = Dose (mL) / 1.25 (mL/vial)
Example:
1. Cohort dose: 75 mg
2. Dose to be added into infusion bag:
Dose (mL) = 75 mg / 20 (mg/mL) = 3.8 mL
3. The theoretical number of vials required for dose preparation:
Number of vials = 3.8 (mL) / 20 (mL/vial) = 1 vial
or
Number of vials = 3.8 (mL) / 1.25 (mL/vial) = 3 vials
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Clinical Study Protocol
Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
Appendix 8
Contact Details
Sponsor:
GETNE (Spanish  Group of Neuroendocrine and Endocrine Tumors)
C/ Secretari Coloma, 64-68 esc. B entresuelo 5ª
08024 Barcelona
Phone: + 34 93 434 44 12
e-mail: getne@getne.org
Coordinating Investigator: Dr. Jaume Capdevila
Vall d'Hebron University Hospital
Medical Oncology Service
Passeig de la Vall d'Hebron, 119-129, 08035. Barcelona
CRO:
MFAR Clinical Research
C/ Sinfonía, 28, 2ª planta Nº1. 28054 Madrid
Email: investigacion@mfar.net
Phone: (34) 91 061 62 28 / 93 434 44 12; Fax: (34) 93 253 11 68
Appendix 9
Sites and Investigators Participants
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
SITE
Principal Investigator
1 -
H.U. Vall d'Hebron
Dr. Jaume Capdevila
2 -
H.U. Ramón y Cajal
Dra. Teresa Alonso
3 -
H. Duran i Reynals - ICO L'Hospitalet
Dr. Alexandre Teulé
4 -
H.U. 12 de Octubre
Dra. Rocío García-Carbonero
5 -
H.U. Marqués de Valdecilla
Dr. Carlos López
6 -
H.G.U. Morales Meseguer
Dr. Alberto Carmona
7 -
H.U. Virgen de la Victoria
Dra. Isabel Sevilla
8 -
H. Universitario de Burgos
Dr. Guillermo Crespo
9 -
H.U. Gregorio Marañón
Dra. Montserrat Blanco
10 -
H.U. La Paz
Dra. Ana Belén Custodio
11 -
H.U. Central de Asturias
Dra. Paula Jiménez
12 -
H. Universitario de Canarias
Dra. Marta Llanos
13 -
H.U. HM Sanchinarro
Dr. Antonio Cubillo
14 -
Complejo Hospitalario de Navarra
Dra. Ruth Vera García
15 -
H.U. Virgen de las Nieves
Dra. Encarnación González
16 -
H.U. Miguel Servet
Dr. Vicente Alonso
17 -
ICO Badalona
Dr. José Luis Manzano
18 -
H.U. Virgen del Rocío
Dra. Marta Benavent
19 -
H.U. i Politècnic La Fe
Dr. Ángel Segura
20 -
H.U. Donostia
Dra. Adelaida La Casta
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Drug Substance DURVALUMAB/TREMELIMUMAB
Study Number ESR 15-11561-61-DUNE
EudraCT Nº: 2016-002858-20
Edition Number: 5.0 dated on June 09th, 2021
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