A Phase II Study of Durvalumab (MEDI4736) Plus Tremelimumab for the Treatment of Patients With Progressive, Refractory Advanced Thyroid Carcinoma - The DUTHY Trial
Phase: PHASE2
Conditions: Metastatic Thyroid Papillary Carcinoma, Metastatic Thyroid Follicular Carcinoma, Metastatic Thyroid Cancer
Sponsor: Grupo Espanol de Tumores Neuroendocrinos

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Investigational Drug
Durvalumab
(MEDI4736) and
tremelimumab
Study Number
GETNE - T1812
Version Number
6.0
Date
05/12/2022
A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of
patients with progressive, refractory advanced thyroid carcinoma-The DUTHY trial
Sponsor:
GETNE (Spanish Group of Neuroendocrine and Endocrine Tumors)
C/ Balmes 243, Escalera A 5º1ª
08006 Barcelona
Phone: +34 93 434 44 12
E-mail: getne@getne.org
Coordinating Investigator:
Dr. Jaume Capdevila
Vall d’Hebrón University Hospital
Medical Oncology Service
P. Vall d’Hebron, 119-129
Phone: +34 93 274 60 85
Fax: +34 93 274 60 59
E-mail: jacapdevila@vhebron.net
Page 1 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
PROTOCOL SIGNATURE PAGE
Study title: A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of
patients with progressive, refractory advanced thyroid carcinoma - The DUTHY trial
Study code: GETNE - T1812
Version number and date: 05/12/2022
Dr. Jaume Capdevila
Coordinating investigator and GETNE
Chairman
__________________
Signature
__________________
Signature date
(DD-Mmm-YYYY)
Site:____________________________________
____________________________________
Principal Investigator’s Name
__________________
Signature
__________________
Signature date
(DD-Mmm-YYYY)
Page 2 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
PROTOCOL SYNOPSIS
Clinical Protocol GETNE -T1812
Study Title:
A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of patients
with progressive, refractory advanced thyroid carcinoma-The DUTHY trial
Protocol Number:
GETNE-T1812
EudraCT:  
2018-001066-42
Clinical Phase:
II
Study Duration:
42 months
Investigational Product(s) and Reference Therapy:
Durvalumab (MEDI4736) will be supplied in glass vials containing 500 mg of liquid solution at a
concentration of 50 mg/mL durvalumab for intravenous (IV) infusion after dilution.
Tremelimumab is supplied as a sterile solution for IV infusion. Tremelimumab will be supplied in
glass vials containing 400 mg or 25 mg of liquid solution at a concentration of 20 mg/mL for
infusion after dilution.
Research Hypothesis
First-line and second-line therapy with multikinase inhibitors (sorafenib/lenvatinib in DTC and
vandetanib/cabozantinib in MTC) achieve a 6-month PFS rate of 70-80%. However, beyond
second-line treatment with other MKIs out of clinical trial in both DTC and MTC median PFS
achieve 6-7 months with no partial remissions reported4. The PFS-rate at 6 months of placebo
arms in first and second-line in patients with documented disease progression in DTC and MTC is
between 20-30%.
Anaplastic thyroid cancer (ATC) has no standard therapy that demonstrates benefit in overall
survival. Prognosis is very poor and median overall survival is 3-4 months.
Our hypothesis is that Durvalumab plus Tremelimumab may improve PFS-rate at 6 months in
advanced thyroid cancer from 25% up to 45% based on the initial report of early clinical trials
with immune checkpoint inhibitors in advanced thyroid cancer. For ATC, we hypothesize that the
combination therapy may improve overall survival rate at 6 months from 5% to 35%.
Objectives:
Primary Objectives:
1.
Progression-free survival (PFS) rate at 6 months for DTC and MTC cohorts
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
2.
Overall survival (OS) rate at 6 months for ATC cohort
Secondary Objectives:
1.
Overall response rate (ORR) by irRECIST and RECIST.
2.
To assess the duration of response according to irRECIST/RECIST.
3.
To assess the median progression-free survival time (PFS) according to RECIST.
4.
To assess the safety profile of Durvalumab and Tremelimumab in subjects with advanced
thyroid neoplasms.
5.
To assess the median overall survival (OS) time.
6.
To assess response status according to irRECIST/RECIST at 6 and 12 months after start of
study treatment.
Exploratory objective(s)
1.
To evaluate biochemical response (changes in thyroglobulin, calcitonin and CEA levels)
and its association with response rate and progression-free survival.
2.
To assess whether baseline tumor and blood biomarkers may be predictive of response to
durvalumab and tremelimumab therapy (if feasible).
3.
To explore additional hypotheses related to biomarkers and relationship to durvalumab
and tremelimumab efficacy and/or toxicity and thyroid cancer evolution that may arise
from internal or external research activities (if feasible).
Study Design:
Patients will be included following review of inclusion/exclusion criteria in a prospective,
non-randomized, open label, single arm, three parallel cohorts (DTC, MTC and ATC) phase II
study in a Simon-II stage design to receive durvalumab 1500 mg plus tremelimumab 75 mg every
4 weeks up to 4 cycles followed by durvalumab 1500 mg every 4 weeks until disease
progression, unacceptable toxicity or patients’ decision.
Number of Centres:
15
Number of Patients:
●
46 patients in stage I
-
17 patients for cohort DTC
-
17 patients for cohort MTC
-
12 patients for cohort ATC
●
38 patients in stage II
-
19 patients for cohort DTC
-
19 patients for cohort MTC
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Study Population:
Advanced, radioiodine-refractory differentiated thyroid carcinoma, including papillary, follicular,
Hürtle Cell and poorly-differentiated thyroid carcinoma (DTC).
Advanced medullary thyroid carcinoma (MTC)
Advanced anaplastic thyroid cancer (ATC)
Inclusion Criteria:
●
Written informed consent obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations.
●
Age g 18 years at time of study entry.
●
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
●
Body weight >30kg.
●
Confirmed differentiated thyroid cancer (papillary, follicular, poorly differentiated and
Hürtle cell), medullary thyroid cancer or anaplastic thyroid cancer.
●
Available tumor and blood samples for translational research
●
Patients should meet one of the following criteria:
o
Cohort 1: Patients with locally advanced or metastatic differentiated thyroid
cancer (including the subtypes of papillary, follicular, poorly differentiated and
Hürthle cell carcinoma) after disease progression on systemic therapy with
MKIs. Patients could be recruited in the study after progression to Lenvatinib
(regardless prior lines) or progression on at least two prior MKIs which may or
not include Lenvatinib. No prior therapy with immune checkpoint inhibitors is
allowed. Patients with intolerable toxicity to MKIs that meet the prior inclusion
criteria and experience disease progression by RECIST v1.1 after stopping
therapy may be included.
o
Cohort 2: Patients with locally advanced or metastatic medullary thyroid cancer
after progression on systemic therapy with MKIs. Patients could be recruited in
the study after progression to Vandetanib (regardless prior lines) or progression
to at least two prior MKIs that may or not include Vandetanib. No prior therapy
with immune checkpoint inhibitors is allowed. Patients with intolerable toxicity
to MKIs that meet the prior inclusion criteria and experience disease progression
by RECIST v1.1 after stopping therapy may be included.
o
Cohort 3: Patients with locally advanced or metastatic anaplastic thyroid cancer
regardless of prior therapy. No prior therapy with immune checkpoint inhibitors
is allowed.
●
No limitation of number of prior therapies.
●
Life expectancy >3 months
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
●
Adequate normal organ and marrow function as defined below:
●
Haemoglobin g9.0 g/dL.
●
Absolute neutrophil count (ANC) > 1500 per mm3.
●
Platelet count g100,000 per mm3.
●
Serum bilirubin f1.5 x institutional upper limit of normal (ULN). This will not apply to
patients 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.
●
AST (SGOT)/ALT (SGPT) f2.5 x institutional upper limit of normal unless liver metastases
are present, in which case it must be f 5x ULN.
●
Measured creatinine clearance (CL) >40 mL/min or Calculated 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)
●
Evidence of post-menopausal status or negative urinary or serum pregnancy test for female
pre-menopausal patients. Women will be considered post-menopausal if they have been
amenorrheic for 12 months without an alternative medical cause. The following age-specific
requirements apply:
o
Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
o
Women g50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous
hormonal treatments, had radiation-induced menopause with last menses >1
year ago, had chemotherapy-induced menopause with last menses >1 year ago, or
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy
or hysterectomy).
Patient is willing and able to comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations including follow up.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Exclusion Criteria:
●
Participation in another clinical study with an investigational product during the last 21
days (washing period < 21 days)
●
Concurrent
enrolment
in
another
clinical
study,
unless it is an observational
(non-interventional) clinical study or during the follow-up period of an interventional
study.
●
Any previous treatment with a PD1, PD-L1 or CTLA-4 inhibitor, including durvalumab
and tremelimumab.
●
Any previous treatment with immunotherapy, including combinations of immunotherapy
and other anticancer or targeted agents.
●
Mean QT interval corrected for heart rate (QTc) g470 ms calculated from 3
electrocardiograms (ECGs) using Fridericia’s Correction.
●
Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. The following are exceptions to this
criterion:
o
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular
injection).
o
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent.
o
Steroids
as
premedication
for
hypersensitivity
reactions
(e.g.,
CT
scan
premedication).
●
Any unresolved toxicity NCI CTCAE Grade g2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:
o
Patients with Grade g2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician.
o
Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the
Study Physician.
●
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
replacement therapy) is acceptable.
●
History of allogenic organ transplantation.
●
Active
or
prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
o
Patients with vitiligo or alopecia.
o
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement.
o
Any chronic skin condition that does not require systemic therapy.
o
Patients without active disease in the last 5 years may be included but only after
consultation with the study physician.
o
Patients with celiac disease controlled by diet alone.
●
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection,
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina
pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal
conditions associated with diarrhea, or psychiatric illness/social situations that would
limit compliance with study requirement, substantially increase risk of incurring AEs or
compromise the ability of the patient to give written informed consent.
●
History of another primary malignancy except for:
o
Malignancy treated with curative intent and with no known active disease g5
years before the first dose of IP and of low potential risk for recurrence.
o
Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease.
o
Adequately treated carcinoma in situ without evidence of disease.
●
History of active primary immunodeficiency.
●
Active infection including tuberculosis (clinical evaluation that includes clinical history,
physical examination and radiographic findings, and TB testing in line with local
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C,
or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past
or resolved HBV infection (defined as the presence of hepatitis B core antibody
[anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV)
antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
●
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccines whilst receiving IP and up to 30 days
after the last dose of IP.
●
Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
screening to 90 days after the last dose of durvalumab monotherapy and 180 days for
combined treatment with durvalumab and tremelimumab.
●
Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
●
Judgment by the investigator that the patient is unsuitable to participate in the study and
the patient is unlikely to comply with study procedures, restrictions and requirements.
Investigational Product(s), Dose, and Mode of Administration:
Durvalumab 1500 mg plus tremelimumab 75 mg via IV infusion Q4W, starting on Week 0, for up
to a maximum of 4 doses/cycles followed by durvalumab monotherapy 1500 mg via IV infusion
Q4W, starting 4 weeks after the last infusion of the combination, until disease progression,
unacceptable toxicity or patients’ decision.
Study Assessments and Criteria for Evaluation:
Safety Assessments:
The safety objective of this trial is to characterize the safety and tolerability of durvalumab in
combination with tremelimumab in subjects with advanced thyroid cancer. The primary safety
analysis will be based on subjects who experienced toxicities as defined by CTCAE, v5.0 The
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant
medications administered will be recorded. AEs will be analysed including but not limited to all
AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific immune-related adverse
events (iris) 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-tumour activity of durvalumab
in combination with tremelimumab in subjects with advanced thyroid cancer measured by the
PFS rate at 6 months for the cohorts of DTC and MTC and overall survival for the cohort of ATC.
Pharmacodynamic/Pharmacokinetic Assessments (if applicable):
Correlative blood samples for pharmacodynamic studies will be obtained during the course of
the trial.
Archival tumour tissue will be required at baseline.
Statistical Methods and Data Analysis:
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) 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.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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 analyse DFS, 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 who are lost to follow-up or who discontinued treatment will be included in
the final analysis by ITT of primary endpoint if they have at least one tumour evaluation.
Sample Size Determination:
Simon-II design was applied for sample size estimation for DTC (cohort 1) and MTC (cohort 2).
For cohorts 1 and 2, we hypothesize that the experimental therapy will improve the probability
of being progression free at 6 months, from 25% in historical cohorts up to 45% in the current
study.
With 80% of power (³ = 0.2) and unilateral alpha (0.05), 36 patients per arm are needed to
demonstrate the primary hypothesis. The Simon-II design suggested to observe g 5 patients free
of disease progression or unacceptable toxicity at 6 months within the first 17 patients included
in the first stage. If g 5 out of 17 patients in each cohort (DTC and MTC) are free of disease
progression or unacceptable toxicity at 6 months in the first stage, study will continue recruiting
19 additional patients up to 36 patients per cohort. If g13 pts out of a total of 36 patients are
alive and progression-free at the final analysis, the study should be declared positive. If stage I is
reached only in one cohort, recruitment will continue in the successful cohort and stop in the
non-effective cohort.
For sample size estimation for cohort 3, we hypothesize that the experimental therapy will
improve the probability of being alive at 6 months from 5% in historical cohorts up to 35% in the
current study. With 80% of power (³ = 0.2) and unilateral alpha (0.05), 12 patients are needed to
demonstrate the primary hypothesis. Cohort 3 will include the 12 patients only in one stage. No
second stage is planned in the current study. If the hypothesis is reached for cohort 3, the study
should be considered positive and further confirmatory studies will be needed.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
SCHEDULE OF STUDY ASSESSMENTS
Screening
C1
C1
D15
C2
C2
D15
C3
C3
D15
C4
C5 to PD
End of
Treatment
For
details
see
Section
Week
-4 to -1
0
Q4W ±3 days unless dosing needs to be held for toxicity
reasons
Day
-28 to -1
1a
Q28 days ±3 days unless dosing needs to be held for
toxicity reasons
Informed Consent
Informed consent:
study proceduresb
X
4.1
8.1.1
Consent: genetic
sample and analysis
(optional)
X
12.3
Study procedures
Physical exam (full)
X
8.2.2
Targeted physical
exam (based on
symptoms)
X
X
X
X
X
X
X
X
X
8.2.2
Vital signsc
X
X
X
X
X
X
X
X
X
X
8.2.4
ECGd
X
As clinically indicated
8.2.3
Concomitant
medications
<----------------------------------------------------------------------------------------------------------------------------->
7.2
Demography,
including baseline
characteristics and
tobacco use
X
3.2
Eligibility criteria
X
4.1
4.2
Laboratory Assessments
Clinical chemistrye
X
Xf
X
X
X
X
X
X
X
X
8.2.5
Hematologye
X
Xf
X
X
X
X
X
X
X
X
8.2.5
TSHg, (reflex free T3
or free T4h)
X
X
X
X
X
X
X
X
X
X
8.2.5
Hepatitis B and C and
HIV
X
8.2.5
Pregnancy testi
X
8.2.5
Monitoring
ECOG performance
status
X
X
X
X
X
X
X
X
X
X
AE/SAE assessment l
<------------------------------------------------------------------------------------------------------------>
10.2
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Patient follow up
contact / Patient
review for safety
Midway through Cycles 1, 2 and 3: days 14 of  C1, 2 and 3
3.3
IP administration
Durvalumab m,n
X
X
X
X
X
5.2.1
Tremelimumab m,n
X
X
X
X
5.2.1
Other assessments and assays
Tumor biopsy
(archival, if available)
X
8.3
Efficacy evaluations
Tumor evaluation
(CT or MRI)
(RECIST 1.1) o,p
X
q12w ± 1w until confirmed objective disease progression/death (whichever comes
first).  The schedule of q12w ± 1 week MUST be followed regardless of any delays in
dosing. In case of suspected pseudo progression, treatment should be continued until
PD is confirmed in the following imaging.
9
Biomarkers
x
x
x
a
Every effort should be made to minimize the time between randomization and starting treatment. (i.e. within 1
day of randomization)
b
Informed consent of study procedures may be obtained prior to the 28-day screening window. If laboratory or
imaging procedures were performed for alternate reasons prior to signing consent, these can be used for
screening purposes with consent of the patient. However, all screening laboratory and imaging results must
have been obtained within 28 days of randomization.
c
Body weight is recorded at each visit along with vital signs.
d
Any clinically significant abnormalities detected require triplicate ECG results.
e
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more
frequently if clinically indicated.
f
If screening clinical chemistry and haematology assessments are performed within 3 days prior to Day 1 (first
infusion day), they do not need to be repeated at Day 1.
g
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at day 1.
h
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to
the endocrine system.
i
For women of childbearing potential only.
A urine or serum pregnancy test is acceptable. Women of
childbearing potential are required to have a pregnancy test within 7 days prior to the first dose of study drug.
Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating physician or
Investigator prior to commencing an infusion
l
For AEs/SAEs reported during screening, additional information such as medical history and concomitant
medications may be needed
m
During the combination portion of treatment, tremelimumab will be administered first; the durvalumab
infusion will start approximately 1 hour (maximum 2 hours) after the end of the tremelimumab infusion. If
there are no clinically significant infusion reactions with the first cycle, and at the discretion of the investigator,
then for all other cycles, the durvalumab can be given immediately after the tremelimumab infusion has
finished.
n
Results for LFTs, electrolytes and creatinine must be available before commencing an infusion (within 3 days)
and reviewed by the treating physician or Investigator prior to dosing.
o
RECIST assessments will be performed on images from CT (preferred) or MRI, each preferably with IV
contrast of the neck, chest, abdomen (including liver and adrenal glands) and pelvis. Pelvic imaging is
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
recommended only when primary or metastatic disease in the pelvic region is likely. Additional anatomy
should be imaged based on signs and symptoms of individual patients at baseline and follow-up. Baseline
assessments should be performed no more than 28 days before the date of randomization and, ideally, should
be performed as close as possible to and prior to the start of IP. The confirmatory scans should be performed
preferably at the next scheduled imaging visit and no less than 4 weeks after the prior assessment of PD (in the
absence of clinically significant deterioration). If an unscheduled assessment was performed and the patient
has not progressed, every attempt should be made to perform the subsequent assessments at their next
scheduled visit.
p
Patients will have scans done q12w until confirmed objective disease progression.
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated. C  Cycle;
ECG  Electrocardiogram;
IM  Intramuscular;
LFT  Liver
function
test;
PGx  Pharmacogenetics
research;
qXw  Every X weeks; qXw  Every X weeks; SNP  Single nucleotide polymorphism; T3  Triiodothyronine; T4  Thyroxine;
TSH  Thyroid-stimulating hormone.
Page 13 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS
2
Exploratory objective(s)
4
ABBREVIATIONS AND DEFINITION OF TERMS
21
1. INTRODUCTION
26
1.1 Disease background
26
1.1.1. Immunotherapies
28
1.1.2. Durvalumab
29
1.1.3. Tremelimumab
30
1.1.4. Durvalumab in combination with tremelimumab
30
1.2. Research hypothesis
30
1.3. Rationale for conducting this study
31
1.3.1. Durvalumab + tremelimumab combination therapy dose rationale
32
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 + tremelimumab
35
1.4.1.2. Overall risks
36
1.4.1.3. Durvalumab
36
1.4.1.4. Tremelimumab
38
1.4.2. Durvalumab + tremelimumab
39
1.4.3. Overall benefit-risk
41
2. STUDY OBJECTIVE
42
2.1.  Primary objective(s)
42
2.2.  Secondary objective(s)
42
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
2.3.  Exploratory objective(s)
42
3. STUDY DESIGN
43
3.1. Overview of study design
43
3.2. Study schema
43
Screening phase
43
Follow-up phase
44
3.3. Study oversight for safety evaluation
45
4. PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, RESTRICTIONS,
DISCONTINUATION AND WITHDRAWAL
46
4.1. Inclusion criteria
46
4.2. Exclusion criteria
48
4.3. Withdrawal of patients from study treatment and/or study
50
4.4. Replacement of patients
51
5. INVESTIGATIONAL PRODUCT(S)
52
5.1. Durvalumab and tremelimumab
52
5.1.1. Formulation/packaging/storage
52
5.2. Dose and treatment regimens
52
5.2.1. Treatment regimens
52
5.2.2. Duration of treatment and criteria for retreatment
53
5.2.3. Study drug preparation of durvalumab and tremelimumab
54
5.2.4. Monitoring of dose administration
55
5.2.5. Accountability and dispensation
56
5.2.6. Disposition of unused investigational study drug
56
6. TREATMENT PLAN
58
6.1. Patient enrolment and allocation
58
6.1.1. Procedures for allocation
58
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
6.1.2. Procedures for handling patients incorrectly enrolled
58
6.2. Dose modification and toxicity management
58
6.2.1. Durvalumab and tremelimumab
58
7. RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENT(S)
60
7.1. Restrictions during the study
60
7.2. Concomitant treatment(s)
61
7.2.1. Permitted concomitant medications
62
7.2.2. Excluded concomitant medications
62
8. STUDY PROCEDURES
64
8.1. Schedule of study procedures
64
8.1.1. Screening phase
64
8.1.2. Treatment phase
65
8.1.3. End of treatment
67
8.2. Description of study procedures
68
8.2.1. Medical history and physical examination, electrocardiogram, weight and vital signs
68
8.2.2. Physical examination
68
8.2.3. Electrocardiograms
68
8.2.4. Vital signs
68
8.2.5. Clinical laboratory tests
69
8.3. Biological sampling procedures
72
8.3.1. Biomarker/pharmacodynamics sampling and evaluation methods
73
8.3.2. Estimate of volume of blood to be collected for biomarkers studies
76
8.3.3. Archival tumor samples use beyond PD-L1
76
8.3.3.1. Archival tumor samples
76
8.3.4. Withdrawal of informed consent for donated biological samples
76
9. DISEASE EVALUATION AND METHODS
77
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
9.1. Efficacy variable
77
10. ASSESSMENT OF SAFETY
79
10.1. Safety parameters
79
10.1.1. Definition of adverse events
79
10.1.2. Definition of serious adverse events
79
10.1.3. Durvalumab + tremelimumab adverse events of special interest
79
10.2. Assessment of safety parameters
81
10.2.1. Assessment of severity
81
10.2.2. Assessment of relationship
82
10.3. Recording of adverse events and serious adverse events
82
10.3.1. Study recording period and follow-up for adverse events and serious adverse events
83
10.3.2. Causality collection
84
10.3.3. Relationship to protocol procedures
84
10.3.4. Adverse events based on signs and symptoms
84
10.3.5. Adverse events based on examinations and tests
84
10.3.6. Hy9s Law
85
10.3.7. Disease progression
85
10.3.8. New cancers
85
10.3.9. Deaths
85
10.3.10. Reporting of serious adverse events
86
10.3.10.1. Reporting of deaths
86
10.3.11. Other events requiring reporting
87
10.3.11.1. Overdose
87
10.3.11.2. Pregnancy
87
10.3.12. Maternal exposure
87
10.3.13.  Paternal exposure
88
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
10.4. Medication error
88
11. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION
90
11.1. Description of analysis sets
90
11.2. Methods of statistical analyses
91
11.2.1. Safety analyses
91
11.2.2. Efficacy analyses
91
11.2.3. Secondary objective(s)
92
11.2.4. Exploratory objective(s)
92
11.2.5. Interim analyses
92
11.3. Determination of sample size
93
12. ETHICAL AND REGULATORY REQUIREMENTS
94
12.1. Ethical conduct of the study
94
12.2. Ethics and regulatory review
94
12.3. Informed consent
94
12.4. Changes to the protocol and informed consent form
95
12.5. Audits and inspections
95
12.6. Confidentiality
95
12.7. Insurance
96
12.8. Publications
96
13. STUDY MANAGEMENT
98
13.1. Training of study site personnel
98
13.2. Monitoring of the study
98
13.2.1. Source data
98
13.3. Retention of Records
98
13.4. Quality assurance
99
13.5. Study timetable and end of study
99
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
14. DATA MANAGEMENT
100
14.1. Study governance and oversight
100
15. INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
101
15.1. Identity of investigational product(s)
101
16. LIST OF REFERENCES
102
APPENDICES
106
Appendix 1.
106
List of Abbreviations
153
Appendix 2.  Schedule of study procedures: follow-up for patients who have  completed durvalumab
and tremelimumab treatment and achieved disease control (until confirmed progression of disease)
and patients who have discontinued durvalumab or tremelimumab due to toxicity in the absence of
confirmed progression of disease
155
Appendix 3. Schedule of study procedures: follow-up for patients who have discontinue durvalumab
and tremelimumab treatment due to confirmed progression of disease at the investigator discretion157
Appendix 4. Durvalumab dose volume calculations
159
Appendix 5.  Tremelimumab dose volume calculations
160
Appendix 6. Contact details
161
Appendix 7. Sites and Investigators Participants
162
Appendix 8. Drug shipment form
163
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
LIST OF TABLES
Table 1. Highly effective methods of contraception (<1% failure rate)
62
Table 2. Supportive medications
63
Table 3. Prohibited concomitant medications
63
Table 4. Clinical chemistry
71
Table 5. Hematology
72
Table 6. Urinalysis
72
Table 7. List of investigational products for this study
104
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or
special term
Explanation
AChE
Acetylcholine esterase
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
ATC
Anaplastic thyroid carcinoma
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
BICR
Blinded Independent Central Review
BoR
Best objective response
BP
Blood pressure
C
Cycle
CD
Cluster of differentiation
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
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
DTC
Differentiated thyroid carcinoma
EC
Ethics Committee, synonymous to Institutional Review Board and
Independent Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
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
IgG
Immunoglobulin G
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
L-T4
Levothyroxine
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Minister of Health, Labor, and Welfare
miRNA
Micro-ribonucleic acid
MKIs
Multi kinase inhibitors
MRI
Magnetic resonance imaging
MTC
Medullary Thyroid Carcinoma
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
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
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 Frederica'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
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
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
US
United States
WBDC
Web-Based Data Capture
WHO
World Health Organization
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
1.
INTRODUCTION
Thyroid cancer is the most common endocrine malignancy, although it is a relatively rare tumor,
representing less than 1% of all human malignancies. The incidence of thyroid cancer has been increasing
in many countries over the last 30 years but without notable increase in mortality. The age and
gender-adjusted incidence of thyroid cancer has increased faster than that of any other malignancy in
recent years, with the increased incidence seen in both genders and all ethnic backgrounds. In Europe,
according to GLOBOCAN in 2012 there were almost 53000 new cases of thyroid cancer, with more than
6300 deaths. The increasing incidence reflects better detection of subclinical disease with an increased
detection of small papillary cancers, but an analysis of the National Cancer Institute's SEER database
found an increase in detection of differentiated thyroid cancer of all sizes, including tumors greater than 4
cm, that may be also related to improved screening.
Thyroid cancer is a heterogeneous disease that is classified into: differentiated thyroid cancer (this
category includes papillary, follicular, poorly differentiated histologic and Hürthle cell types), anaplastic
thyroid carcinoma and medullary thyroid carcinoma. Differentiated carcinomas (DTC) are by far the most
common type (approximately 90%: papillary 80%, follicular 10%; poorly differentiated <5%) medullary
thyroid cancer (MTC) accounts for 5-10% of cases and anaplastic carcinomas for less than 5%.
1.1
Disease background
For patients with early stage disease, thyroidectomy represents the backbone of treatment. Radioiodine
treatment is undertaken post-operatively in patients with documented persistent disease or at high risk of
persistent or recurrent disease (according to the surgeon9s and pathologist9s report). Recurrent disease
occurs in 10–15% of cases, mostly in patients with extensive disease (with large thyroid tumors, extension
beyond the thyroid capsule, and lymph node metastases) and in those with an aggressive histologic type.
In the majority of cases, recurrent disease is confined in the neck only, in lymph nodes, or in the thyroid
bed. Patients with persistent or recurrent disease should be treated with l-T4 at doses high enough to
suppress TSH because increased serum TSH level may enhance tumor growth. For these patients with
neck recurrence treatment includes surgery, radioiodine, and in some patients external radiation therapy.
Complete remission is achieved in more than two-thirds of patients with recurrent disease in lymph nodes,
but recurrences in the thyroid bed or in soft tissues are often associated with a poorer prognosis.
Less than 10% of DTC patients will develop distant metastases, with half of them being detected at
presentation. Usually these metastases are located in the lungs (50%), bones (25%), lungs and bones
(20%), or rarely at other sites (5%). Treatment includes l-T4 treatment at doses that suppress TSH, local
treatment modalities (such as surgery, radiation therapy, and radiofrequency ablation), and radioiodine in
the two-thirds of patients who demonstrate significant radioiodine uptake in their metastases.
Unfortunately, these methods provide a complete remission in only one-third of patients with distant
metastases. The other patients have radioiodine refractory disease (defined as having at least one target
lesion without radioiodine uptake or that has progressed within a year following radioiodine treatment or
with persistent disease after the administration of a cumulative activity of more than 22 GBq (600 mCi)
radioiodine). These tumors may remain stable with time or show a slow progression, and in such patients,
follow-up with imaging every 6 months is recommended. However, in case of progression and significant
tumor burden, systemic treatment may become indicated.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
For these patients systemic cytotoxic chemotherapy offers limited benefit. The most widely tested
cytotoxic agent in DTC is doxorubicin, either as single agent or in combination with cisplatin. However
response rate is low (0-20%) and short lasting and toxicity is high.
As in many other tumors, tyrosine kinases play a crucial role in thyroid tumor proliferation, angiogenesis,
invasion, metastasis, and avoidance of apoptosis. Small molecule tyrosine kinase inhibitors (TKIs)
targeting signalling tyrosine kinases have been tested in patients with advanced differentiated thyroid
cancer, given the oncogenic roles of mutations described above (BRAF, RET, RAS, as well as the VEGFR
pathway). Several different tyrosine kinase inhibitors (TKIs) such as sorafenib, sunitinib, axitinib,
pazopanib, and lenvatinib have been tested in patients with DTC in the context of phase II trials. Based on
the results of two phase III trials, sorafenib and lenvatinib are approved in this setting (Brose M, et al.
Lancet 2014; Schlumberger M, et al. N Engl J Med 2015). The phase III trial of sorafenib included
patients with refractory DTC in first-line therapy. However, the lenvatinib phase III study included
patients in both first and second-line therapy. Based on data available from phase III trials, lenvatinib has
showed efficacy after a prior TKIs but no evidence of efficacy of sorafenib after TKIs therapy is
available.
The primary treatment of both hereditary and sporadic forms of MTC is total thyroidectomy and removal
of all neoplastic tissue present in the neck. Total thyroidectomy is preferred because up to 30% of patients
with sporadic MTC and all patients with inherited MTC have bilateral or multifocal disease. MTC usually
spreads to neck nodes and therefore routine dissection of the adjacent nodal tissue is recommended. After
surgery T4 treatment is given with the objective to maintain the TSH level within the normal range and
the patients are followed-up with serum calcitonin (and CEA) measurements. Patients who have
undetectable serum calcitonin values are considered biochemically cured. On the contrary if basal serum
calcitonin remains detectable then the patient is not cured and must be evaluated for residual disease.
Postoperative radiation therapy may be indicated in patients who underwent an incomplete resection, have
microscopic positive margins or even in patients with detectable postoperative serum calcitonin in the
absence of distant metastases because this will decrease the risk of local recurrence.
Surgery is the main treatment for local and regional recurrences whenever feasible.
Patients with progressive or symptomatic metastatic disease who cannot be treated by surgery or
radiotherapy should be considered candidates for systemic therapy. Treatment with traditional cytotoxic
agents offers limited benefit and increased toxicity. The most commonly used agents were dacarbazine,
doxorubicin and 5-FU (either in combination or single agent). Partial responses are reported in
approximately in 10 percent of patients, but long-term responses are uncommon and no benefit on PFS
has been demonstrated.
Similarly to DTC, because of the RET activating mutations observed in MTC several TKIs have been
tested.
Vandetanib
and
cabozantinib
have
demonstrated
benefit
on
PFS
in
two
phase
III
placebo-controlled clinical trials (Wells SA, et al. J Clin Oncol 2012; Elisei R, et al. J Clin Oncol 2013).
Vandetanib is widely approved in this setting. However, the percentage of grade 3-4 toxicity reported in
the phase III study of cabozantinib has limited its approval in most of countries.
Despite the significant advances in the management of refractory DTC and advanced MTC it should be
noted that unfortunately, in the majority of patients, the disease eventually progresses, highlighting the
need for new effective therapies as second and beyond treatment lines.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
The history of anaplastic thyroid cancer (ATC) is completely different. ATC is one of the most aggressive
solid tumors in humans. No standard therapy has demonstrated survival benefit in this setting. For
localized disease, surgery and local radiotherapy is the standard of care, but for locally advanced disease
or metastatic setting, the usefulness of chemotherapy and radiotherapy is controversial, and best
supportive care is mandatory.
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 2004)
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell
activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells (Keir et al 2008). 
It has 2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) (Okazaki and Honjo
2007). The PD-1 and PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as
co-inhibitory factors, which can halt or limit the development of T cell response. When PD-L1 binds to
PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production and
suppresses T-cell proliferation. Tumor cells exploit this immune checkpoint pathway as a mechanism to
evade detection and inhibit immune response.
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 2016). 
Importantly, PD-L1 is commonly over-expressed on tumor cells or on non-transformed cells in the tumor
microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells binds to PD-1 receptors on the
activated T-cells leading to the inhibition of cytotoxic T cells. These deactivated T cells remain inhibited
in the tumor microenvironment. The PD-1/PD-L1 pathway represents an adaptive immune resistance
mechanism that is exerted by tumor cells in response to endogenous anti-tumor activity.
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of evading
immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 receptor inhibits the
interaction of PD-L1 with the PD-1 and CD80 receptors expressed on immune cells. This activity
overcomes PD-L1–mediated inhibition of antitumor immunity. While functional blockade of PD-L1
results in T-cell reactivation, this mechanism of action is different from direct agonism of a stimulatory
receptor such as CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody could be
used therapeutically to enhance antitumor immune responses in patients with cancer. Results of
non-clinical and clinical studies of monoclonal antibodies (mAbs) targeting the PD-L1/PD-1 pathway
have shown evidence of clinical activity and a manageable safety profile, supporting the hypothesis that
an anti-PD-L1 antibody could be used to therapeutically enhance antitumor immune response in cancer
patients (Brahmer et al. 2012; Hirano et al. 2005; Iwai et al. 2002; Okudaira et al. 2009; Topalian et al.
2012; Zhang et al. 2008) with responses that tend to be more pronounced in patients with tumors that
express PD-L1 (Powles et al. 2014; Rizvi et al. 2015; Segal et al. 2015). In addition, high mutational
burden e.g., in bladder carcinoma (Alexandrov et al. 2013) may contribute to the responses seen with
immune therapy.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively expressed by
regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a negative regulatory signal to T
cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on antigen-presenting cells. (Fife and
Bluestone, 2008) Blockade of CTLA-4 binding to CD80/86 by anti-CTLA-4 antibodies results in
markedly enhanced T-cell activation and antitumor activity in animal models, including killing of
established murine solid tumors and induction of protective antitumor immunity. Therefore, it is expected
that treatment with an anti-CTLA-4 antibody will lead to increased activation of the human immune
system, increasing antitumor activity in patients with solid tumors.
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade of negative
regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death
ligand 1 (PD-L1) has promising clinical activity. Ipilimumab was granted United States (US) Food and
Drug Administration (FDA) approval for the treatment of metastatic melanoma and is currently under
investigation for several other malignancies whilst nivolumab and pembrolizumab, two anti-PD-1 agents
and atezolizumab, an anti PD-L1 agent have been granted approvals by agencies such as the United States
of America Food and Drug Administration and the European Medicines Agency approval for the
treatment of a number of malignancies including metastatic melanoma, squamous and non-squamous cell
non-small-cell lung cancer and urothelial carcinoma. In addition, data from agents in the anti-PD-1/PD-L1
class shows clinical activity in a wide range of tumor types.
1.1.2. Durvalumab
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass
that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and
CD80 (B7.1) on immune cells (IC). It 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.) The proposed
mechanism of action (MOA) for durvalumab is interference in the interaction of PD-L1 with PD-1 and
CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune
responses, including those that may result in tumor elimination. In vitro studies demonstrate that
durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored
proliferation of IFN-´ (Stewart et al 2015). In vivo studies have shown that durvalumab inhibits tumor
growth in xenograft models via a T-cell-dependent mechanism (Stewart et al 2015). Based on these data,
durvalumab is expected to stimulate the patient9s antitumor immune response by binding to PD-L1 and
shifting the balance toward an antitumor response. Durvalumab has been engineered to reduce
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
As of the data cut-off (DCO) date (12 July 2017), across the entire clinical development program over
than 8000 patients, an estimated 4067 patients have been exposed to 1 or more doses of durvalumab in
ongoing 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 externally sponsored/investigator-initiated clinical trials (ESR/IITs).
Details on the safety profile of durvalumab monotherapy are summarized in Section 6.5. Refer to the
current durvalumab Investigator9s Brochure for a complete summary of non-clinical and clinical
information including safety, efficacy and pharmacokinetics.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
1.1.3. Tremelimumab
Tremelimumab is a human immunoglobulin (Ig) G2 mAb that is directed against CTLA-4; cluster of
differentiation [CD] 152), a cell surface receptor that is expressed primarily on activated T cells and acts
to inhibit their activation. Tremelimumab completely blocks the interaction of human CTLA-4 with CD80
and CD86, resulting in increased release of cytokines (interleukin [IL]-2 and interferon [IFN]-´) from
human T cells, peripheral blood mononuclear cells and whole blood (Tarhini and Kirkwood 2008).
Tremelimumab is being developed by AstraZeneca for use in the treatment of cancer.
To date tremelimumab has been given to more than 1500 patients as part of ongoing studies either as
monotherapy or in combination with other anticancer agents. Details on the safety profile of
tremelimumab monotherapy are summarized in the current tremelimumab Investigator9s Brochure for a
complete
summary
of
non-clinical
and
clinical
information
including
safety,
efficacy
and
pharmacokinetics.
1.1.4. Durvalumab in combination with tremelimumab
Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant targeting both PD-1 and
CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012); therefore, in addition to
evaluating both agents in the monotherapy setting in a number of cancer indications AstraZeneca is also
investigating the use of durvalumab + tremelimumab combination therapy for the treatment of cancer.
Study D4190C00006 is a Phase Ib dose-escalation study to establish the safety, PK/pharmacodynamics,
and preliminary anti-tumor activity of durvalumab + tremelimumab combination therapy in patients with
advanced NSCLC. The dosing schedule utilized is durvalumab every 2 or 4 weeks (Q2W, Q4W) up to
12 months, combined with tremelimumab Q4W up to Week 24 for 7 doses then every 12 weeks (Q12W)
for 2 additional doses for up to 12 months. The study is ongoing and continues to accrue. In addition,
other clinical studies have since started looking at the combination in both NSCLC and other oncology
indications.
To date more than 1000 patients have received the combination, using a number of doses and dosing
schedules. Details on the safety profile of durvalumab + tremelimumab combination therapy are
summarized in Sections 1.4.2. Refer to the current editions of the durvalumab and tremelimumab IBs for
a complete summary of non-clinical and clinical information including safety, PK and efficacy.
1.2.
Research hypothesis
The treatment options for patients with DTC and MTC who have progressed on one line of therapy are
limited and there is no treatment that is generally considered as standard of care. No clinically meaningful
benefit has yet been demonstrated with cytotoxic chemotherapy. On the other hand patients are still in
good general condition and may still benefit from treatment and experience survival prolongation.
First-line and second-line therapy with TKIs (sorafenib/lenvatinib in DTC and vandetanib/cabozantinib in
MTC) achieve a 6-month PFS rate of 70-80%. However, beyond second-line treatment with other MKIs
out of clinical trial in both DTC and MTC median PFS achieve 6-7 months with no partial remissions
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
reported (Massicotte MH, et al. Eur J of Endocr 2014). The PFS-rate at 6 months of placebo arms in first
and second-line in patients with documented disease progression in DTC and MTC is between 20-30%.
Anaplastic thyroid cancer has no standard therapy that demonstrated benefit in overall survival. Prognosis
is very poor and median overall survival is 3-4 months.
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 behaviour is more
aggressive and the probability of immune escape process is higher.
Our hypothesis is that Durvalumab plus Tremelimumab may improve PFS-rate at 6 months in advanced
thyroid cancer from 25% up to 45% based on the initial report of early clinical trials with immune check
point inhibitors in advanced thyroid cancer.
For ATC, we hypothesize that the combination therapy may improve overall survival rate at 6 months
from 5% to 35%.
1.3.
Rationale for conducting this study
The treatment of advanced DTC and MTC has evolved dramatically during the last 5 years with the
arrival of TKIs that have changed the natural history of these diseases. However, when tumors became
resistant to TKIs, no additional therapies have showed activity in these settings. The initial good
prognosis of DTC and MTC changes completely when these diseases progress to TKIs therapy with a
higher aggressiveness and poor outcome. The ATC evolution is even worse, being refractory to
chemotherapy upfront and with no real options to control the disease.
The scientific rationale for the use of immunotherapy in advanced thyroid cancer includes:
1. The presence of an inflammatory infiltrate in a large percentage of tumors (in particular DTC).
2. The presence of a driver mutation in most DTCs and MTC. However, the number of mutations per
tumor is rather low in classical thyroid cancers but is significantly higher in refractory thyroid
cancers.
3. Anaplastic thyroid cancer is characterized for carrying a high mutational tumor load that increases the
probability of neoantigens and the usefulness of immunotherapy in this setting.
4. Positive immunohistochemistry with antibodies directed against PDL1 has been reported between
50-80% in different series, correlated with worse prognosis.
5. Microsatellite instability has been reported in up to 50% of DTC. This microsatellite instability has
been correlated with a higher mutational tumor load.
The evidence of efficacy of immune checkpoint inhibitors in thyroid cancer is still very preliminary,
including initial data from phase I/Ib clinical trials. The data currently reported from the KEYNOTE-028
showed a 9% of partial responses by RECIST, tumor shrinkage in almost 50% of patients and mPFS of
6.8 months in refractory setting, including long responders (Mehnert JM, et al. ASCO 2016).
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Tremelimumab and Durvalumab would be the first immune combination agents showing efficacy in
advanced thyroid cancer including all the histologies (DTC, MTC and ATC).
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
and responses have been observed in patients with PD-L1-positive tumors and patients with
PD-L1-negative tumors. Additionally, 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. In fact, combining immunotherapy agents has been shown to result
in improved response rates (RRs) relative to monotherapy.
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.
Pharmacokinetics/Pharmacodynamics data
Study D4190C00006 included dose cohorts with both a Q4W and a Q2W schedule of durvalumab in
combination with a Q4W schedule of tremelimumab. The Q4W schedule was included to align with the
Q4W dosing of tremelimumab. PK simulations from 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 dosing with durvalumab. The observed
durvalumab PK data from the D4190C00006 study were in line with the predicted monotherapy PK data
developed pre-clinically and in line with that seen in the first-time-in-human (FTIH), single agent study
(CD-ON-MEDI4736-1108) in patients with advanced solid tumors. 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 maximum plasma
concentration 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.
Clinical data
In Study D4190C00006 various dose combinations have been explored, with doses of tremelimumab
ranging from 1 to 10 mg/kg and doses of durvalumab ranging from 3 to 20 mg/kg. Tremelimumab was
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
given on a Q4W schedule whilst durvalumab was explored in both a Q4W and Q2W schedule, with the
goal of identifying the dose combination that best optimizes the benefit-risk profile in an acceptable range
of PK and pharmacodynamic values.
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events (AEs),
including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 10 mg/kg
durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg tremelimumab cohorts
treated at the q2w schedule, the number of patients reporting any AE, Grade 3 AEs, SAEs, and
treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg tremelimumab cohort than the
10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A similar pattern was noted in the q4w regimens,
suggesting that, as the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related
events may be anticipated. Further, the SAEs frequently attributed to immunotherapy, pneumonitis and
colitis, were more commonly seen in cohorts using either 3 or 10 mg/kg of tremelimumab compared to
the 1-mg/kg dose cohorts. Together, these data suggest that a combination using a tremelimumab dose of
1 mg/kg appeared to minimize the rate of toxicity when combined with durvalumab. As a result, all
combination doses utilizing either the 3 or 10 mg/kg doses of tremelimumab were eliminated in the final
dose selection.
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab did not
show an increase in the rate of AEs. The data suggested that increasing doses of durvalumab may not
impact the safety of the combination as much as the tremelimumab dose. Further, safety data between the
10-mg/kg and 20-mg/kg cohorts were similar, with no change in safety events with increasing dose of
durvalumab.
In Study D4190C00006, of all treatment cohorts, the cohort of patients treated in the 20 mg/kg
durvalumab + 1 mg/kg tremelimumab group had a tolerable safety profile, but still showed strong
evidence of clinical activity. No dose-limiting toxicities (DLTs) were reported in this cohort.
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 14 patients in this cohort,
there were 4 patients (29%) with PR, 4 patients (29%) with SD, and 2 patients (14%) with PD. Two
patients were not evaluable for response.
Altogether, 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 Investigator9s Brochure for a complete summary of non-clinical and
clinical information on the durvalumab + tremelimumab combination, including safety, efficacy and
pharmacokinetics.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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).
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of durvalumab
and tremelimumab) also show an approximately dose-proportional increase in PK exposure for
durvalumab over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W. (For further information on
PK observations in Study 006, please see the current IB).
The observed durvalumab PK data from the combination study were well in line with the predicted
monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen.
The durvalumab + tremelimumab combination regimen will be administered for 4 doses Q4W followed
by durvalumab monotherapy Q4W until disease progression.
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data from a Phase I 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 the PK of durvalumab (coefficient of f0.5).
The impact of body WT-based (10 mg/kg Q2W or 20 mg/kg Q4W) and fixed dosing (750 mg Q2W or
1500 mg Q4W) of durvalumab was evaluated by comparing predicted steady state PK exposures
(AUCss,0-28, Cmax,ss, and Cmin,ss) using the population PK model. A fixed dose of 750 mg Q2W was
selected to approximate 10 mg/kg Q2W and a fixed dose of 1500 mg Q4W was selected to approximate
20 mg/kg Q4W (based on median body WT of ~75 kg). A total of 1000 patients were simulated using
body WT distribution of 40–120 kg. Simulation results demonstrate that body WT-based (10 mg/kg
Q2W) and fixed dosing (750 mg Q2W) regimens yield similar median steady state Q2W and a fixed dose
of 1500 mg Q4W was selected to approximate 20 mg/kg Q4W.
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 f0.5).
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 kg 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-patient
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
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies (Wang
et al. 2009). 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-patient variability in
pharmacokinetic/pharmacodynamics parameters (Zhang et al. 2012).
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing
errors. Given expectation of similar pharmacokinetic exposure and variability, we considered it feasible to
switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W
durvalumab (equivalent to 20 mg/kg Q4W) and a fixed dose of 75 mg Q4W tremelimumab (equivalent to
1 mg/kg Q4W) is included in the current study.
1.4.
Benefit-risk and ethical assessment
Natural history of advanced DTC and MTC is usually prolonged. Well differentiated thyroid cancers 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. The arrival of TKIs have
changed the management of refractory disease. However, the toxicity profile of these drugs, the need for
prolonged treatments and the lack of efficacy in overall survival have limited the expanded use of these
therapies, otherwise being the only treatment option in advanced stages.
In ATC, the lack of approved therapies with impact in OS, PFS or even response rate, urgently increases
the need for effectives therapies that could change the very poor prognosis of this disease.
1.4.1. Potential benefits
1.4.1.1.
Durvalumab + tremelimumab
Available data suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may have
profound and durable benefits in patients with melanoma. 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 immune checkpoint inhibitor 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 immune
checkpoint inhibitors, especially for drug combination. 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.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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 (e.g., 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 from the combination of tremelimumab to durvalumab, the ORR can be
increased in patients with PD-L1 negative NSCLC.
In the particular case of thyroid cancers, the expression of PD-L1 has been described between 50-80%,
and the combination of durvalumab plus tremelimumab could offer benefit to the whole refractory
population. Data from anti PD-L1/PD-1 monotherapy has reported <10% of partial remissions in DTC,
that could also be increased with the combination of durvalumab and tremelimumab.
1.4.1.2.
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell death
ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or cytotoxic
T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses directed against tumor
cells. By stimulating the immune system however, there is the potential for adverse effects on other
tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are thought to be
due to the effects of inflammatory cells on specific tissues. These risks are generally events with a
potential inflammatory or immune mediated mechanism and which may require more frequent monitoring
and/or unique interventions such as corticosteroids, immunosuppressants and/or endocrine therapy. These
immune mediated effects, can occur in nearly any organ system, and are most commonly seen as
gastrointestinal AEs such as colitis and diarrhoea, pneumonitis/interstitial lung disease (ILD), hepatic AEs
such as hepatitis and liver enzyme elevations, skin events such as rash and dermatitis and
endocrinopathies including hypo- and hyperthyroidism.
1.4.1.3.
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhoea/colitis, pneumonitis/interstitial lung
disease (ILD), endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper-
and hypothyroidism, type I diabetes mellitus (which may present with diabetic ketoacidosis), and diabetes
insipidus),
hepatitis/increases
in
transaminases,
nephritis/increases
in
creatinine,
rash/dermatitis
(including pemphigoid, myocarditis, myositis/polymyositis, immune thrombocytopenia, infusion-related
reactions, hypersensitivity reactions, pancreatitis, encephalitis serious infections, subcutaneous injection
site reaction, and other rare or less frequent inflammatory events including neuromuscular toxicities (eg,
Guillain-Barré syndrome, myasthenia gravis).
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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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
In monotherapy clinical studies, AEs at an incidence of g 20% include events such as fatigue and
decreased appetite. Approximately 10% of participants discontinued the drug due to an AE.
Please see the current version of the IB for a detailed summary of the monotherapy data including AEs,
serious adverse events (SAEs), and Common Terminology Criteria for Adverse Events (CTCAE) Grade 3
to 5 events reported across the durvalumab program.
Serious adverse reactions for durvalumab monotherapy considering expected;
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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.
1.4.1.4.
Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, diarrhoea,
enterocolitis, intestinal perforation), endocrine disorders (hypo and hyperthyroidism, hypophysitis and
adrenal insufficiency), skin effects (rash, and pruritus), elevations in lipase and amylase and clinical
manifestations of pancreatitis, other gastrointestinal events e.g. ulcerative colitis, dehydration, nausea and
vomiting; hepatic events including autoimmune hepatitis, ; pneumonitis and ILD; nervous system events
including encephalitis, peripheral motor and sensory neuropathies, Guillain-Barre and proximal muscle
weakness; cytopenias including thrombocytopenia, anemia and neutropenia; infusion-related reactions,
anaphylaxis, and allergic reactions; renal events including renal failure, acute kidney injury, nephritis,
nephrotic syndrome, autoimmune nephritis and electrolyte abnormalities such as hypokalemia;
autoimmune diseases including autoimmune arthritis, Sjogren's syndrome and giant cell temporal arteritis;
hyperglycemia and diabetes mellitus; and pyrexia.
For information on all identified and potential risks with tremelimumab please always refer to the current
version of the tremelimumab IB.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Using pooled data from monotherapy clinical studies AEs (all grades) reported very commonly (g 10% of
patients)
were diarrhea, nausea, fatigue, pruritus, decreased appetite, rash,
vomiting, dyspnoea,
constipation, cough, pyrexia, abdominal pain, decreased weight, headache, asthenia, and anaemia.
Approximately 16% of patients experienced an AE that resulted in permanent discontinuation of
tremelimumab and approximately 45% of patients experienced an SAE.
Further information on these risks can be found in the current version of the tremelimumab IB.
Serious adverse reactions for tremelimumab monotherapy considering expected;
1.4.2. Durvalumab + tremelimumab
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the ongoing
dose escalation and dose expansion Study 006, in patients with NSCLC, and is being studied in a number
of other ongoing clinical trials, in a number of different indications, and has to date shown a manageable
safety and tolerability profile.
The types of risks with the combination of durvalumab and tremelimumab (based on an equivalent
durvalumab dose of 20 mg/kg and a tremelimumab dose of 1 mg/kg) are similar to those for durvalumab
monotherapy with additional risks of amylase increased, lipase increased, intestinal perforation and large
intestinal perforation, pulmonary embolism which are unique risks for the durvalumab and tremelimumab
combination.
For information on all identified and potential risks with the durvalumab and tremelimumab combination
please always refer to the current version of the durvalumab IB.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
In durvalumab+tremelimumab combination studies at the dose of durvalumab 20 mg/kg and
tremelimumab 1 mg/kg AEs (all grades) reported very commonly (g 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.
Serious adverse reactions for durvalumab plus tremelimumab combination considered expected.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the current
version of the durvalumab IB.
1.4.3. Overall benefit-risk
Considering the refractory setting of the design of the current study and the safety profile of the
combination of durvalumab and tremelimumab, the overall benefit-risk of the treatment combination of
this trial is expected to be favourable.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
2.
STUDY OBJECTIVE
2.1.
Primary objective(s)
The study will include patients with advanced thyroid cancer in three different cohorts with the following
primary endpoints:
Primary endpoint for cohorts 1 and 2 (DTC and MTC):
6-months progression-free survival by Response Evaluation Criteria in Solid Tumors (RECIST), which is
defined as the percentage of patients achieving complete response, partial response (PR), or stable disease
(SD) at 24 weeks after durvalumab plus tremelimumab was started without observing disease progression
or death at this time point.
Primary endpoint for cohort 3 (ATC):
6-months overall survival rate, which is defined as the percentage of patients alive at 24 weeks after
durvalumab plus tremelimumab was started.
2.2.
Secondary objective(s)
1.
Overall response rate (ORR) by irRECIST and RECIST.
2.
To assess the duration of response according to irRECIST/RECIST.
3.
To assess the median progression-free survival time (PFS) according to RECIST.
4.
To assess the safety profile of Durvalumab and Tremelimumab in subjects with advanced thyroid
neoplasms.
5.
To assess the median overall survival (OS) time.
6.
To assess response status according to irRECIST/RECIST at 6 and 12 months after start of study
treatment.
2.3.
Exploratory objective(s)
1.
To evaluate biochemical response (changes in thyroglobulin, calcitonin and CEA levels) and its
association with response rate and progression-free survival.
2.
To assess whether baseline tumor and blood biomarkers may be predictive of response to
durvalumab and tremelimumab therapy.
3.
To explore additional hypotheses related to biomarkers and relationship to durvalumab and
tremelimumab efficacy and/or toxicity and thyroid cancer evolution that may arise from internal
or external research activities.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
3.
STUDY DESIGN
3.1.
Overview of study design
This is a prospective, multi-centre, open label, stratified, exploratory phase II study evaluating the
efficacy and safety of durvalumab plus tremelimumab in different cohorts of patients with thyroid
cancers.
The study will include patients in three different cohorts:
●
Cohort 1: Patients with locally advanced or metastatic differentiated thyroid cancer
(including the subtypes of papillary, follicular, poorly differentiated and Hürthle cell
carcinoma) after progression to systemic therapy with MKIs. Patients could be recruited
in the study after progression to Lenvatinib (regardless prior lines) or progression to at
least two prior MKIs that could or not include Lenvatinib. No prior therapy with immune
checkpoint inhibitors is allowed.
●
Cohort 2: Patients with locally advanced or metastatic medullary thyroid cancer after
progression to systemic therapy with MKIs. Patients could be recruited in the study after
progression to Vandetanib (regardless prior lines) or progression to at least two prior
MKIs that could or not include Vandetanib. No prior therapy with immune checkpoint
inhibitors is allowed.
●
Cohort 3: Patients with locally advanced or metastatic anaplastic thyroid cancer
regardless of prior therapy.
The study includes a Simon-II design to assess efficacy and rule out futility. The first stage will include 17
patients per cohort 1 and 2 and 12 patients per cohort 3. The patient recruitment period of the study for
this first stage will last approximately 18 months. The maximum treatment period for each subject on
study is anticipated to be approximately 24 months (based on long responders of preliminary data of
current trials with immune checkpoint inhibitors in this setting). However, subjects will continue on active
treatment until disease progression or unacceptable toxicity and also active follow-up to determine
secondary endpoints of duration of response, median progression-free survival, median overall survival
and safety profile. The second stage will be assessed after completion of first stage and only in the cohort
that reached the specified clinical benefit. For stage II, study will continue recruiting 19 additional
patients up to 36 patients per cohort. Stage II only may apply to cohort 1 and 2.
This study will be conducted in 3 phases: a screening phase, a treatment phase stratified by tumor origin
(three 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
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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.
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 discontinues the study drug.
Subjects will be allocated in each primary tumor cohort to receive durvalumab 1500 mg Q4W plus
tremelimumab 75 mg Q4W for up to 4 doses during the first 4 cycles of combined therapy. After the first
4 cycles (or before is tremelimumab is stopped due to toxicity), patients will continue to receive
durvalumab 1500 mg Q4W until disease progression or unacceptable toxicity. Cycles are defined by 4
weeks or 28 days. Subjects will undergo safety and efficacy assessment as defined per protocol.
If a toxicity 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.
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 disease progression during the treatment phase or if they
present unacceptable toxicity. For patients that complete the scheduled treatment, the follow-up phase will
begin to determine survival endpoints. Tumor assessments will continue every 12 weeks or clinically
indicated following local protocol assessments.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
and
clinical
chemistry;
physical
examinations; and regular measurement of vital signs, and
electrocardiograms (ECGs) as detailed in the schedule of visits and procedures.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
4.
PATIENT
SELECTION,
ENROLLMENT,
RANDOMIZATION,
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL
Approximately 46 patients will be enrolled and allocated in a balanced manner into either the three
cohorts of patients at approximately 15 sites in Spain during the first stage of the trial (Simon-II design).
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 circumstances, will there be exceptions to this rule.
In a second stage, 38 additional patients may be included in cohorts 1 and 2 (19 in each cohort
respectively) if they meet the efficacy endpoint.
4.1.
Inclusion criteria
For inclusion in the study, patients should fulfil the following criteria:
1.
Written informed consent obtained from the subject prior to performing any protocol-related
procedures, including screening evaluations.
2.
Age g 18 years at time of study entry.
3.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4.
Body weight >30kg.
5.
Confirmed differentiated thyroid cancer (papillary, follicular, poorly differentiated and Hürtle
cell), medullary thyroid cancer and anaplastic thyroid cancer.
6.
Available tumor and blood samples for translational research
7.
Patients should meet one of the following criteria:
a.
Cohort 1: Patients with locally advanced or metastatic differentiated thyroid cancer
(including the subtypes of papillary, follicular, poorly differentiated and Hürthle cell
carcinoma) after disease progression on systemic therapy with MKIs. Patients could be
recruited in the study after progression to Lenvatinib (regardless prior lines) or
progression on at least two prior MKIs which may or not include Lenvatinib. No prior
therapy with immune checkpoint inhibitors is allowed. Patients with intolerable toxicity
to MKIs that meet the prior inclusion criteria and experience disease progression by
RECIST v1.1 after stopping therapy may be included.
b.
Cohort 2: Patients with locally advanced or metastatic medullary thyroid cancer after
progression on systemic therapy with MKIs. Patients could be recruited in the study after
progression to Vandetanib (regardless prior lines) or progression to at least two prior
MKIs that may or not include Vandetanib. No prior therapy with immune checkpoint
inhibitors is allowed. Patients with intolerable toxicity to MKIs that meet the prior
inclusion criteria and experience disease progression by RECIST v1.1 after stopping
therapy may be included.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
c.
Cohort 3: Patients with locally advanced or metastatic anaplastic thyroid cancer
regardless of prior therapy. No prior therapy with immune checkpoint inhibitors is
allowed.
8.
No limitation of number of prior therapies.
9.
Life expectancy >3 months
10. Adequate normal organ and marrow function as defined below:
a.
Haemoglobin g9.0 g/dL.
b.
Absolute neutrophil count (ANC) > 1500 per mm3.
c.
Platelet count g100,000 per mm3.
d.
Serum bilirubin f1.5 x institutional upper limit of normal (ULN). This will not apply to
patients with confirmed Gilbert9s 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.
e.
AST (SGOT)/ALT (SGPT) f2.5 x institutional upper limit of normal unless liver
metastases are present, in which case it must be f 5x U
f.
Measured creatinine clearance (CL) >40 mL/min or Calculated 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)
11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female
pre-menopausal patients. Women will be considered post-menopausal if they have been
amenorrheic for 12 months without an alternative medical cause. The following age-specific
requirements apply:
a.
Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels
in the post-menopausal range for the institution or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy).
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
b.
Women g50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
12. Patient is willing and able to comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations including follow up.
4.2.
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Participation in another clinical study with an investigational product during the last 21
days.(washing period < 21days)
2.
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional)
clinical study or during the follow-up period of an interventional study.
3.
Any previous treatment with a PD1, PD-L1 or CTLA-4 inhibitor, including durvalumab and
tremelimumab.
4.
Any previous treatment with immunotherapy, including combinations of immunotherapy and
other anticancer or targeted agents.
5.
Mean QT interval corrected for heart rate (QTc) g470 ms calculated from 3 electrocardiograms
(ECGs) using Fridericia9s Correction.
6.
Current or prior use of immunosuppressive medication within 28 days before the first dose of
durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an
equivalent corticosteroid. The following are exceptions to this criterion:
a.
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular
injection).
b.
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
its equivalent.
c.
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
7.
Any unresolved toxicity NCI CTCAE Grade g2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:
a.
Patients with Grade g2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician.
b.
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment
with durvalumab may be included only after consultation with the Study Physician.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
8.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent
use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is
acceptable.
9.
History of allogenic organ transplantation.
10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory
bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis],
systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are
exceptions to this criterion:
a.
Patients with vitiligo or alopecia.
b.
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement.
c.
Any chronic skin condition that does not require systemic therapy.
d.
Patients without active disease in the last 5 years may be included but only after
consultation with the study physician.
e.
Patients with celiac disease controlled by diet alone.
11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection,
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris,
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated
with diarrhea, or psychiatric illness/social situations that would limit compliance with study
requirement, substantially increase risk of incurring AEs or compromise the ability of the patient
to give written informed consent.
12. History of another primary malignancy except for:
a.
Malignancy treated with curative intent and with no known active disease g5 years before
the first dose of IP and of low potential risk for recurrence.
b.
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease.
c.
Adequately treated carcinoma in situ without evidence of disease.
13. History of active primary immunodeficiency.
14. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical
examination and radiographic findings, and TB testing in line with local practice), hepatitis B
(known
positive
HBV
surface
antigen
(HBsAg)
result),
hepatitis
C,
or
human
immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg)
are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
reaction is negative for HCV RNA.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
15. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if
enrolled, should not receive live vaccines whilst receiving IP and up to 30 days after the last dose
of IP.
16. 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 90 days
after the last dose of durvalumab monotherapy and 180 days for combined treatment with
durvalumab and tremelimumab
17. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
18. Judgment by the investigator that the patient is unsuitable to participate in the study and the
patient is unlikely to comply with study procedures, restrictions and requirements.
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3
If a patient withdraws from participation in the study, then his or her enrolment/randomization code
cannot be reused. Withdrawn patients will not be replaced.
4.3.
Withdrawal of patients from study treatment and/or study
Permanent discontinuation of study treatment
An individual patient will not receive any further investigational product if any of the following occur in
the patient in question and will enter in the follow-up phase:
1.
An individual patient will not receive any further durvalumab + tremelimumab combination
therapy or durvalumab monotherapy if their weight falls to 30 kg or less.
2.
Withdrawal of consent or lost to follow-up
3.
Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further
dosing
4.
Patient 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
5.
Pregnancy or intent to become pregnant
6.
Any AE that meets criteria for discontinuation as defined in Section 0.
7.
Grade g3 infusion reaction
8.
Patient noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal;
e.g., refusal to adhere to scheduled visits
9.
Initiation of alternative anticancer therapy including another investigational agent
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
10.
Confirmation of PD and investigator determination that the patient is no longer benefiting
from treatment with durvalumab + tremelimumab or durvalumab monotherapy. Patients 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
11.
Patients who are permanently discontinued from receiving investigational product will be
followed for safety per Section 10 and Appendix 2 or Appendix 3, including the collection of
any protocol-specified blood specimens, unless consent is withdrawn or the patient is lost to
follow-up or enrolled in another clinical study. All patients will be followed for survival.
Patients 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
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice to further
treatment.
Patients who withdraw consent for further participation in the study will not receive any further IP or
further study observation, with the exception of follow-up for survival, which will continue until the end
of the study unless the patient has expressly withdrawn their consent to survival follow-up. Note that the
patient may be offered additional tests or tapering of treatment to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and the
presence of any AE. The Investigator will follow up AEs outside of the clinical study.
Any AE that meets criteria for discontinuation as defined in the Dosing Modification and Toxicity
Management Guidelines (Appendix 1)
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to:
●
all further participation in the study including any further follow up (e.g., survival contact
telephone calls)
●
withdrawal of consent to the use of their study generated data
●
withdrawal to the use of any samples
4.4.
Replacement of patients
If a patient withdraws from participation in the study, then his or her enrolment/randomization code
cannot be reused.  Withdrawn patients will not be replaced.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
5.
INVESTIGATIONAL PRODUCT(S)
5.1.
Durvalumab and tremelimumab
The Investigational Products Supply section of AstraZeneca/MedImmune will supply durvalumab and
tremelimumab to the sponsor as a solution for infusion after dilution. It is the sponsor9s responsibility to
provide the sites with the study drug.
5.1.1. Formulation/packaging/storage
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion after
dilution. 
The
solution
contains
50
mg/mL
durvalumab
(MEDI4736),
26
mM
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v)
polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10.0 mL. Investigational product vials are
stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in secondary
packaging until use to prevent excessive light exposure.
Tremelimumab
Tremelimumab will be supplied by AstraZeneca either as a 400-mg or a 25-mg vial solution for infusion
after dilution. The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine hydrochloride,
222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% weight/volume (w/v)
polysorbate 80; it has a pH of 5.5 and density of 1.034 g/mL. The nominal fill volume is 20.0 mL for the
400-mg vial and 1.25 mL for the 25-mg vial. Investigational product vials are stored at 2°C to 8°C (36°F
to 46°F) and must not be frozen. Drug product should be kept in original container until use to prevent
prolonged  light exposure.
5.2.
Dose and treatment regimens
5.2.1. Treatment regimens
Durvalumab + tremelimumab combination therapy followed by durvalumab monotherapy
Patients will receive durvalumab (MEDI4736) (1500 mg Q4W) in combination with tremelimumab
(75 mg IV Q4W) for up to 4 doses/cycles each, followed by durvalumab (MEDI4736) 1500 mg Q4W
until confirmed disease progression unless there is unacceptable toxicity, withdrawal of consent, or
another discontinuation criterion is met. The first durvalumab (MEDI4736) monotherapy dose at 1500
mg Q4W will be 4 weeks after the final dose of durvalumab (MEDI4736) in combination with
tremelimumab.
See Figure 2. (N.B An individual patient will not receive any further durvalumab +
tremelimumab combination therapy or durvalumab monotherapy if their weight falls to 30 kg or less).
Tremelimumab will be administered first; the durvalumab (MEDI4736) infusion will start approximately
1 hour (maximum 2 hours) after the end of the tremelimumab infusion. Standard infusion time for each is
1 hour. In the event that there are interruptions during infusion, the total allowed time should not exceed
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
8 hours at room temperature per infusion. If there are no clinically significant concerns after the first
cycle, then, at the discretion of the Investigator, all other cycles of durvalumab (MEDI4736) can be given
immediately after the tremelimumab infusion has finished.
Figure 1. Durvalumab (MEDI4736) + tremelimumab combination therapy dosing schedule
The trial medication (i.e., Durvalumab and Tremelimumab) and its packaging will be labelled in
accordance with annex 13 of EU to Good Manufacturing Practice. Storage will be done according IB and
labelling specifications.
5.2.2. Duration of treatment and criteria for retreatment
All treatment will be administered beginning on Day 1 until confirmed PD unless there is unacceptable
toxicity, withdrawal of consent, or another discontinuation criterion is met.
Patients with rapid tumour progression or with symptomatic progression that requires urgent medical
intervention (e.g., central nervous system metastasis, respiratory failure due to tumor compression, spinal
cord compression) will not be eligible for continuing durvalumab (MEDI4736) ± tremelimumab.
For all patients who are treated through progression, the investigator should ensure patients do not have
any significant, unacceptable or irreversible toxicities that indicate continuing would not further benefit
the patient.
Patients who the sponsor and the Investigator determine may not continue treatment after PD will be
followed up for survival. Patients who have discontinued treatment due to toxicity or symptomatic
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
deterioration, or who have commenced subsequent anticancer therapy, will be followed up until
confirmed disease progression and for survival.
5.2.3. Study drug preparation of durvalumab and tremelimumab
Based on average body WT of 75 kg, 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.
Preparation of durvalumab doses for administration with an IV bag
The dose of durvalumab (MEDI4736) for administration must be prepared by the Investigator9s or site9s
designated IP manager using aseptic technique. Total time from needle puncture of the durvalumab
(MEDI4736) vial to the start of administration should not exceed:
●
24 hours at 2°C to 8°C (36°F to 46°F)
●
4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement of
administration.
A dose of 1500 mg (for patients >30kg in weight) will be administered using an IV bag containing 0.9%
(w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) concentration ranging from 1 to
15 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. Add
30.0 mL of durvalumab (MEDI4736) (ie, 1500 mg of durvalumab [MEDI4736]) to the IV bag. The IV
bag size should be selected such that the final concentration is within 1 to 15 mg/mL. Mix the bag by
gently inverting to ensure homogeneity of the dose in the bag.
An individual patient will not receive any further durvalumab + tremelimumab combination therapy or
durvalumab monotherapy if their weight falls to 30 kg or less.
Standard infusion time 1 hour. In the event that there are interruptions during infusion, the total allowed
infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent 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.
If either preparation time or infusion time exceeds the time limits a new dose must be prepared from new
vials. Durvalumab (MEDI4736) does not contain preservatives, and any unused portion must be
discarded.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Preparation of tremelimumab doses for administration with an IV bag
The dose of tremelimumab for administration must be prepared by the Investigator9s or site9s 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 (36°F to 46°F)
●
4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement of
administration.
A dose of 75 mg (for patients >30kg in weight) will be administered using an IV bag containing 0.9%
(w/v) saline or 5% (w/v) dextrose, with a final tremelimumab concentration ranging from 0.10 to 10
mg/mL and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. Add 3.8 mL
(i.e.75 mg of tremelimumab, with the dose volume rounded to the nearest tenth mL) to the IV bag. The IV
bag size should be selected such that the final concentration is within 0.10 to 10 mg/mL. Mix the bag by
gently inverting to ensure homogeneity of the dose in the bag.
An individual patient will not receive any further durvalumab + tremelimumab combination therapy or
durvalumab monotherapy if their weight falls to 30 kg or less.
Standard infusion time is 1 hour.
In the event that there are interruptions during infusion, the total
allowed infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent 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.
If either preparation time or infusion time exceeds the time limits 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 fGrade 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 fGrade 2 infusion-related reaction, subsequent infusions may be
administered at 50% of the initial rate. Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or
equivalent medications per institutional standard may be administered at the discretion of the investigator.
If the infusion-related reaction is gGrade 3 or higher in severity, study drug will be discontinued. For
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
management of patients who experience an infusion reaction, please refer to the toxicity and management
guidelines in Appendix 1.
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. Study drug will be destroyed at local hospital pharmacy and not
returned to the promoter/sponsor. 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 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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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
6.
TREATMENT PLAN
6.1.
Patient enrolment and allocation
6.1.1. Procedures for allocation
Patients will be allocated in one of the following cohorts regarding primary tumour site:
1.
Cohort 1: Patients with locally advanced or metastatic differentiated thyroid cancer (including the
subtypes of papillary, follicular, poorly differentiated and Hürthle cell carcinoma) after
progression to systemic therapy with MKIs. Patients could be recruited in the study after
progression to Lenvatinib (regardless prior lines) or progression to at least two prior MKIs that
may or not include Lenvatinib. No prior therapy with immune checkpoint inhibitors is allowed.
2.
Cohort 2: Patients with locally advanced or metastatic medullary thyroid cancer after progression
to systemic therapy with MKIs. Patients could be recruited in the study after progression to
Vandetanib (regardless prior lines) or progression to at least two prior MKIs that may or not
include Vandetanib. No prior therapy with immune checkpoint inhibitors is allowed.
3.
Cohort 3: Patients with locally advanced or metastatic anaplastic thyroid cancer regardless of
prior therapy. No prior therapy with immune checkpoint inhibitors is allowed.
6.1.2. Procedures for handling patients 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
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and
non-immune-mediated reactions for durvalumab are provided in the durvalumab/tremelimumab Toxicity
Management Guidelines (TMGs). Please see Appendix 1. The most current version of the TMGs is also
available through the following link: https://tmg.azirae.com. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out neoplastic,
infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, immunologic, and
histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. In the absence of a
clear alternative etiology, events should be considered potentially immune related.
In addition, there are certain circumstances in which durvalumab and tremelimumab should be
permanently discontinued (see Section 4.3 of this protocol and the Dosing Modification and Toxicity
Management Guidelines in Appendix 1.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Following the first dose of IP, subsequent administration of durvalumab and tremelimumab can be
modified based on toxicities observed as described in the Dosing Modification and Toxicity Management
Guidelines in Appendix 1. These guidelines have been prepared to assist the Investigator in the exercise
of his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs considered
causally related to durvalumab monotherapy and the durvalumab + tremelimumab regimen by the
reporting investigator.
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the Study
Physician.
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out neoplastic,
infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, immunologic, and
histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. In the absence of a
clear alternative aetiology, events should be considered potentially immune related.
All toxicities will be graded according to NCI CTCAE, Version 5.0.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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 patient of child-bearing potential
●
Female patients of childbearing potential who are not abstinent and intend to be sexually active
with a non-sterilized male partner must use at least 1 highly effective method of contraception
(Table 1) from the time of screening throughout the total duration of the drug treatment and the
drug washout period (180 days after the last dose of durvalumab + tremelimumab combination
therapy or 90 days after the last dose of durvalumab monotherapy). Non-sterilised male partners of
a female patient of childbearing potential must use male condom plus spermicide throughout this
period. Cessation of birth control after this point should be discussed with a responsible physician.
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of
birth control.  Female patients should also refrain from breastfeeding throughout this period.
Male patients with a female partner of childbearing potential
●
Non-sterilized male patients who are not abstinent and intend to be sexually active with a female
partner of childbearing potential must use a male condom plus spermicide from the time of
screening throughout the total duration of the drug treatment and the drug washout period (180
days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the
last dose of durvalumab monotherapy). However, periodic abstinence, the rhythm method, and the
withdrawal method are not acceptable methods of contraception. Male patients should refrain from
sperm donation throughout this period.
●
Female partners (of childbearing potential) of male patients must also use a highly effective method
of contraception throughout this period (Table 1).
N.B Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.
Women will be considered post-menopausal if they have been amenorrheic for 12 months without an
alternative medical cause.  The following age-specific requirements apply:
Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12
months or more following cessation of exogenous hormonal treatments and if they have luteinizing
hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution.
Women g50 years of age would be considered post-menopausal if they have been amenorrheic for 12
months or more following cessation of all exogenous hormonal treatments, had radiation-induced
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1
year ago.
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., less than
1% per year) when used consistently and correctly are described in Table 1. Note that some contraception
methods are not considered highly effective (e.g., male or female condom with or without spermicide;
female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device;
progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode
of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined
oral contraceptive pills).
Table 1. Highly effective methods of contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal Methods
●
Copper T intrauterine device
●
Levonorgestrel-releasing intrauterine system
(e.g., Mirena®)a
●
Implants: Etonogestrel-releasing
implants: e.g. Implanon® or Norplant®
●
Intravaginal:
Ethinylestradiol/etonogestrel-releasing
intravaginal devices: e.g. NuvaRing®
●
Injection: Medroxyprogesterone
injection: e.g. Depo-Provera®
●
Combined Pill: Normal and low dose
combined oral contraceptive pill
●
Patch:
Norelgestromin/ethinylestradiol-releasin
g transdermal system: e.g. Ortho Evra®
●
Minipill: Progesterone based oral
contraceptive pill using desogestrel:
Cerazette® is currently the only highly
effective progesterone based pill
a
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 180 days after last infusion of 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.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Restricted, prohibited, and permitted concomitant medications are described in the following tables. Refer
to Section 6.2 for guidance on management of IP-related toxicities.
7.2.1. Permitted concomitant medications
Table 2. Supportive medications
Supportive medication/class of drug
Usage
Concomitant
medications
or
treatments
(e.g., acetaminophen or diphenhydramine) deemed
necessary
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,
correction
of
metabolic
disorders,
optimal
symptom
control,
and
pain
management [including palliative radiotherapy to
non-target lesions, etc.])
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the influenza
vaccine
Permitted
7.2.2.
Excluded concomitant medications
Table 3. Prohibited concomitant medications
Prohibited medication/class of drug
Usage
Any investigational anticancer therapy other than
those under investigation in this study
Should not be given concomitantly whilst the
patient is on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 other than
those under investigation in this study
Should not be given concomitantly whilst the
patient is on study treatment
Any
concurrent
chemotherapy,
radiotherapy,
immunotherapy, or biologic or hormonal therapy for
cancer
treatment
other
than
those
under
investigation in this study
Should not be given concomitantly whilst the
patient is on study treatment. (Concurrent use of
hormones
for
non-cancer-related
conditions
[e.g., insulin
for
diabetes
and
hormone
replacement
therapy]
is
acceptable.
Local
treatment of isolated lesions, excluding target
lesions, for palliative intent is acceptable [e.g., by
local surgery or radiotherapy])
Immunosuppressive medications including, but not
limited
to,
systemic
corticosteroids
at
doses
exceeding
<<10
mg/day>>
of
prednisone
or
equivalent, methotrexate, azathioprine, and tumor
necrosis factor-α blockers
Should not be given concomitantly or used for
premedication prior to the I-O infusions. The
following are allowed exceptions:
●
Use of immunosuppressive medications for
the management of IP-related AEs,
●
Use in patients with contrast allergies.
●
In addition, use of inhaled, topical, and
intranasal corticosteroids is permitted.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
A temporary period of steroids will be allowed if
clinically indicated and considered to be essential for
the management of non-immunotherapy related
events experienced by the patient (e.g., chronic
obstructive pulmonary disease, radiation, nausea,
etc.).
Drugs with laxative properties and herbal or natural
remedies for constipation
Should be used with caution through to 90 days
after the last dose of tremelimumab during the
study
Sunitinib
Should not be given concomitantly or through 90
days after the last dose of tremelimumab (acute
renal failure has been reported with combination
therapy of tremelimumab and sunitinib)
EGFR TKIs
Should not be given concomitantly.
Should be used with caution in the 90 days post
last dose of durvalumab.
Increased incidences of pneumonitis (with third
generation EGFR TKIs) and increased incidence of
transaminase increases (with 1st generation EGFR
TKIs) has been reported when durvalumab has
been given concomitantly.
Live attenuated vaccines
Should not be given through 30 days after the last
dose of IP (including SoC)
Herbal
and
natural
remedies which may have
immune-modulating effects
Should not be given concomitantly unless agreed
by the sponsor
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
8.
STUDY PROCEDURES
8.1.
Schedule of study procedures
Before study entry, throughout the study, and following study drug discontinuation, various clinical and
diagnostic laboratory evaluations are outlined. The purpose of obtaining these detailed measurements is to
ensure adequate safety and tolerability assessments. Clinical evaluations and laboratory studies may be
repeated more frequently if clinically indicated. The Schedules of Assessments during the screening and
treatment period is provided following the Protocol Synopsis.
For all treatment periods (durvalumab-tremelimumab combination and durvalumab monotherapy)
●
PRO and tumor efficacy (RECIST) assessment dates are not affected by dose delays and
remain as originally scheduled, as they are based on the date of inclusion (not the date of
therapy).
●
All other scheduled assessments must be performed relative to the start of the dosing cycle
such that all laboratory procedures, etc. required for dosing should be performed within 3 days
prior to dosing.
For durvalumab monotherapy or durvalumab + tremelimumab combination period
●
Patients may delay dosing under certain circumstances.
−
Dosing may be delayed per Toxicity Management Guidelines, due to either an
immune or a non-immune-related AE.
−
If dosing must be delayed for reasons other than treatment-related toxicity, dosing
will resume as soon as feasible
−
Dosing intervals of subsequent cycles may be shortened as clinically feasible in
order to gradually align treatment cycles with the schedule of tumor efficacy
(RECIST) and PRO assessments. Subsequent time between 2 consecutive doses
cannot be less than 22 days, based on the half-lives of durvalumab and
tremelimumab
(see
current
Investigator
Brochures
for
durvalumab
and
tremelimumab.
8.1.1. Screening phase
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified. All
patients must first read, understand, and sign the IRB/REB/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, patients will be enrolled in the study. Procedures that are performed prior
to the signing of the ICF and are considered standard of care may be used as screening assessments if they
fall within the 28-day screening window.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
●
Vitals signs, weight and height
●
12-lead ECG (in triplicate [2-5 minutes apart])
●
Archival tumor sample
●
Review of prior/concomitant medications
●
Imaging by CT/MRI
●
Clinical laboratory tests for:
o
Clinical chemistry (see Table 4)
o
Hematology (see Table 5)
o
TSH
o
Coagulation (PT, PTT, INR)
o
Creatinine Clearance
o
Serum pregnancy test (for women of childbearing potential only)
o
Hepatitis serology
o
Disease-specific tumor markers (thyroglobulin for DTC, calcitonin and CEA for MTC)
o
Collect blood samples for biomarker analyses
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
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.
Cycle 1/Day 1
•
Obtain vital signs (resting BP, HR, RR, body temperature) and weight.
•
Evaluate ECOG performance status.
•
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:
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
•
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.
•
Biochemistry and hematology up to 72 hours prior the visit.
•
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 (up to 72 hours before),
including TSH, fT3 and fT4.
•
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.
•
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.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
•
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, including TSH, fT3 and fT4.
•
Administer study drugs.
•
Record all concomitant medication use.
•
Record any AEs or SAEs.
Cycle 3/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.
•
Record all concomitant medication use.
•
Record any AEs or SAEs.
Cycle 4 through Last Cycle/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 Table 5for the tests to be
performed), including TSH, fT3 and fT4.
•
Administer study drugs.
•
Perform tumor assessments at time points indicated in the Schedule of Visits and Procedures.
•
Record all concomitant medication use.
•
Record any AEs or SAEs.
•
Record survival data.
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.
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.
8.1.3. End of treatment
End of treatment is defined as the last visit where the decision is made to discontinue treatment. All
required procedures of the Final Visit schedule may be completed within ±7 days of the end of treatment
visit. Repeat disease assessment is not required if performed within 28 days prior to the end of treatment
visit.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Assessments for patients 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 patients who have discontinued durvalumab or tremelimumab treatment due to
confirmed PD are presented in Appendix 3.
All patients will be followed for survival until the end of the study regardless of further treatments, or
until the sponsor ends the study.
8.2.
Description of study procedures
8.2.1. Medical history and physical examination, electrocardiogram, weight and
vital signs
Findings from medical history (obtained at screening) and physical examination shall be given a baseline
grade according to the procedure for AEs. Increases in severity of pre-existing conditions during the study
will be considered AEs, with resolution occurring when the grade returns to the pre-study grade or below.
Physical examinations will be performed on study days noted in the Schedule of Assessments.
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
utilized 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.
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 (e.g., 30 minutes) to confirm the finding.
Situations in which ECG results should be reported as AEs are described in Section 10.3.1
8.2.4.
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated according to
the assessment schedules Body weight is also recorded at each visit along with vital signs.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
First infusion
On the first infusion day, patients in the durvalumab + tremelimumab combination therapy schema <<and
the durvalumab monotherapy group>> will be monitored and vital signs collected/recorded in eCRF prior
to, during and after infusion of IP as presented in the bulleted list below.
BP and pulse will be collected from patients in the I-O arms 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 [i.e., 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)
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. A 1-hour observation period is
recommended after the first infusion of durvalumab and tremelimumab.
Subsequent infusions
BP, pulse and other vital signs should be measured, collected/recorded in eCRF prior to the start of the
infusion. Patients should be carefully monitored and BP and other vital signs should be measured during
and post infusion as per institution standard and as clinically indicated. Any clinically significant changes
in vital signs should be entered onto an unscheduled vital signs CRF page.
8.2.5.
Clinical laboratory tests
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will be taken
at the times indicated in the assessment schedules and as clinically indicated (see Table 2 through Table
5).
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed clinical
laboratory according to local standard procedures. Sample tubes and sample sizes may vary depending on
the laboratory method used and routine practice at the site. Urine pregnancy tests may be performed at the
site using a licensed test (urine or serum pregnancy test). Abnormal clinically significant laboratory
results should be repeated as soon as possible (preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the Investigator. The
date, time of collection, and results (values, units, and reference ranges) will be recorded on the
appropriate eCRF.
The laboratory variables to be measured are presented in Table 4 (clinical chemistry), Table 5
(hematology), and Note: For coagulation parameters, activated partial thromboplastin time and
international normalized ratio are to be assessed at baseline on Day 0 (unless all screening laboratory
haematology assessments are performed within 3 days prior to Day 0), and as clinically indicated.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Other safety tests to be performed at screening include assessment for hepatitis B surface antigen,
hepatitis C antibodies and HIV antibodies.
The following laboratory variables will be measured:
Table 4. Clinical chemistry
Albumin
Uric acid
Total protein
Alkaline phosphatase
Urea or blood urea nitrogen,
depending on local practice
TSH
ALTa
Gamma glutamyltransferasec
T3 freec (reflex)
Amylaseb
Glucose
T4 freec (reflex)
ASTa
Lactate dehydrogenase
Bicarbonatec
Lipaseb
Calcium
Magnesiumc
Chloridec
Potassium
Creatinine clearancec
Sodium
Creatinine
Total bilirubin
a Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If total bilirubin is
g2 × upper limit of normal (and no evidence of Gilbert9s syndrome) then fractionate into direct and indirect bilirubin.
bIt is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these parameters is routinely
measured then either lipase or amylase is acceptable.
c Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium testing are to be
performed at baseline, on Day 0 (unless screening laboratory assessments are performed within 3 days prior to Day 0), and if
clinically indicated.
d Creatinine Clearance will be calculated by data management using Cockcroft-Gault (using actual body weight).
e If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at day Free T3 or free T4
will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related to the endocrine system.
ALT Alanine aminotransferase; AST Aspartate aminotransferase, TSH Thyroid Stimulating Hormone.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Table 5. Hematology
Basophils
Mean corpuscular volume
Eosinophils
Neutrophils
Absolute neutrophil count
Platelet count
Absolute lymphocyte count
Red blood cell count
Hematocrit
Total white cell counta
Hemoglobin
Mean corpuscular hemoglobin
Lymphocytes
Mean corpuscular hemoglobin concentration
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to be assessed at
baseline on Day 0 (unless all screening laboratory haematology assessments are performed within 3 days prior to Day 0), and as
clinically indicated.
a Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by DM if entered as percentage. Total
white cell count therefore has to be provided.
Table 6. Urinalysis
Urinalysis should be done at baseline (screening) and then as clinically indicated
Bilirubin
Ketones
Blood
pH
Colour and appearance
Protein
Glucose
Specific gravity
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red blood cells.
If a patient shows an AST or ALT g3x ULN together with total bilirubin g2x ULN, refer to Appendix 1
for further instructions on cases of increases in liver biochemistry and evaluation of Hy9s Law. These
cases should be reported as SAEs if, after evaluation, they meet the criteria for a Hy9s law case or if any
of the individual liver test parameters fulfil any of the SAE criteria.
All patients should have further chemistry profiles performed at 30 days (±3 days), 2 months (±1 week)
and 3 months (±1 week) after permanent discontinuation of IP (see Table 4).
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Any clinically significant abnormal laboratory values should be repeated as clinically indicated and
recorded on the eCRF. Situations in which laboratory safety results should be reported as AEs are
described in Section 10.3.5.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation from IP must
have further tests performed until the laboratory values have returned to Grade 1 or 2, unless these values
are not likely to improve because of the underlying disease.
8.3.
Biological sampling procedures
Blood samples and plasma for the development of exploratory predictive biomarkers will be collected
from all subjects prior to the first dose of study drug, 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 and tremelimumab clinical studies may also be assessed in
samples collected from subjects enrolled in this study.
Archived, fixed tumor tissue will be collected for all subjects for confirmation of histology (if needed)
and assessment of somatic mutations of genes which may be important in the development and
progression of thyroid cancers. 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 thyroid 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 promoter will decide whether to perform all or part of the pharmacogenetics/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. Instructions for the processing, storage, and shipping of samples
will be provided in the Laboratory Manual.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
8.3.1. Biomarker/pharmacodynamics sampling and evaluation methods
PD-L1 Testing
To ensure comparability of data across all studies of durvalumab and/or tremelimumab and to gain real
world experience on the performance of this assay, it is strongly encouraged that all studies that include
PD-L1 testing utilize the Ventana SP263 assay. Testing should be restricted to the Ventana SP263 assay
and should be performed in accordance with the package insert on the Ventana Benchmark platform
(Ultra or XT).
The Ventana SP263 assay is fully analytically validated test characterized through to the completion of
reader precision studies in the non-small cell lung cancer (NSCLC), and squamous cell carcinoma of the
head & neck (SCCHN). For these tumors, the Ventana SP263 assay has a fully reproducibility data
package supporting cut-off and scoring algorithm. In other cancer types (pancreatic, gastric,
hepatocellular, triple negative breast, ovarian, oesophageal, nasopharyngeal, glioblastoma, soft tissue
sarcoma, cholangiocarcinoma, small cell lung, melanoma and cervical HPV + cancers), the Ventana
SP263 assay has only limited clinical performance data.
Sample collection for PD-L1 testing
●
The preferred tumor sample for the determination of a patient9s 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.
●
In AstraZeneca studies, 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-month-old was not available, patients were asked to
undergo a new biopsy if considered clinically appropriate by their treating physician.
●
Samples should be collected via a core needle of 18 gauge or larger or be collected by an
incisional or excisional tumor biopsy. Where institutional practice uses a smaller gauge needle,
samples should be evaluated for tumor cell quantity (i.e., >100 tumor cells) to allow for adequate
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 3 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 (ecode or unique identifier)
●
Specimen identifier (written on the specimen)
●
Site identifier
●
Specimen collection date
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
●
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
●PD-L1 status (positive, negative or NA) in tumor cells
●Total percent positivity of PD-L1 in infiltrating immune cells
The Ventana SP263 assay to measure PD-L1 in tumors is experimental. As with all tests, there is a chance
of false positive (the test shows high PD-L1 when it is not there) or false negative (the test does not show
PD-L1 when it is there) results may occur.
Sample processing and if indicated submission process for PD-L1 testing
Preparing Stored samples for testing
●
Where samples already exist, they should be retrieved from the Biobank storage location. These
blocks should undergo quality review, prior to evaluation or shipment. Where it is not possible or
indicated to ship the block to a testing laboratory, unstained slides should be prepared from the
paraffin-embedded tumor sample block (described below) prior to evaluation or shipment.
Preparing newly acquired samples for PD-L1 testing
●
If patients are undergoing a biopsy procedure that provides the option to submit newly acquired
samples, this sample should be used to determine PD-L1 status. Where clinically acceptable, a
minimum of 2 core biopsies should be collected and processed to FFPE in a single block. The
provision of 2 cores is advised in order to provide sufficient tissue for PD-L1 assessment.
●
It is recommended that core needle tumor biopsies are collected using an 18 gauge or larger
needle and the process should be image-guided. Excisional or incisional samples are also
adequate. If this is not per the institutions normal practice and a smaller gauge needle is used then
the number of cores collected should be increased to allow sufficient material for successful
PD-L1 testing (>100 tumor cells) and embedded in the same block. If available, a single
excisional biopsy of at least 4 mm in diameter may substitute for all core biopsies.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Fixation of biopsy samples for PD-L1 testing
●
Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing. To fix newly
acquired tissue, place immediately (within 30 min of excision) into an adequate volume of 10%
v/v neutral buffered formalin (NBF). Samples should remain in fixative for 24 – 48 hours at room
temperature.
●
It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10 volume
excess) and that large specimens (if any) are incised prior to fixation to promote efficient tissue
preservation.
Embedding in paraffin for PD-L1 testing
●
An overnight processing schedule into paraffin wax is recommended.
Storage of tumor blocks for PD-L1 testing
●
FFPE blocks should be stored at ambient temperature and protected from light until shipment by
courier at ambient temperature. FFPE blocks are stable under these conditions for an indefinite
period.
Quality control of samples to be used for PD-L1 testing
●
Tissue should be assessed by the site pathologist prior to PD-L1 testing.
●
Each sample should be reviewed for:
●
Adequate fixation.
●
Good preservation of morphology.
●
Presence of tumor tissue.
●
Histopathology consistent with indication.
●
Greater than 100 tumor cells are required to determine PD-L1 status – tumor cell content
must be reviewed prior to testing in order for PD-L1 obtain a valid result.
If indicated, shipping samples to a PD-L1 testing laboratory
●
When submitting sample to for PD-L1 testing the recommendation is to ship the block in order
for sectioning to occur at the laboratory. Blocks should be shipped - containing enough material
to be provided to allow a minimum of 5, and preferably 10, sections to be cut (each 4 microns
thick) to be used for PD-L1 testing.
Sectioning instructions
●
Where it is not possible or indicated to ship the block to laboratory for PD-L1 testing, unstained
slides should be prepared from the paraffin-embedded tumor sample block as described below:
●
A minimum of 5-10 x 4 micron (μm) thick, unstained sections should be provided for
PD-L1 testing.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
●
A new disposable microtome blade must be used for each block to prevent contamination
between patient samples.
●
Slides are stable under these conditions for 6 months.
●
Apply one section per slide to positively-charged Superfrost glass slides.
●
The sections should be dried overnight between room temperature and 37°C. Do not dry
sections at temperatures above 37°C.
Sections should be stored at ambient temperature and protected from light until use or shipment to testing
lab by courier at ambient temperature. It is recommended that slides are cut freshly prior to 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 for biomarkers studies
The total of two blood and two plasma samples will be drawn from each subject in this study (at baseline,
C2D1, end of treatment/progression) for biomarkers analyses and will be managed according the
laboratory manual and stored -80ºC (-20ºC if not available) in the investigators centres. 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 use beyond PD-L1
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 patient withdraws consent to the use of donated samples, the samples will be disposed of/destroyed,
and the action documented.
The Principal Investigator:
●
Ensures that biological samples from that patient, 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 patient is informed about the sample disposal.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
9.
DISEASE EVALUATION AND METHODS
The response to immunotherapy may differ from the typical responses observed with cytotoxic
chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013):
●
Response to immunotherapy may be delayed.
●
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 Agency9s <Guideline on the evaluation of anticancer
medicinal products in man= (EMA/CHMP/205/95/Rev.4) for immune modulating anticancer compounds,
the study may wish to implement the following in addition to standard RECIST 1.1 criteria:
●
RECIST will be modified so that PD must be confirmed at the next scheduled visit, preferably,
and no earlier than 4 weeks after the initial assessment of PD in the absence of clinically
significant deterioration. Treatment with durvalumab + tremelimumab would continue between
the initial assessment of progression and confirmation for progression.
●
In addition, patients may continue to receive durvalumab + tremelimumab beyond confirmed PD
in the absence of clinically significant deterioration and if investigators consider that patients
continue to receive benefit from treatment.
Modification of RECIST as described may discourage the early discontinuation of durvalumab +
tremelimumab and provide a more complete evaluation of its antitumor 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 anticancer 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
RECIST v1.1 and irRECIST 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 v1.1 but always considering the irRECIST
1.1 assessment (secondary endpoint) conducted by the Investigator.
Confirmation of progression guidelines are set for the following reasons:
●
for patient management and treatment decisions
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
●
in the absence of significant clinical deterioration, to promote the collection of additional scans
after the first radiologic RECIST 1.1 assessment of progressive disease (PD) in order to
distinguish pseudoprogression from true radiologic progression, also known as RECIST 1.1
modified for confirmation of progression
Confirmed objective disease progression refers to either of the following scenarios: 1. clinical
progression/deterioration followed by a radiologic verification scan (PD by RECIST 1.1); or 2. in the
absence of significant clinical deterioration, radiologic PD by RECIST 1.1 followed by a second
radiologic confirmation scan with PD assessed according to the specific confirmation of progression
criteria listed below. RECIST 1.1 modified for confirmation of progression refers to the second scenario
above. The confirmatory scan should occur preferably at the next scheduled imaging visit and no earlier
than 4 weeks following the date of the immediate prior assessment of RECIST 1.1 PD.
Immediate prior radiologic progression would be considered confirmed if any the following criteria are
met in the confirmatory scan:
●
g20% increase in the sum diameters of target lesions (TLs) compared with the nadir at 2
consecutive visits, with an absolute increase of at least 5 mm in sum of diameters compared to
nadir,
●
and/or significant progression (worsening) of non-target lesions (NTLs) and/or of pre-existing
new lesions at the confirmatory scan time-point compared with the immediate prior time-point
(Note: Pre-existing new lesions are evaluated as NTLs at the confirmatory scan time-point),
●
and/or additional new unequivocal lesions at the confirmatory scan time-point.
NOTE: In order to have confirmed objective disease progression, there should be two consecutive
assessments meeting the PD definition:
the first PD by RECIST 1.1 and the second PD using the
confirmation of progression criteria (above). If the first assessment fulfilling the PD definition by
RECIST 1.1 is not confirmed, continue with assessments until the next PD by RECIST 1.1, which in turn
will need its own immediate subsequent confirmation scan.
In the absence of significant clinical deterioration, treatment with study drug may continue between the
initial assessment of progression and the scan to confirm progression.
If the confirmation scan confirms progression, then the date of the prior scan with PD should be declared
as the date of progression.
If progression is not confirmed, in the absence of significant clinical deterioration, then the patient should
continue study drug and on-treatment assessments until the next PD which will also require a follow-up
confirmation scan. If the first PD is not confirmed by the immediate next scan, then the Investigator
should not change the PD assessment of the first scan.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to radiologic
progression, then the patient should still continue to be followed until confirmed objective disease
progression.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
An adverse event is the development of an undesirable medical condition (other than progression of the
malignancy under evaluation) or the deterioration of a pre-existing medical condition following or during
exposure to a pharmaceutical product, whether or not considered causally related to the product. An
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia,
enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).
In clinical studies, an AE can include an undesirable medical condition occurring at any time, including
run-in or washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
10.1.2. Definition of serious adverse events
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, treatment,
wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the following criteria:
●
Results in death
●
Is immediately life-threatening
●
Requires in-patient hospitalization or prolongation of existing hospitalization
●
Results in persistent or significant disability or incapacity
●
Is a congenital abnormality or birth defect in offspring of the patient
●
Is an important medical event that may jeopardize the patient or may require medical intervention
to prevent one of the outcomes listed above
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by the
investigator(s) and communicated to AstraZeneca.
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 An AESI may be serious
or non-serious, however an expedited report is required using the SAE form, indicating an event of
special interest.
AESIs for durvalumab ±tremelimumab include but are not limited to events with a potential inflammatory
immune-mediated mechanism and which may require more frequent monitoring and/or interventions such
as steroids, immunosuppressant and/or hormone replacement therapy. <These AESIs may require close
monitoring in clinical studies with durvalumab monotherapy and durvalumab combination therapy.= An
immune-mediated adverse event (imAE) is defined as an AESI that is associated with drug exposure and
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
is consistent with an immune-mediated mechanism of action and where there is no clear alternate
etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support
an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, metabolic,
toxin, or other etiologic causes of the imAE.
If the Investigator has any questions in regards to an event being an imAE, the Investigator should
promptly contact the Study Physician.
AESIs observed with durvalumab ±tremelimumab include:
●
Diarrhea / Colitis and intestinal perforation
●
Pneumonitis / ILD
●
hepatitis / transaminase increases
●
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper-
and hypothyroidism, blood TSH increase, blood TSH decrease, and type I diabetes mellitus)
●
Rash / Dermatitis
●
Nephritis / Blood creatinine increases
●
Pancreatitis  / serum lipase and amylase increases immune-mediated
●
Myocarditis
●
Myositis / Polymyositis
●
Pemphigoid
●
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)
●
Other inflammatory responses that are rare / less frequent with a potential immune-mediated
aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events
involving the eye, skin, haematological and rheumatological events.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different
underlying pharmacological aetiology are also considered AESIs.
Events with an inflammatory or immune mediated mechanism could occur in nearly all organs. 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.
Further information on these risks (e.g. presenting symptoms) can be found in the current version of the
durvalumab and tremelimumab Investigator9s Brochures. More specific guidelines for their evaluation
and treatment are described in detail in the Dosing Modification and Toxicity Management Guidelines
(please see Appendix 1). These guidelines have been prepared by the Sponsor to assist the Investigator in
the exercise of his/her clinical judgment in treating these types of toxicities. These guidelines apply to
AEs considered causally related to the study drug/study regimen by the reporting investigator.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality suggestive of
pneumonitis/interstitial lung disease is observed, toxicity management as described in detail in the Dosing
Modification and Toxicity Management Guidelines (see Appendix 1) will be applied. The results of the
full diagnostic workup (including high-resolution computed tomography (HRCT), blood and sputum
culture, hematological parameters etc.) will be captured in the eCRF. It is strongly recommended to
perform a full diagnostic workup, to exclude alternative causes such as lymphangitic carcinomatosis,
infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT
scans where other causes of respiratory symptoms have been excluded, a diagnosis of pneumonitis (ILD)
should be considered and the Dosing Modification and Toxicity Management Guidelines should be
followed.
Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to enhance the
investigation and diagnosis of potential cases of pneumonitis. The results of the assessment will be
collected.
●
Physical examination
−
Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including auscultation
for lung field will be assessed.
●
SpO2
−
Saturation of peripheral oxygen (SpO2).
●
Other items
−
When pneumonitis (ILD) is suspected during study treatment, the following markers
should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and ³-D-glucan.
(ii)
Tumour markers: Particular tumour markers which are related to disease
progression.
Additional Clinical chemistry: CRP, LDH
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 v5.0. 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.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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 patient.
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
patient.
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 patient to perform activities of daily living (eating, ambulation, toileting,
etc.).
Grade 5 (fatal)
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure of
intensity whereas seriousness is defined by the criteria in Section 10.2.1. 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
AEs and SAEs will be collected from the time of the patient signing the informed consent form until the
follow-up period is completed (90 days after the last dose of durvalumab ± tremelimumab). If an event
that starts post the defined safety follow up period noted above is considered to be due to a late onset
toxicity to study drug then it should be reported as an AE or SAE as applicable.
During the course of the study, all AEs and SAEs should be proactively followed up for each patient for
as long as the event is ongoing. Every effort should be made to obtain a resolution for all events, even if
the events continue after the patient has discontinued study drug or the study has completed.
Any AEs that are unresolved at the patient9s last visit in the study are followed up by the Investigator
for as long as medically indicated, but without further recording in the eCRF. AstraZeneca retains the
right to request additional information for any patient with ongoing AE(s)/SAE(s) at the end of the
study, if judged necessary.
The following variables will be collected for each AE:
In addition, the following variables will be collected for SAEs as applicable:
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●
AE (verbatim)
●
The date when the AE started and stopped
●
The maximum CTCAE grade reported
●
Changes in CTCAE grade
●
Whether the AE is serious or not
●
Investigator causality rating against the IPs (yes or no)
●
Action taken with regard to IPs
●
Administration of treatment for the AE
●
Outcome
In addition, the following variables will be collected for SAEs:
●
Date the AE met criteria for SAE
●
Date the Investigator became aware of the SAE
●
Seriousness criteria fulfilled
●
Date of hospitalization
●
Date of discharge
●
Probable cause of death
●
Date of death
●
Whether an autopsy was performed
●
Causality assessment in relation to study procedure(s)
●
Causality assessment in relation to other medication, as explained in
Section 6.3.4.
●
Description of the SAE
The grading scales found in the revised NCI CTCAE version 5.0 will be utilized for all events with an
assigned CTCAE grading. For those events without assigned CTCAE grades, the recommendation in the
CTCAE criteria that converts mild, moderate, and severe events into CTCAE grades should be used. A
copy of the CTCAE version 5.0 can be downloaded from the Cancer Therapy Evaluation Program
website (http://ctep.cancer.gov).
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
If a patient 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 patient returns to baseline
status, or until the condition has stabilized with the expectation that it will remain chronic, even if this
extends beyond study participation.
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Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
10.3.2.
Causality collection
The Investigator will assess causal relationship between the IPs and each AE and answer <yes= or <no= to
the question <Do you consider that there is a reasonable possibility that the event may have been caused
by the investigational product?=
For SAEs causal relationship will also be assessed for other medication and study procedures. Note that
for SAEs that could be associated with any study procedure, the causal relationship is implied as <yes.=
A guide to the interpretation of the causality question is found in Appendix 1.
10.3.3.
Relationship to protocol procedures
The Investigator is also required to provide an assessment of the relationship of SAEs to protocol
procedures on the SAE report form. This includes both non-treatment–emergent (i.e., SAEs that occur
prior to the administration of IP) and treatment-emergent SAEs. A protocol-related SAE may occur as a
result of a procedure or intervention required during the study (e.g., blood collection). The following
guidelines should be used by Investigators to assess the relationship of SAEs to the protocol:
●
Protocol related: The event occurred due to a procedure or intervention that was described in
the protocol for which there is no alternative etiology present in the patient9s medical record.
●
Not protocol related: The event is related to an etiology other than the procedure or
intervention that was described in the protocol. The alternative etiology must be documented
in the study patient9s medical record.
10.3.4.
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question from the study
personnel: <Have you had any health problems since the previous visit/you were last asked?= or revealed
by observation will be collected and recorded in the eCRF. When collecting AEs, the recording of
diagnoses is preferred, when possible, to recording a list of signs and symptoms. However, if a diagnosis
is known and there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis
and each sign or symptom will be recorded separately.
10.3.5.
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs measurements will be summarized in
the CSR. Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs
should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the reason for
discontinuation of treatment with the IPs.
If deterioration in a laboratory value or vital sign is associated with clinical signs and symptoms, the sign
or symptom will be reported as an AE and the associated laboratory result or vital sign will be considered
as additional information. Whenever possible, the reporting Investigator should use the clinical rather than
the laboratory term (e.g., anemia versus low hemoglobin value). In the absence of clinical signs or
symptoms, clinically relevant deteriorations in non-mandated parameters should be reported as AEs.
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Edition Number V6.0
Date 05/12/2022
Deterioration of a laboratory value that is unequivocally due to disease progression should not be reported
as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as
compared with the baseline assessment will be reported as an AE.
10.3.6.
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation and
occurrences of AST or ALT g3 × ULN together with total bilirubin g2 × ULN may need to be reported as
SAEs. Please refer to Appendix 1. Toxicity Management Guidelines for further instruction on cases of
increases in liver biochemistry and evaluation of Hy9s law.
10.3.7.
Disease progression
Disease progression can be considered as a worsening of a patient9s condition attributable to the disease
for which the IP is being studied. It may be an increase in the severity of the disease under study and/or
increases in the symptoms of the disease. The development of new or progression of existing metastasis to
the primary cancer under study should be considered as disease progression and not an AE. Events that
are unequivocally due to disease progression should not be reported as an AE during the study.
10.3.8.
New cancers
The development of a new cancer should be regarded as an SAE. New primary cancers are those that are
not the primary reason for the administration of the IP and have been identified after the patient9s
inclusion in this study.
10.3.9.
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined follow-up period
after the administration of the last dose of study drug, must be reported as follows:
●
Death clearly resulting from disease progression should be reported to the Study
Monitor/Physician at the next monitoring visit and should be documented in the eCRF in the
Statement of Death page. It 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 the Study Monitor/Physician as an SAE within 24 hours.
It should also be documented in the Statement of Death page in the eCRF. The report should
contain a comment regarding the co involvement of PD, if appropriate, and should assign main
and contributory causes of death.
●
Deaths with an unknown cause should always be reported as an SAE. It should also be
documented in the Statement of Death page in the eCRF. A post mortem may be helpful in the
assessment of the cause of death, and if performed, a copy of the post-mortem results should
be forwarded to AstraZeneca Patient Safety or its representative within the usual timeframes.
Deaths occurring after the protocol defined safety follow up period after the administration of the last
dose of study drug should be documented in the Statement of Death page. If the death occurred as a result
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Edition Number V6.0
Date 05/12/2022
of an event that started after the defined safety follow up period and the event is considered to be due to a
late onset toxicity to study drug, then it should also be reported as an SAE.
The sponsor retains the right to request additional information for any patient with ongoing AE(s)/SAE(s)
at the end of the study, if judged necessary.
10.3.10.
Reporting of serious adverse events
SAE report and accompanying cover page will be sent by the investigator to the sponsor representative,
by way of email to
DEPARTAMENTO DE INVESTIGACIÓN, MFAR Clinical Research.
Fax: +34 93 253 11 68
Email: investigacion@mfar.net
All SAEs will be reported, whether or not considered causally related to the investigational product, or to
the study procedure(s). The Sponsor is responsible for reporting to the Regulatory Authorities of the SAE
as per local requirements. A copy of the report must be sent by email to AstraZeneca Patient Safety data
entry site at the time the event is reported to the Competent Authorities. It is the responsibility of the
investigator to compile all necessary information and ensure that the Competent Authorities receives a
report according to the regulatory agencies and competent authorities reporting requirement timelines and
to ensure that these reports are also submitted to AstraZeneca at the same time.
* A cover page should accompany report indicating the following:
• External Scientific Research
• The IND number assigned by the regulatory agencies and competent authorities
• The Sponsor9s name and address
• The trial name/title and AstraZeneca ESR reference number
* Investigative site must also indicate, either in the SAE report or the cover page, the causality of events
in relation to all study medications and if the SAE is related to disease progression, as determined by the
principal investigator.
* CRO representative will send SAE report and accompanying cover page by way of Email to:
AEMailboxClinicalTrialTCS@astrazeneca.com
10.3.10.1.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 appropriate CRO
representatives as a SAE within 24 hours (see Section 10.3.2 for further
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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 occurring after the protocol defined safety follow up period after the administration of the last
dose of study drug should be documented in the Statement of Death page. If the death occurred as a result
of an event that started after the defined safety follow up period and the event is considered to be due to a
late onset toxicity to study drug, then it should also be reported as an SAE.
10.3.11.
Other events requiring reporting
10.3.11.1. Overdose
Use of durvalumab or tremelimumab in doses in excess of that specified in the protocol is considered to
be an overdose. There is currently no specific treatment in the event of overdose of durvalumab or
tremelimumab, and possible symptoms of overdose are not established.
●
An overdose with associated AEs will be recorded as the AE diagnosis or symptoms in the
relevant AE modules of the eCRF and in the Overdose eCRF module.
●
An overdose without associated symptoms will only be reported in the Overdose eCRF module.
If an overdose occurs in the course of the study, then the Investigator or other site personnel will inform
appropriate CRO representatives immediately, or 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 AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4. For other
overdoses, reporting must occur within 30 days.
10.3.11.2. Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor except for:
●
Pregnancy discovered before the study patient has received any study drugs.
●
Pregnancy of a female partner of male patient, providing there is no restriction of male patient
fathering a child.
10.3.12.
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
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Edition Number V6.0
Date 05/12/2022
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, i.e., 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 AstraZeneca Patient Safety data entry site within 1 to 5 calendar days for
SAEs and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
10.3.13.
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.
Pregnancy of the patient9s 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 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 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 patient9s partner. Therefore, the local study team should adopt
the generic ICF template in line with local procedures and submit it to the relevant Ethics Committees
(ECs)/Institutional Review Boards (IRBs) prior to use.
10.4. Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in the
treatment process for an AstraZeneca study drug that either causes harm to the patient or has the potential
to cause harm to the patient.
A medication error is not lack of efficacy of the drug, but rather a human or process related failure while
the drug is in control of the study site staff or patient.
Medication error includes situations where an error.
●
occurred
●
was identified and intercepted before the patient received the drug
●
did not occur, but circumstances were recognize that could have led to an error
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Edition Number V6.0
Date 05/12/2022
Examples of events to be reported in clinical studies as medication errors:
●
Drug name confusion
●
Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to the
patient
●
Drug not administered as indicated, for example, wrong route or wrong site of administration
●
Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a solid
tablet
●
Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature
●
Wrong patient received the medication (excluding IVRS/IWRS errors)
●
Wrong drug administered to patient (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
●
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the
above listed events that would otherwise have been a medication error
●
Patient accidentally missed drug dose(s) e.g. forgot to take medication
●
Accidental overdose (will be captured as an overdose)
●
Patient failed to return unused medication or empty packaging
●
Errors related to background and rescue medication, or standard of care medication in open
label studies, even if an AZ product
Medication errors are not regarded as AEs but AEs may occur as a consequence of the medication error.
If a medication error occurs in the course of the study, then the Investigator or other site personnel
informs the appropriate sponsor representatives within 1 day i.e., immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated sponsor representative works with the Investigator to ensure that all relevant information
is completed within 1 or 5 calendar days if there is an SAE associated with the medication error (see
Section 10.3.10) and within 30 days for all other medication errors.
The designated sponsor representative and CRO for the trial is:
MFAR Clinical Research
Sinfonía, 28 2ª Planta, nº 1 - 28054 – Madrid
C/ Balmes 243, Escalera A 5º1ª - 08006 Barcelona
Tel: +34 93 434 44 12
Fax: +34 93 253 11 68
Email: investigacion@mfar.net
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Edition Number V6.0
Date 05/12/2022
11.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION
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.
11.1. Description of 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 Protocol
Analysis Set.
Analysis of primary efficacy variable
The analysis of progression-free survival 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 6 months after start of first infusion of study treatment or have progressed. The primary objective of the
study will be based on the investigator assessment.
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Edition Number V6.0
Date 05/12/2022
11.2.
Methods of statistical analyses
Strategic decisions about future development of immune therapy in thyroid 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 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 exploratory variables and primary endpoint. Survival analysis will be performed
to analyse 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. In the per protocol analysis set, patients with loss 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.
11.2.1. 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.
Toxicity profile (short and long-term) will be described per patient to show all the AE information about
grade, relationship to study treatment and severity. Toxicity will be evaluated according NCI CTCAE vs
5.0 criteria.
11.2.2.
Efficacy analyses
●
Primary endpoint for cohorts 1 and 2 (DTC and MTC):
6-months progression-free survival by Response Evaluation Criteria In Solid Tumors (RECIST), which is
defined as the percentage of patients achieving complete response, partial response (PR), or stable disease
(SD) at month 6 after durvalumab plus tremelimumab was started without observing disease progression
or death at this timepoint.
●
Primary endpoint for cohort 3 (ATC):
6-months overall survival rate, which is defined as the percentage of patients alive at 6 months after
durvalumab plus tremelimumab was started.
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Edition Number V6.0
Date 05/12/2022
11.2.3.
Secondary objective(s)
1.
Overall response rate (ORR) by irRECIST and RECIST.
ORR includes patients with partial (PR) and complete response (CR) as best response by RECIST v 1.1
and irRECIST.
2.
To assess the duration of response according to irRECIST/RECIST.
Patients with PR and/or CR will be followed to determine the duration of the response. Patients with
stable disease (SD) will also be followed to assess the duration of the SD to be able to define the clinical
benefit rate (PR, CR and SD) as best responses of treatment.
3.
To assess the median progression-free survival time (PFS) according to RECIST.
Together with the primary endpoints of PFS rate and overall survival rate at 6 months, patients will be
followed by imaging with the same periods (every 12 weeks) to assess the median PFS.
4.
To assess the safety profile of Durvalumab and Tremelimumab in subjects with advanced
thyroid neoplasms.
Toxicity will be evaluated according NCI CTCAE v 5.0 criteria.
5.
To assess the median overall survival (OS) time.
Patients will be followed after completion of the study treatment period to assess the median OS.
6.
To assess response status according to irRECIST/RECIST at 6 and 12 months after start of
study treatment.
11.2.4.
Exploratory objective(s)
1.
To evaluate biochemical response (changes in thyroglobulin, calcitonin and CEA levels) and
its association with response rate and progression-free survival.
2.
To assess whether baseline tumor and blood biomarkers may be predictive of response to
durvalumab and tremelimumab therapy.
3.
To explore additional hypotheses related to biomarkers and relationship to durvalumab and
tremelimumab efficacy and/or toxicity and thyroid cancer evolution that may arise from
internal or external research activities.
11.2.5.
Interim analyses
The trial is designed following a Simon-II strategy. The first stage will include 17 patients in cohorts 1
and 2. If 5 out of 17 patients in each cohort (DTC and MTC) are free of disease progression or
unacceptable toxicity at 6 months in the first stage, study will continue recruiting 19 additional patients up
to 36 patients per cohort. g13 pts out of a total of 36 patients have to be alive and progression-free at the
final analysis to declare a positive study. If stage I is reached only in one cohort, recruitment will continue
in the successful cohort and stop in the non-effective cohort.
No interim analysis is planned for cohort 3. All 12 patients will be included in one stage.
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Edition Number V6.0
Date 05/12/2022
11.3.
Determination of sample size
Simon-II design was applied for sample size estimation for DTC and MTC cohorts.
For cohorts 1 and 2 (DTC and MTC, respectively), we hypothesize that the experimental therapy will
improve the probability of being progression free at 6 months, from 25% in historical cohorts up to 45%
in the current study.
With 80% of power (³ = 0.2) and unilateral alpha (0.05), 36 patients per arm are needed to demonstrate
the primary hypothesis. The Simon-II design suggested to observe 5 patients free of disease progression
or unacceptable toxicity at 6 months within the first 17 patients included in the first stage. If 5 out of 17
patients in each cohort (DTC and MTC) are free of disease progression or unacceptable toxicity at 6
months in the first stage, study will continue recruiting 19 additional patients up to 36 patients per cohort.
If stage I is reached only in one cohort, recruitment will continue in the successful cohort and stop in the
non-effective cohort. If g13 pts out of a total of 36 patients are alive and progression-free at the final
analysis the study will be considered positive.
For sample size estimation for cohort 3, we hypothesize that the experimental therapy will improve the
probability of being alive at 6 months from 5% in historical cohorts up to 35% in the current study. With
80% of power (³ = 0.2) and unilateral alpha (0.05), 12 patients are needed to demonstrate the primary
hypothesis. Cohort 3 will include the 12 patients in one stage. To consider the study positive, 4 patients
should be alive at 6 months after the first drug infusion.
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Edition Number V6.0
Date 05/12/2022
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
Patient 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 and the regulatory authorities with a brief report of the outcome of the study.
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 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 subject9s legally acceptable
representative, and after the subject or the subject9s legally acceptable representative has orally consented
to the subject9s 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. An unsigned copy of an
EC and sponsor-approved written informed consent must be prepared in accordance with ICH E 6,
Section 4, and all applicable local regulations and provided to the sponsor. Each subject must sign an
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
approved informed consent prior to study participation.
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 centre.
The subject or the subject9s legally authorized representative should be informed in a timely manner if
new information becomes available that may be relevant to the subject9s 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 sponsor9s 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 sponsor9s Clinical Quality Assurance department
conducts audits of clinical research activities in accordance with the sponsor9s 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.
The investigators and institutions will allow the monitoring, auditing and inspection activities related to
this clinical trial including direct access to source data and documents.
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 investigator9s staff, and the EC and will not be 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
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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 with patient code
(clinical trial number) to maintain subject confidentiality throughout the trial. 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 the EEA General Data Protection Regulation (GDPR) 2016/679 and the
Spanish implementation
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 co-workers 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
-
Policy Number: ESLC234638
12.8.
Publications
The sponsor led by the principal investigator commits to responsible publication of both the positive and
negative results from its clinical trials as required by all governing regulatory and health authorities.
Investigators will not publish the global study results (all sites) unless the sponsor has not done so in a
suitable time period after the clinical study report (CSR) has been available. Should the Investigator(s)
independently seek to publish results of this study which occur at their study site(s), they must inform the
study sponsor of any/all drafts (including, but not limited to papers, manuscripts or abstracts) at least 60
days before submission to the congress, meeting or journal. The sponsor and Investigator(s) will agree
with all aspects related to any proposed publications with regards to the following: 1) any proposed
publications will be drafted in agreement with international recommendations, such as those from the
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Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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.
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Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
13.
STUDY MANAGEMENT
13.1.
Training of study site personnel
The principal investigator will maintain a record of all centre 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 centre prior to the study start.
13.2.
Monitoring of the study
The sponsor9s or representative (e.g., CRO9s 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 subject9s corresponding original medical records (source
documents) are to be fully available for review by the sponsor9s 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 are subject to inspection by the local regulatory agency.
13.2.1. 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), polysomnographs, and pulmonary function tests (regardless of
how these images are stored, including microfiche and photographic negatives);
•
Records of telephone contacts;
•
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 subject9s treatment between physicians or memoranda sent to the EC;
13.3.
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.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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.
13.4.
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 sponsor9s or CRO9s qualified compliance auditing team, which is an
independent function from the study conduct team.
13.5.
Study timetable and end of study
End of study is defined as Last Subject Last Visit.
●
Expected Recruitment period will be:
o
Stage I
18 months
o
Stage II
12 months
●
Research Agreement executed:
2Q 2018
●
Projected IRB/IEC approval:
4Q 2018 (Actual: 01/Feb/2019)
●
First Subject In:
4Q 2018 (Actual: 10/Apr/2019)
●
50% Enrollment:
3Q 2020
●
Last Subject In (100% enrollment):
3Q 2021
●
Last Subject Last Visit:
3Q 2022
●
Publication:
4Q 2022
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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 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, 8the 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 subject9. 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, initialled, 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.
14.1.
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by AstraZeneca
representatives in consultation with Patient Safety. Issues identified will be addressed; for instance, this
could involve amendments to the study protocol and letters to Investigators.
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
50 mg/mL solution for infusion
after dilution
MedImmune
Tremelimumab
20 mg/mL solution for infusion
after dilution
MedImmune
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
16.
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Drake CG, McDermott DF, Sznol M, Choueiri TK, Kluger HM, Powderly JD et al. Survival, safety, and
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Herbst et al. 2013
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Paterson et al. 2011
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
APPENDICES
Appendix 1.
Dosing Modification and Toxicity Management Guidelines (TMGs) for Durvalumab
Monotherapy, Durvalumab in Combination with other Products, or Tremelimumab Monotherapy.
28 October2022.
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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Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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., National
Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (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 imAEs is essential to ensure safe use of the study drug.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying
imAEs. 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 and/or tremelimumab should be withheld and
corticosteroids administered. Upon improvement to Grade f 1, corticosteroid should be tapered over
g 28 days. More potent immunosuppressive agents 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 the need for 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.
Considerations for Prophylaxis for Long Term use of Steroids for Patients Receiving Immune
Checkpoint Inhibitor Immunotherapy
Infection Prophylaxis: Pneumocystis jirovecii pneumonia (PJP), antifungal and Herpes Zoster
reactivation
Gastritis: Consider prophylaxis for patients at high risk of gastritis (e.g. NSAID use, anticoagulation)
when the patient is taking steroid therapy
Osteoporosis: Consider measures for prevention and mitigation of osteoporosis .
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Edition Number V6.0
Date 05/12/2022
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
Pediatric Considerations Regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
The criteria for permanent discontinuation of
study drug/study regimen based on  CTCAE
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 f 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 intravenous
immunoglobulin (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 g 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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Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the
Event
Dose Modifications
Toxicity Management
Pneumonitis/Intersti
tial Lung Disease
(ILD)
Any Grade
(Refer to NCI CTCAE
applicable version
in study protocol for
defining  the  CTCAE
grade/severity)
General Guidance
For Any Grade
−       Patients should be thoroughly
evaluated to rule out any alternative
etiology with similar clinical
presentation (e.g. infection,
progressive disease)).
−       Monitor patients for signs  (e.g.
tachypnoea)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 etiologies 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 (including clinically relevant
culture specimens to rule out
infection), and high- resolution
computed tomography (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.
Page 108 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2
Hold study
drug/study regimen
dose until Grade 2
resolution to Grade
f1.
●
- If toxicity improves
to Grade f1, then the
decision to reinitiate
study drug/study
regimen will be based
upon treating
physician’s clinical
judgment and after
completion of steroid
taper (<10 mg
prednisone or
equivalent).
For Grade 2
−         Monitor symptoms daily and
consider hospitalization , as clinically
indicated.
−        Consider Pulmonary and
Infectious Diseases Consults;
−         Promptly start systemic steroids
(e.g., prednisone 1 to 2 mg/kg/day PO
or IV equivalent).
−   Consider HRCT or chest CT with
contrast, Repeat imaging study  as
clinically indicated
−   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 as
tumor necrosis factor (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 or relevant practice
guidelines). Caution: It is important to
rule out sepsis and refer to infliximab
label for general guidance before using
infliximab.
- Consider discussing with Clinical Study
Lead.
Page 109 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 3 or 4
Permanently
discontinue study
drug/study regimen.
For Grade 3 or 4
−         Hospitalize the patient.
−         Promptly initiate empiric IV
methylprednisolone 1 to 4 mg/kg/day
or equivalent.
−    Obtain Pulmonary and Infectious
Diseases Consults; consider discussing
with Clinical Study Lead,, as needed.
−         Consider starting anti-infective
therapy if infection is still a
consideration on the basis of other
diagnostic testing despite negative
culture results
−         Supportive care (e.g., oxygen).
−         If no improvement within 2
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 or relevant practice
guidelines). Caution: rule out sepsis
and refer to infliximab label for
general guidance before using
infliximab.
Page 110 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Diarrhea/Colitis
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTCAE
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).
− Consider further evaluation with
imaging study with contrast.
− Consult a gastrointestinal (GI)
specialist for consideration of further
workup.
−         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.
Page 111 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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.
Page 112 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2
Hold study drug/study
regimen until
resolution to Grade f1
· If toxicity improves
to Grade f1, then
study drug/study
regimen can be
resumed after
completion of steroid
taper (<10 mg
prednisone, or
equivalent).
For Grade 2
−  Consider symptomatic treatment,
including hydration, electrolyte
replacement, dietary changes (e.g.,
American Dietetic Association colitis
diet), and loperamide and/or
budesonide.
− Consider further evaluation with
imaging study with contrast.
− Consider consult of a gastrointestinal
(GI) specialist for
consideration of further workup.
−  Promptly start prednisone 1 to 2
mg/kg/day PO or IV equivalent.
−   If  no improvement within 3 days
despite  therapy with 1 to 2 mg/kg IV ,
prednisone equivalent, reconsult GI
specialist and, if indicated ,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 or relevant practice guidelines.
a Caution: it is important 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.
−  Consider, as necessary, discussing
with Clinical Study Lead if no resolution
to Grade f1 in 3 to 4 days.
Page 113 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 3 or 4
Grade 3
- For patients treated
with durvalumab
monotherapy,  hold
study drug/study
regimen until
resolution to Grade f1;
study drug/study
regimen can be
resumed after
completion of steroid
taper (<10 mg
prednisone per day, or
equivalent).
-For patients treated
with durvalumab
in combination with
other products
(not tremelimumab),
decision to be
made at the discretion
of the study
investigator, in
discussion with
AstraZeneca Clinical
Study Lead.
-For patients treated
with durvalumab in
combination with
tremelimumab or
tremelimumab
monotherapy,
Permanently
discontinue  both
durvalumab and
tremelimumab for 1)
Grade 3 diarrhea colitis
or 2) Any grade of
intestinal perforation
Grade 4
Permanently
discontinue
study drug/study
regimen.
For Grade 3 or 4
−  Urgent GI consult and imaging
and/or colonoscopy as appropriate.
−         Promptly initiate empiric IV
methylprednisolone 1 to 2 mg/kg/day or
equivalent.
−         Monitor stool frequency and
volume and maintain hydration.
−         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 or relevant practice
guidelines).  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.
Page 114 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Hepatitis
Infliximab should
not be used for
management of
immune-relatd
hepatitis.
PLEASE SEE
shaded area
immediately
below this section
to find guidance
for management
of <Hepatitis
(elevated LFTS)=
in hepatocellular
carcinoma (HCC)
patients (or
secondary tumour
involvement of the
liver with
abnormal
baseline values
[BLV])
Any Grade
(Refer to NCI
CTCAE applicable
version in study
protocol for
defining the
CTCAE
grade/severity)
General Guidance
For Any Grade
−  Patients should be thoroughly
evaluated to rule out
any alternative etiology (e.g., viral
hepatitis, disease
progression, concomitant
medications).
−    Monitor and evaluate:
transaminases (  aspartate
aminotransferase (AST) ) , alanine
aminotransferase (ALT), alkaline
phosphatase (ALP)) , and total
bilirubin .
ALT or AST f 3
x ULN or total
bilirubin
f 1.5 x ULN
−No dose
modifications.
−
If it worsens, then
consider holding
therapy.
−  Continue  transaminase and total
bilirubin monitoring per protocol.
ALT or AST > 3
f 5 x ULN or
total bilir bin
> 1.5 f 3 x ULN
   - Hold study drug/study
regimen dose until ALT
or  AST f3 x ULN or total
bilirubin <1.5 x ULN.
Resume study
drug/study regimen
after completion of
steroid taper (<10 mg
prednisone or
equivalent).
- Permanently
discontinue study
drug/study regimen for
any case meeting Hy’s
law laboratory criteria
(AST or ALT >3 × ULN
AND  bilirubin >2 × ULN
without initial findings
of cholestasis (i.e.,
elevatedALP) and in the
absence of any
alternative cause.b
−         Regular and frequent checking of
transaminases and total bilirubin(e.g.,
every 1 to 2 days) until  transaminases
and total bilirubin elevations improve
or resolve.
−         If no resolution to  ALT or AST f 3
x ULN or total bilirubin f 1.5 x ULN  in
1 to 2 days, consider discussing with
Clinical Study Lead, as needed.
−         If event is persistent (>2 to 3
days) or worsens, promptly start
prednisone 1 to 2 mg/kg/day PO or IV
eq uivalent.
Page 115 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
ALT or AST
> 5-f 10 x ULN
Hold study drug/study
regimen:
·      Resume study
drug/study regimen if
elevations downgrade
to  ALT or AST f 3 x
ULN or total bilirubin
f 1.5 x ULN and after
completion of steroid
taper (<10 mg
prednisone, or
equivalent).
If in combination with
tremelimumab, do not
restart tremelimumab.
−         Promptly initiate empiric IV
methylprednisolone at 1 to 2
mg/kg/day or equivalent.
−     Perform Hepatology Consult,
abdominal workup, and imaging as
appropriate.
−         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
or relevant practice guidelines).
Discuss with Clinical Study Lead if
mycophenolate is not available.
Infliximab should NOT be used.
Page 116 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Concurrent ALT
or AST > 3 x ULN
and total
bilirubin
> 2 x ULN
ALT or AST
> 10 x ULN OR
total
bilirubin
> 3 x ULN
Permanently
discontinue study
drug/study regimen.
− 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
additional
immunosuppressant.(e.g.,
mycophenolate mofetil
0.5 – 1 g every 12 hours then taper in
consultation
with hepatology consult or relevant
practice
guidelines). Discuss with Clinical
Study Lead if
mycophenolate is not available.
Infliximab should
NOT be used.
− Perform Hepatology Consult,
abdominal workup,
and imaging as appropriate.
Page 117 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Hepatitis
(elevated
transaminases and
total bilirubin)
Infliximab should not
be used for
management o
immune-related
hepatitis.
THIS shaded area is
guidance only for
management of
<Hepatitis
(elevated LFTs)= in
HCC patients (or
secondary tumour
involvement of the
liver with abnormal
baseline values [BLV])
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 T. Bili
as Described
Below
General Guidance
For Any Elevations Described
− Patients should be thoroughly
evaluated to rule out any
alternative etiology (e.g., viral
hepatitis, disease progression,
concomitant medications,
worsening of liver cirrhosis [e.g.,
portal vein thrombosis]).
− Monitor and evaluate AST, ALT, ALP,
and T. Bili.
− For hepatitis B (HBV) + patients:
evaluate quantitative HBV viral
load, quantitative Hepatitis B
surface antigen (HBsAg), or
Hepatitis B envelope antigen
(HBsAg).
− For hepatitis C (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 g2-fold.
− For HCV+ with Hepatitis B core
antibody (HBcAb)+: Evaluate for
both HBV and HCV as above.
Page 118 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Isolated AST or
ALT
>ULN and
f2.5×BLV
- 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 or signs of
DILI/liver
decompensation
Page 119 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
ALT or AST > 2.5-
f 5X BLV and f
20xULN
·      Hold study
drug/study regimen
dose until resolution
to  AST or ALT f2.5.0
x BLV /
-
If toxicity worsens,
then treat as
described for
elevations  in the
rows below. If
toxicity improves to
AST or ALT f2.5 x
BLV, resume study
drug/study regimen
after completion of
steroid taper (<10
mg prednisone, or
equivalent).
−         Regular and frequent checking of
Transaminases and total bilirrubin
(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 Clinical Study Lead
−         If event is persistent (>2 days to
3 days) or worsens,  and  investigator
suspects toxicity to be an imAE,  start
prednisone at 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 or equivalent,
consider additional  work up. If still no
improvement within 2 to 3 days
despite 2 mg/kg/day of IV
methylprefnisolone, consider
additional abdominal workip
(including liver biopsy) and imagin
(i.e; liver ultrasound) and consider
starting additional
immunosuppresants (e.g.,.,
mycophenolate mofetil 0.5 – 1 g every
12 hours then taper in consultation
with t hepatology consult  or relevant
practice guidelines). Discuss  Clinical
Study Lead if mycophenolate mofetil is
not available.
Infliximab should NOT be used.
ALT or AST
>5-7X BLV
20XULN OR
concurrent
2.5-5X BLV
and f 20XULN
AND total
bilirubin > 1.5
- < 2 x
ULNd
-Withhold
durvalumab and
permanently
discontinue
tremelimumab
-Resume study
drug/study regimen
if elevations
downgrade to AST
or ALT f2.5×BLV
and after
completion of
steroid taper (<10
mg prednisone, or
equivalent).
− 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 Clinical
Study Lead, as needed.
− If investigator suspects toxicity to be
immune-mediated, promptly
Page 120 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
- Permanently
discontinue study
drug/study regimen
if if the elevations
do not downgrade
to AST or ALT
f2.5×BLV within 14
days
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
additional immunosuppressant. (e.g.,.,
mycophenolate mofetil 0.5 –
1 g every 12 hours then taper in
consultation with a hepatologist or
relevant practice guidelines). Discuss
with Study Clinical Lead if
mycophenolate is not available.
Infliximab should NOT be used.
ALT or AST
> 7 X BLV OR >
20
ULN
whichever
occurs
first OR
bilirubin >
3ULN
Permanently
discontinue
study drug/study
regimen.
Same as above
(except recommend obtaining liver
biopsy early)
Page 121 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Nephritis and/or
renal dysfunction
Any Grade
(Refer to NCI
CTCAE applicable
version in study
protocol for
defining the
CTCAE
grade/severity)
General Guidance
For Any Grade
−         Patients should be thoroughly
evaluated to rule out any alternative
aetiology (e.g., disease progression,
infections, recent IV contrast,
medications, fluid status).
−          Consider consulting  a
nephrologist.
−       Consider imaging studies to rule
out any alternative etiology
−         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).
Follow urine protein/creatinine ratio
every 3-7 days
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, including hydration,
electrolyte replacement, and
diuretics, as clinically indicated
−    Consider nephrologist consult if
not resolved within 14 days, or earlier
as clinically indicated.
Page 122 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2
Hold study drug/study
regimen until
resolution to Grade f1
or baseline.
·        If toxicity
improves to Grade f1
or baseline, then
resume study
drug/study regimen
after completion of
steroid taper (<10 mg
prednisone, or
equivalent).
For Grade 2
−         Consider, including hydration,
electrolyte replacement, and
diuretics, as clinically indicated.
−        Follow urine protein/creatinine
ratio every 3-7 days
−         Carefully monitor serum
creatinine as clinically warranted.
−         Consult nephrologist and
consider renal biopsy if clinically
indicated.
−   Start prednisone 0.5 – 1 mg/kg/day
if other causes are ruled out.
−         If event is persistent beyond 5
days or worsens,  increase to
prednisone  up to 2 mg/kg/day PO or
IV equivalent.
−         If event is not responsive within
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.
Grade 3 or 4
Permanently
discontinue study
drug/study
regimen.
For Grade 3 or 4
−         Carefully monitor serum
creatinine daily.
− Follow urine protein/creatinine
ratio every 3-7 days
−         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 of steroids or worsens
despite prednisone at 1 to 2
mg/kg/day PO or IV equivalent,
consider additional workup and
prompt treatment with an
immunosuppressant.
Page 123 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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   GRADE
3 PEMPHIGOID OR SEVERE
CUTANEOUS ADVERSE REACTION
(SCAR)1 IS SUSPECTED.
−         PERMANENTLY DISCONTINUE
STUDY DRUG IF SCAR OR GRADE 3
PEMPHIGOID IS CONFIRMED.
Grade 1
No dose
modifications.
For Grade 1
−         Consider symptomatic treatment,
including oral antipruritics (e.g.,
diphenhydramine or hydroxyzine) and
topical therapy (e.g., emolient, lotion, or
institutional standard).
Grade 2
For persistent (>1 week)
Grade 2 events, hold
scheduled study
drug/study regimen
until resolution to Grade
f1 or baseline.
·         If toxicity improves
to Grade f1 or baseline,
then resume drug/study
regimen after
completion of steroid
taper (<10 mg
prednisone, or
equivalent).
For Grade 2
−          Consider dermatology consult
and skin biopsy, as indicated.
−         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  1 week or is
worsening despite symptomatic
treatment and/or use of moderate
strength topical steroid, consider
discussing with Clinical Study Lead,
study physician, as needed, and
promptly start systemic steroids such
as prednisone 1 to 2 mg/kg/day PO or
IV equivalent.
Page 124 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 3
For Grade 3
·         Hold study
drug/study regimen
until resolution to
Grade f1 or baseline.
·         If toxicity
improves to Grade f1
or baseline, then
resume drug/study
regimen after
completion of steroid
taper (<10 mg
prednisone, or
equivalent).
For Grade
−         Reconsult a dermatologist.
Consider skin biopsy (preferably
more than 1) as clinically feasible.
−         Promptly initiate empiric IV
methylprednisolone 1 to 2
mg/kg/day or equivalent.
−         Consider hospitalization.
−         Monitor the extent of rash
[Rule of Nines].
−         Consider, as necessary,
discussing with Clinical Study Lead
Grade 4
For Grade 4
Permanently
discontinue study
drug/study regimen
For Grade 4
− Reconsult a dermatologist.
Consider skin biopsy (preferably
more than 1) as clinically feasible.
− Promptly initiate empiric IV
methylprednisolone 1 to 2
mg/kg/day or equivalent.
− Consider hospitalization.
− Monitor the extent of rash [Rule of
Nines].
− Consider, as necessary, discussing
with Clinical Study Lead.
Page 125 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Endocrinopathy
(e.g.,
hyperthyroidism,
thyroiditis,
hypothyroidism,
type 1 diabetes
mellitus,
hypophysitis,
hypopituitarism,
and adrenal
insufficiency)
Any Grade
(Depending on the
type of
endocrinopathy,
refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTCAE
grade/severity)
General Guidance
For Any Grade
−         Patients should be thoroughly
evaluated to rule out any alternative
etiology (e.g., disease progression
including brain metastases, or
infections).
−         Consider consulting an
endocrinologist for endocrine events.
−         Consider discussing with
Clinical Study Lead, 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.
−         Depending on the suspected
endocrinopathy, monitor and evaluate
thyroid function tests: thyroid
stimulating hormone (TSH), free T3
and free T4 and other relevant
endocrine and related labs (e.g., blood
glucose and ketone levels, hemoglobin
A1c( 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.
Page 126 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
adrenocorticotropin hormone
(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.
Page 127 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2, 3, or 4
·         For Grade 2-4
endocrinopathies
other than
hypothyroidism
and type 1
diabetes mellitus
(TIDM), 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 (<10
mg prednisone, or
equivalent).
·         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.
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
−         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 magnetic resonance
imaging ( MRI) scans), repeat
laboratory assessments/MRI as
clinically indicated.
Page 128 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Amylase/Lipase
increased
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTCAE
grade/severity)
General Guidance
For Any Grade
−         Patients should be thoroughly
evaluated to rule out
any alternative etiology (e.g. disease
progression, viral infection,
concomitant medications, substance
abuse).
−         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
gastroenterology
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
CTCAE
grade/severity)
General Guidance
For Any Grade
−         Patients should be thoroughly
evaluated to rule out any alternative
etiology.
−         Consider Gastroenterology
referral
Grade 2
Consider holding
study drug/regimen
Grade 2
−      Consider IV hydration
−      Consider Gastroenterology
referral
Page 129 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 3, or 4
For Grade 3
Hold study
drug/study regimen
until resolution of
elebated enzymes
and no radiologic
findings. If no
elevation in
enzymes or return
to baseline values,
then resume study
drug/study regimen
after completion of
steroid taper (<10
mg
prednisone, or
equivalent).
For Grade 4
Permanently
discontinue study
drug/study
regimen.
For Grade, 3, or 4
−         Promptly start systemic
steroids prednisone 1 to 2
mg/kg/day PO or IV equivalent.
−         IV hydration
Nervous System Disorders
Aseptic Meningitis
Any Grade
( Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTCAE
grade/severity)
General Guidance
− Symptoms may
include headache,
photophobia, and
neck stiffness,
nausea/ vomiting
which may resemble
an infectious
meningitis.
− Patients may be
febrile.
− Mental status
should be normal
For Any Grade
−  Consider  neurology consult
−  Consider MRI brain with and
without contrast with pituitary
protocol and a lumbar puncture for
diagnosis.
− Exclude bacterial and viral
infections. (ie HSV)
− Consider IV acyclovir until
polymerase chain reactions are
available
Any Grade
Permanently
discontinue study
drug/study regimen
For Any  Grade
−  Consider neurology consult
− Consider MRI brain with and
without contrast with pituitary
protocol and a lumbar puncture for
diagnosis.
− Exclude bacterial and viral
infections. (ie HSV)
Page 130 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Encephalitis
− Consider IV acyclovir until
polymerase chain reactions are
available
− Consider, as necessary, discussing
with Clinical Study Lead.( Last
bullet)
− Consider hospitalization.
− Once infection has been ruled out
promptly initiate empiric IV
methylprednisolone 1 to 2
mg/kg/day or equivalent.
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTCAE
grade/severity)
General Guidance
Symptoms may
include Confusion,
altered behaviour,
headaches,
seizures, short-term
memory loss,
depressed level of
consciousness,
focal weakness, and
speech
abnormality.
For Any Grade
− Consider neurology consult
− Consider testing including MRI of
the brain with and without contrast,
lumbar puncture,
electroencephalogram (EEG) to
evaluate for subclinical seizures, ESR,
CRP, antineutrophil cytoplasmic
antibody (ANCA) (if vasculitic process
suspected),
thyroid panel including TPO and
thyroglobulin and additional
autoantibodies to rule out
paraneoplastic disorders.
− Exclude bacterial and viral
infections. (ie HSV)
Consider IV acyclovir until
polymerase chain reactions are
available.
Grade 2
For Grade 2
Permanently
discontinue study
drug/study regimen
For Grade 2
−         Consider, as necessary,
discussing with the Clinical Study
Lead.
−          Once infection has been ruled
out methylprednisolone  1  2
mg/kg/day.
−         For progressive symptoms or if
oligoclonal bands are present
consider methylprednisolone 1 g IV
daily for 3-5 days plus IVIG or
plasmapheresis.
Page 131 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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 Clinical Study Lead.
−   Consider hospitalization.
−   Once infection is ruled out, start
methylprednisolone g IV daily for 3-5
days for progressive symptoms.
−Consider adding IVIG or
plasmapheresis.
Transverse Myelitis
Any Grade
General Guidance
− Permanently
discontinue
immunotherapy
− Consider MRI of the
spine and brain
Once imaging is
complete, consider
lumbar puncture
− Consider testing to
rule out additional
aetiologies: B12, HIV,
rapid plasma reagin
(RPR), ANA, anti-
Ro/La antibodies,
aquaporin-4 IgG,
myelin
oligodendrocyte
glycoprotein (MOG)
IgG, paraneoplastic
panel for anti-Hu and
anti-CRMP5/CV2
For Any Grade
− Consider neurology consult
− Inpatient care
− Consider prompt initiation of high
methylprednisolone pulse dosing
− Strongly consider IVIG or
plasmapheresis
Page 132 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Peripheral
neuropathy
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTCAE
grade/severity)
Grade 1
General Guidance
No dose
modifications.
For Any Grade
−         Patients should be evaluated to
rule out any alternative etiology for
neuropathy (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, are
routinely indicated upon suspicion of
such conditions and may be best
facilitated by means of a neurology
consultation.
For Grade 1
−
Consider discussing with the
Clinical Study Lead, as needed.
−
Monitor symptoms for
interference with ADLS, gait
difficulties, imbalance, or autonomic
dysfunction.
Page 133 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2
Grade 3 or 4
Hold study
drug/study regimen
dose until
resolution to Grade
f1.
For Grade 3 or 4
·
Permanently
discontinue study
drug/study regimen.
For Grade 2
−    Consider discussing with the
Clinical Study Lead, as needed.
−  Consider EMG/NCS
−  Consult a neurologist.
−   Observation  for  additional
symptoms o or consider initiating
prednisone 0.5-1 mg/kg orally.
− If progression, initiate
methylprednisolone 2–4 mg/kg/day
and treat as GBS.
−  Sensory neuropathy/neuropathic
pain may be managed by appropriate
medications (e.g., gabapentin or
duloxetine).
For Grade 3 or 4
−
Consider discussing with Clinical
Study Lead, as needed.
−   Recommend hospitalization.
−
Monitor symptoms and consult a
neurologist.
−Treat per Guillain-Barré Syndrome
recommendations
Page 134 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Guillain-Barré
Syndrome (GBS)
General Guidance
−  Recommend hospitalization
−  Obtain neurology consult
−Obtain MRI of spine to rule out
compression lesion
− Obtain lumbar puncture
− Antibody tests for GBS variants
− Pulmonary function tests
−
Obtain
electromyography
(EMG)
and nerve conduction studies
−
Frequently
monitor
pulmonary
function tests and neurologic
evaluations
−Monitor for concurrent autonomic
dysfunction
−Initiate medication as needed for
neuropathic pain
Grade 2-4
Grade 2-4
Permanently
discontinue
−  Start IVIG or plasmapheresis in
addition to methylprednisolone 1
gram daily for 5 days, then taper over
4 weeks.
Myasthenia gravis
General Guidance
− Obtain neurology consult
− Recommend hospitalization
− Obtain pulmonary function tests
− Obtain labs: ESR, CRP, creatine
phosphokinase (CPK), aldolase
and anti-striational antibodies
− Consider cardiac exam, ECG,
troponin, transthoracic
echocardiogram for possible
concomitant myocarditis
− Obtain electromyography (EMG)
and nerve conduction studies
− Consider MRI of brain/spine to rule
out CNS involvement by disease
− Avoid medications that might
exacerbate MG (e.g. beta blockers,
some antibiotics, IV magnesium)
Page 135 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2
Permanently
discontinue
− Consider pyridostigmine 30mg
three times daily and gradually
increase based on symptoms (max
dose 120mg four times daily)
− Consider starting low dose
prednisone 20mg daily and increase
every 3-5 days. (Target dose
1mg/kg/day. Max dose 100mg daily)
Grade 3-4
Permanently
discontinue
− Start methylprednisolone
1-2mg/kg/day. Taper steroids based
on symptom improvement
− Start plasmapheresis or IVIG
− Consider rituximab if refractory to
plasmapheresis or IVIG
− Frequent PFT assessments
− Daily neurologic evaluations
Page 136 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Myocarditis
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTCAE
grade/severity)
General Guidance
Discontinue drug
permanently if
biopsy-proven
immune-mediated
myocarditis.
For Any Grade
−
Initial work-up should include
clinical evaluation, B-type natriuretic
peptide (BNP), cardiac enzymes,
electrocardiogram (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)
−The prompt diagnosis of
immune-mediated myocarditis is
important, particularly in patients
with baseline cardiopulmonary
disease and reduced cardiac function.
−
Consider discussing with the
Clinical Study Lead, 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 as
indicated. Spiral CT or cardiac MRI
can complement ECHO to assess wall
motion abnormalities when needed.
Page 137 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2, 3 or 4
-
If Grade 2-4,
permanently
discontinue
study
drug/study
regimen.
For Grade 2-4
−
Monitor symptoms daily,
hospitalize.
− Consider cardiology consultation
and a prompt start of high-
dose/pulse corticosteroid therapy
−
Supportive care (e.g., oxygen).
−
If no improvement  consider
additional immunosuppressive
therapy such as TNF inhibitors (e.g.,
infliximab , IVIG or plasmapheresis
or other therapies depending on the
clinical condition of the patient,
based on  the discretion of the
treating  specialist consultant or
relevant practice guidelines).
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.
Page 138 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Myositis/
Polymyositis
Any Grade
(Refer to NCI
CTCAE
applicable
version in study
protocol for
defining the
CTC
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly
evaluated to rule out any alternative
etiology (e.g., disease progression,
other medications, or infections).
−
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, and 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 Clinical Study
Lead
−
Initial work-up should include
clinical evaluation, creatine kinase,
aldolase,lactate
dehydrogenase ( LDH), blood urea
nitrogen (BUN)/creatinine,
erythrocyte sedimentation rate or
C-reactive protein (CRP) 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
Page 139 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
guide need for rheumatoid factor,
antinuclear antibody, anti-smooth
muscle, antisynthetase [such as
anti-Jo-1], and/or signal-recognition
particle antibodies). Confirmatory
testing may include
electromyography, nerve conduction
studies, MRI of the muscles, and/or a
muscle biopsy. Consider Barium
swallow for evaluation of dysphagia
or dysphonia.
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 Clinical Study
Lead.
Page 140 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2
·
Hold study
drug/study
regimen dose
until resolution
to Grade f1.
·         Permanently
discontinue
study
drug/study
regimen if it
does not resolve
to Grade f1
within 30 days
or if there are
signs of
respiratory
insufficiency.
For Grade 2
−
Monitor symptoms daily and
consider hospitalization.
−
Consider Rheumatology or
Neurology consult, and initiate
evaluation.
−
Consider, as necessary,
discussing with the Clinical Study
Lead.
−
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 3 days, consider  additional
immunosuppressive therapy such as
TNF inhibitors (e.g., infliximab IVIG
or plasmapheresis, or other therapies
based on the discretion of the
treating  specialist consultant or
relevant practice) guideline.
Caution: It is important to rule out
sepsis and refer to infliximab label
for general guidance before using
infliximab.
Page 141 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 3
For Grade 3
·         Hold study
drug/study regimen
dose until resolution
to Grade f1.
·         Permanently
discontinue study
drug/study regimen if
Grade 3 imAE does
not resolve to Grade
f1 within 30 days or if
there are signs of
respiratory
insufficiency.
For Grade 3
−
Monitor symptoms closely;
recommend hospitalization.
−
Consider Rheumatology and / or
Neurology consult
−
Consider discussing with the
Clinical Study Lead, 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 or relevant practice
guidelines). 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.
Page 142 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 4
For Grade 4
Permanently
discontinue
study drug/study
regimen.
Grade 4
− Monitor symptoms closely;
recommend hospitalization.
− Consider Rheumatology and/or
Neurology consult
− Consider discussing with the
Clinical Study Lead, 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 or relevant practice
guidelines). Caution: It is important
to rule out sepsis and refer to
infliximab label for general guidance
before using infliximab.
1 SCAR terms include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme, Acute
Generalized Exanthematous Pustulosis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and
Drug-induced hypersensitivity syndrome.
Page 143 / 158

Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Other–Immune-Mediated Reactions
Severity Grade of the
Event (Refer to NCI
CTCAE applicable
version in study
protocol for defining
the CTCAE
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 Clinical Study
Leadmay 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
fGrade 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 f1 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
For Grade 2, 3, or 4
Treat accordingly, as per
institutional standard,
appropriate clinical practice
guidelines, and society
guidelines (see pag 4))
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
with systemic steroids and
following full taper
Grade 3
Hold study drug/study regimen
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 Clinical Study Lead.=
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 CTCAE
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).
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
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
f2 infusion reactions.
Grade 3 or 4
For Grade 3 or 4
Permanently discontinue study
drug/study regimen.
For Grade 3 or 4
−       Manage severe infusion-related
reactions per institutional
standard, appropriate clinical
practice guidelines, and society
guidelines.
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 CTCAE
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.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Grade 2-  3
Hold study drug/study regimen
until resolution to fGrade 1 or
baseline.
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 Clinical Study
Lead.=
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
List of Abbreviations
AChE
Acetylcholinesterase
ILD
Interstitial lung disease
ACTH
Adrenocorticotropic hormone
imAE(s)
Immune-mediated adverse event(s)
ALT
Alanine aminotransferase
INR
International normalized ratio
ASCO
American Society of Clinical Oncology
IU
International units
AST
Aspartate aminotransferase
IV
Intravenous
(T) Bili
(Total) Bilirubin
IVIG
Intravenous immunoglobulin
BNP
B-type natriuretic peptide
LDH
Lactate dehydrogenase
BUN
Blood urea nitrogen
LFTs
Liver function tests
CRP
C-reactive protein
LLN
Lower limit of normal
CSP
Clinical Study Protocol
MRCP
Magnetic resonance cholangiopancreatography
CT
Computed tomography
MRI
Magnetic resonance imaging
CTCAE
Common Terminology Criteria for Adverse
NCCN
National Comprehensive Cancer Network
CTLA-4
Cytotoxic T-lymphocyte antigen-4
NCI
National Cancer Institute
DILI
Drug-induced liver injury
PD-L1
Programmed cell death ligand-1
ECG
Electrocardiogram
PJP
Pneumocystis jirovecii pneumonia
ECHO
Echocardiogram
PO
By mouth
ESMO
European Society of Medical Oncology
SCAR
Severe cutaneous adverse reaction
GI
Gastrointestinal
SITC
Society for Immunotherapy of Cancer
HBcAb
Hepatitis B core antibody
SJS
Stephen Johnson Syndrome
HBeAg
Hepatitis B envelope antigen
T1DM
Type 1 diabetes mellitus
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
HBsAg
Hepatitis B surface antigen
T3
Triiodothyronine
HBV
Hepatitis B virus
T4
Thyroxine
HCC
Hepatocellular cancer
TEN
Toxic Epidermal Necrolysis
HCV
Hepatitis C virus
TMG(s)
Toxicity management guideline(s)
HgA1c
Hemoglobin A1C
TSH
Thyroid stimulating hormone
ICI(s)
Immune checkpoint inhibitor(s)
ULN
Upper limit of normal
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Appendix 2.
Schedule of study procedures: follow-up for patients who
have completed durvalumab and tremelimumab treatment and achieved
disease control (until confirmed progression of disease) and patients who
have discontinued durvalumab or tremelimumab due to toxicity in the
absence of confirmed progression of disease
Evaluation
Time Since Last Dose of MEDI4736
Day (±3)
Months (±1 week)
12 Months and Every
6 Months
(±2 weeks)
30
2
3
4
6
8
10
Physical examinationa
X
Vital
signs
(temperature,
respiratory rate, blood pressure,
pulse)
X
Weight
X
AE/SAE assessment
X
X
X
Concomitant medications
X
X
X
Palliative radiotherapy
As clinically indicated
ECOG performance status
X
X
X
X
X
(and
month
9)
X
X
X
Subsequent anticancer therapy
X
X
X
X
X
X
X
X
Survival
status:
phone
contact
with patients who refuse to return
for evaluations and agree to be
contacted
X
X
X
X
X
X
X (every 2 months)
Hematology
X
X
X
X
Serum chemistry
X
X
X
Thyroid function tests (TSH, and
fT3 and fT4)b
X
Patient
questionnaire
(patient
reported outcomes)c and health
resource use, if applicable
X
X
For patients who achieve disease control following 12
months/48 weeks of treatment, patient questionnaires
and information relating to health resource use should
be completed every 12 weeks relative to the date of
randomisation until confirmed PD by RECIST 1.1 by
investigational site review.
For patients who discontinue study drug due to toxicity
or
a
reason
other
than
confirmed
PD,
patient
questionnaires
and
information
relating
to health
resource use should be completed relative to the date of
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
randomisation as follows: every 8 weeks for the first 48
weeks, then every 12 weeks until confirmed PD by
RECIST 1.1 by investigational site review.
Tumour assessment (CT or MRI)
For
patients
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 see in section 9 for timings of confirmatory
scans.
For patients who discontinue MEDI4736 due to toxicity (or symptomatic
deterioration), tumour assessments should be performed relative to the
relative to the date of first infusion as follows: every 8 weeks for the first 48
weeks (), then every 12 weeks until confirmed PD by RECIST 1.1 by
investigational site review. Please refer for timings of confirmatory scans.
Upon confirmed PD, scans should be conducted according to local standard
clinical practice.
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
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Appendix 3. Schedule of study procedures: follow-up for patients who
have discontinue durvalumab and tremelimumab treatment due to
confirmed progression of disease at the investigator discretion
Evaluation
Time Since Last Dose of MEDI4736
Day
(±3)
Months (±1 week)
12 Months and Every
6 Months
(±2 weeks)
30
2
3
4
6
8
10
Physical examinationa
X
Vital
signs
(temperature,
respiratory
rate, blood pressure,
pulse)
X
Weight
X
AE/SAE assessment
X
X
X
Concomitant medications
X
X
X
Palliative radiotherapy
As clinically indicated
------------------------------------------------------------------->
ECOG performance statusb
X
X
X
X
X
X
X
X
Subsequent anticancer therapy
X
X
X
X
X
X
X
X
Survival status: phone contact with
patients who refuse to return for
evaluations
and
agree
to
be
contacted
X
X
X
X
X
X
X (every 2 months)
Hematology
X
X
X
Serum chemistry
X
X
X
Thyroid function tests (TSH, and
fT3 and fT4)c
X
Circulating
soluble
factors
(to
assess
cytokines,
chemokines,
growth
factors
and
antibodies
against tumor and self-antigens in
circulation), if applicable
X
miRNA/mRNA (to examine immune
cell
gene
expression
profiles in
circulation), if applicable
X
PBMCs, if applicable
X
Patient
questionnaire
(patient
reported
outcomes)d and
health
resource use, if applicable
X
X
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Tumour assessment (CT or MRI)
For patients 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 until MEDI4736 is stopped.
For
patients
who
discontinue
MEDI4736
following
confirmed
progression, scans should be conducted according to local clinical
practice.
a
Full physical exam
b
PS to be collected if available at the 2 monthly calls to obtain subsequent anticancer 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
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Appendix 4. 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 × 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 ×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
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Appendix 5. 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 vial
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Appendix 6.
Contact details
Sponsor:
GETNE – Grupo Español de Tumores Neuroendocrinos y Endocrinos
C/ Balmes 243, Escalera A 5º1ª - 08006 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
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Appendix 7.
Sites and Investigators Participants
1
Hospital Universitari Vall d9Hebron- Dr. Jaume Capdevila Castillón
2
MD Anderson Cancer Center - Dr. Enrique Grande Pulido
3
Hospital Universitario 12 de Octubre - Dra. Lara Iglesias
4
Hospital Universitario Virgen de la Victoria - Dra. Sofía Ruiz Medina
5
Hospital Clínic Barcelona - Dra. Neus Basté
6
Hospital General J.M. Morales Meseguer - Dr. Alberto Carmona Bayonas
7
Clínica Universidad de Navarra - Dr. José María López-Picazo González
8
Hospital Universitario La Paz - Dra. Beatriz Castelo Fernández
9
Hospital Universitario Ramón y Cajal - Dra. Teresa Alonso
10
Institut Català d´Oncologia L'Hospitalet - Dra. María Plana Serrahima
11
Instituto Valenciano de Oncología (IVO) - Dr. Ricardo Yaya Tur
12
Hospital Provincial de Castellón - Dr. Lorente Estellés
13
Hospital Universitario HM Sanchinarro - Dr. Lisardo Ugidos de la Varga
14
Hospital Universitario Clínico San Carlos - Dr. Antonio Casado Herraez
15
Complejo Hospitalario Universitario de Vigo - Dra. Isabel Lorenzo
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Clinical Study Protocol
Investigational Drug Substance: Durvalumab (MEDI4736) and tremelimumab
Study Number GETNE - T1812
Edition Number V6.0
Date 05/12/2022
Appendix 8. Drug shipment form
Document included in the Investigator Site File
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